Physiol Rev 91: 973–1007, 2011
doi:10.1152/physrev.00025.2010
PHYSIOLOGICAL RELEVANCE OF CELL CYCLE
KINASES
Marcos Malumbres
Cell Division and Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain
Malumbres M. Physiological Relevance of Cell Cycle Kinases. Physiol Rev 91: 973–
1007, 2011; doi:10.1152/physrev.00025.2010.—The basic biology of the cell division cycle and its control by protein kinases was originally studied through genetic and
biochemical studies in yeast and other model organisms. The major regulatory mechanisms identified in this pioneer work are conserved in mammals. However, recent
studies in different cell types or genetic models are now providing a new perspective on the function
of these major cell cycle regulators in different tissues. Here, we review the physiological relevance
of mammalian cell cycle kinases such as cyclin-dependent kinases (Cdks), Aurora and Polo-like
kinases, and mitotic checkpoint regulators (Bub1, BubR1, and Mps1) as well as other less-studied
enzymes such as Cdc7, Nek proteins, or Mastl and their implications in development, tissue
homeostasis, and human disease. Among these functions, the control of self-renewal or asymmetric cell division in stem/progenitor cells and the ability to regenerate injured tissues is a central
issue in current research. In addition, many of these proteins play previously unexpected roles in
metabolism, cardiovascular function, or neuron biology. The modulation of their enzymatic activity
may therefore have multiple therapeutic benefits in human disease.
L
INTRODUCTION
CONTROL OF THE CELL DIVISION...
CELL CYCLE KINASES IN DEVELOPMENT...
AN INTEGRATIVE VIEW OF CELL CYCLE...
CELL CYCLE KINASES AND CANCER
SUMMARY AND FUTURE PERSPECTIVES
973
974
980
987
991
997
I. INTRODUCTION
Multicellular organisms require an adequate control of cell
division and differentiation to coordinate multiple different
cell types in functional tissues. The cell division cycle entails
the tightly regulated transduction of mitogenic signals to a
series of biochemical machineries that control the duplication of DNA and its proper segregation to daughter cells.
The molecular basis of this regulation was first studied in
landmark genetic screens in yeast (119, 247, 248). One of
these cell division cycle (Cdc) genes, Cdc28 in Saccharomyces cerevisiae and Cdc2 in Schizosaccharomyces pombe,
was identified as a protein kinase that regulated itself by
phosphorylation (305). This kinase was subsequently
found to be the active component of the mitosis-promoting
factor, a proteinaceous factor that could drive the division
of cells (103).
A number of different studies in yeast and other organisms
have led to a model where cell cycle kinases act as major
engines to promote progression throughout the different
phases of the cell division cycle. These phases include two
major periods of activity in which the genome is first
duplicated (DNA synthesis or S phase) and the two newly
replicated genomes are then distributed between the
daughter cells (mitosis) (FIGURE 1). Additional gap periods, G1 (preceding S phase) and G2 (preceding mitosis),
are required to coordinate DNA synthesis and segregation
with mitogenic signals and to synthesize and assemble the
required proteins and cellular structures. In addition, to
ensure proper progression through the cell cycle phases,
these molecular engines are under the control of internal
checkpoints that monitor proper conditions to generate
healthy daughter cells (120). Thus the cell division cycle can
be defined as the process by which cells monitor proper
conditions for cell division, activate the required biochemical machineries for DNA replication and chromosome segregation, and monitor these steps to generate two genomically stable daughter cells.
Regulation of the cell cycle is well conserved from yeast to
humans, and most original Cdc genes have a mammalian
counterpart. However, as it may be expected from the diversity of mammalian cell types, many of these individual
yeast genes are represented as complex gene families in
mammals. Among these regulators, cell cycle kinases are
known to have a critical role not only as major regulators of
cell cycle progression but also in tissue homeostasis and
human disease (208). Because of their catalytic activity,
these proteins are also considered as druggable targets, and
new small-molecule inhibitors, mostly ATP competitors,
are now in the pipeline of many pharmaceutical companies.
In this review, I focus not only on the relevance of mammalian cell cycle kinases during cell cycle progression but also
973
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
I.
II.
III.
IV.
V.
VI.
MARCOS MALUMBRES
on the physiological regulation of different mammalian tissues. The complexity of this analysis can be predicted from
the presence of multiple family members of many of these
kinases in the mammalian genome (summarized in sect. II)
and their differential expression and activity in the multiple
cell compartments. Since cell proliferation is a major cellular process during development, the relevance of cell cycle
kinases in the formation of tissues and in the regenerative
potential from progenitor cells will be treated in section III.
Their implication in different adult tissues and physiological functions will be further discussed in section IV. Finally,
it is well established that cell cycle kinases are deregulated in
proliferative diseases such as cancer. These alterations and
the therapeutic implications of modulating cell cycle kinase
activity in patients will be finally discussed in section V.
II. CONTROL OF THE CELL DIVISION
CYCLE BY PROTEIN KINASES
A typical eukaryotic cell has to complete sequentially several important processes during the cell cycle. However,
most adult cells are quiescent and do not express many cell
cycle genes. Thus the first requirement for cell cycle entry
relies on the activation of the transcriptional and translational machinery required for the specific expression of cell
cycle genes (212). This machinery is thought to be active
during early cell divisions in the embryo, but a repression
mechanism becomes crucial for those cells that terminally
974
differentiate during organogenesis. The repression program
is likely to be cell type-specific, but it is generally represented by the retinoblastoma protein (pRb). pRb and the
other pocket family members p107 and p130 are transcriptional regulators that repress a large list of genes including
critical cell cycle regulators. This repression is commonly
mediated through the recruitment of repressor complexes,
such as the SWI/SNF complex, histone deacetylases, polycomb group proteins as well as methylases, and the binding
and inactivation of transcription factors such as the E2F
family (52, 206). Thus, in quiescent cells, the expression of
genes required for cell cycle progression is frequently repressed in a pRb-dependent manner (212).
Numerous mitogenic signals are responsible for the inactivation of the pRb repression machinery through the activation of cyclin-dependent kinases (Cdks) (212, 223). These
proteins are usually present in quiescent cells as inactive
kinases due to the lack of their activators, the cyclins. Cyclins are indeed transcriptionally induced in response to
mitogenic signals, leading to the activation of Cdks and
phosphorylation of the pRb protein. This phosphorylation
results in a massive transcription during G1 of genes required for the subsequent cell cycle phases (FIGURE 1). Some
of these genes expressed during late G1 are necessary for
activation of the DNA replication complexes during S
phase. Other kinases participate in DNA replication itself
(Cdc7) or in the duplication of centrosomes, a cellular struc-
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
FIGURE 1 An overview of mammalian cell cycle kinases discussed in the text and their involvement in the
different phases of the cell cycle. Kinases whose function is not clearly established are tagged with a question
mark. Drawings represent a typical cell growing in size after entering into the cell cycle. During the S phase,
the genome (blue) is duplicated and chromosomes condensate during mitosis to be equally segregated
between the two daughter cells. Microtubules are represented as red lines and centrioles as small cylinders.
CELL CYCLE KINASES
A. Cyclin-Dependent Kinases
Not surprisingly, the number of Cdks has significantly increased during evolution. Up to six conserved Cdks exist in
the budding yeast S. cerevisiae, although only one of them,
Cdc28 (Cdk1), is necessary and sufficient to drive the cell
cycle (28, 128). The nonessential Cdk Pho85 is also involved in the earlier phases of the cell cycle, whereas the
other Cdks are thought to function mainly in transcription
(136). Twenty different Cdks (Cdk1–20) exist in mammals
(213). Only four Cdks, Cdk1, 2, 4, and 6 (and perhaps
Cdk3 and Cdk5), are clearly associated with cell cycle control. Whereas a few additional Cdks, Cdk7–11, are involved in the control of transcription, some others do not
have a clear function assigned yet (211, 213).
1. Mitotic Cdks
As indicated above, Cdk1 is the founding member of
the Cdk family. In yeast, Cdk1 can bind and be activated by
all interphase and mitotic cyclins (28). In mammals, Cdk1
has been typically associated with A-type (G2) and B-type
(late G2 and mitosis) cyclins. However, recent studies
have clearly demonstrated that Cdk1 can also bind interphase (D-type and E-type) cyclins in wild-type cells, and
these interactions are enforced in cells deficient in the
interphase Cdks (such as Cdk4 or Cdk2) that are commonly
associated with these interphase cyclins (6, 215, 288). Cdk1
phosphorylates a wide spectrum of proteins including more
than 70 targets validated in yeast (84) and mammals (211)
(TABLE 1). This number is likely to be underestimated since
massive chemical/proteomic studies have identified over
300 potential targets (129, 334). Through these posttranslational modifications, Cdk1 controls critical processes required for mitosis such as nuclear envelop breakdown, disassembly of the Golgi apparatus, chromosome cohesion
and condensation, formation of the spindle, and attachment of chromosomes to the spindle. In addition to these
mitotic processes, Cdk1 may also be crucial for regulating
transcription as well as DNA replication and repair. These
functions have been deeply studied in yeast given the abundant genetic tools in this organism (84). The in vivo requirements for Cdk1 in mammals have been much more difficult
to analyze given the essentiality of this protein within a cell
cycle and the lack of genetic models. Genetic ablation of
Cdk1 in the mouse arrests embryos at the one-cell/two-cell
stage (209, 288), and further analysis has been so far prevented by this early lethality.
Although no other Cdk seems to be able to complement the lack of Cdk1 in mammals, an additional family
member, Cdk11, also plays critical roles during mitosis.
Cdk11-null embryos die at the blastocyst stage due to the
arrest of blastomeres in mitosis (190). Cdk11 may indeed
act as a microtubule stabilizing factor that regulates centrosome maturation and spindle assembly (260, 363) and sister
chromatid cohesion (133). Impaired translation of Cdk11
also leads to other multiple mitotic defects (350). Cdk11 is
also known to play a role in transcription and RNA splicing
(132, 201, 202).
2. Interphase Cdks
Whereas the yeast Cdk1 is able to regulate G1 and S
phase through binding to interphase yeast cyclins, a variety
of Cdks seem to have undertaken this role in mammals.
Cdk4 and Cdk6 are relatively similar to yeast Cdc28 and
Pho85 (209). These mammalian Cdks are activated by Dtype cyclins (D1, D2, and D3), which are the major cell
cycle sensors for mitogenic signals in the cell cycle. D-type
cyclins are transcriptionally induced by virtually all mitogenic signals including major signaling routes such as the
Ras/mitogen-activated protein kinase (MAPK) pathway.
Upon induction of D-type cyclins, Cdk4 and Cdk6 become
active and phosphorylate pocket proteins such as pRb, resulting in the inactivation of the repression machinery
(212). Cdk4/6-cyclin D complexes are therefore major sen-
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
975
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
ture that will be later required during mitosis. During G2,
these centrosomes move towards different poles of the cells.
In addition to some Cdk family members, other kinases are
specifically dedicated to drive centrosome duplication and
maturation and to increase their ability to nucleate microtubules during these stages, including Aurora and Polo-like
kinases or the never in mitosis a (NIMA)-related kinases
(Neks). The critical molecular activity required for entry
into mitosis is Cdk1 (the ortholog to yeast Cdc28/Cdc2)
kinase. During the G2/M transition, a large number of proteins are phosphorylated in a Cdk1-dependent manner
resulting in cytoplasmic changes, Golgi disassembly, nuclear envelop breakdown, and condensation of chromosomes (211). Some other kinase activities, mainly from
Aurora or Polo families, participate in mitotic entry by
helping in the establishment of the proper chromosome
structures and the mitotic spindle. In addition, a new
kinase involved in the inactivation of phosphatases,
known as Mastl, is thought to participate by favoring the
balance between Cdk1-dependent phosphorylation and
dephosphorylation by general phosphatases such as protein phosphatase (PP) 2A. A particular group of kinases,
represented by Bub1, BubR1 kinases and Mps1 (also
known as TTK), are critical components of the spindle assembly checkpoint (SAC or mitotic checkpoint), a signaling
pathway that monitors bipolar attachment of chromosomes to the mitotic spindle. This checkpoint ensures
proper segregation of chromosomes to daughter cells. Finally, Aurora and Polo-like kinases are involved in cytokinesis, the process by which the cytoplasm divides to generate two independent daughter cells (FIGURE 1). Other kinases not directly involved in the regulation of cell cycle
progression such as the enzymes involved in the DNA damage response (ATR/ATM or Chk1/Chk2) have been deeply
reviewed (13, 51, 151, 272, 304) and will be no further
discussed here.
MARCOS MALUMBRES
Table 1
Symbol
Alias
Human cell cycle kinases covered in this review
Function
Regulatory Partners
Substrates (Vertebrates)
Cyclin-dependent kinases
Cdk1
Cdc2a
Mitosis (DNA replication Cylins A, B (D and E)
and DNA damage,
DNA repair)
G1/S transition, DNA
damage, DNA repair
Cyclins E and A (also D),
PCAF
Cdk3
Not clear
Cdk4
PSK-J3
G1/S progression
Cyclins E, A, and C,
Cables
D-type cyclins
Cdk5
TPKII
Neuron biology,
senescence
p35, p39, cyclins D, E,
and I
Cdk6
Cdk7
PLSTIRE
CAK, MO15,
STK1
CDC2L2,
CDC2L3
G1/S progression
Cdk-activating kinase,
transcription
Transcription, splicing,
centriole biology and
cytokinesis
D-type cyclins
Cyclin H
Cdk11
Cyclin D3, L1, L2
Cdt1, Marcks, p107, p130, pRb,
Smad3
AATYK1, Amphiphysin 1, Ape1, ␤2Syntrophin, Cdh1, Disabled1,
Doublecortin, eNOS, Munc18a,
Nude, p53, PSD-95, Sds3, Stat3,
Synapsin 1, tyrosine hydroxylase,
Vsp34
p107, p130, pRb
Cdk1, 2, 4, 5, 6, RNA pol II COOHterminal domain
eIF3, Pak1, RanBPM
Aurora kinases
AurkA
976
Ark1, Btak,
Stk15, Stk6,
Stk7
Centrosome and spindle Ajuba, Arpc1b, PAK1,
function
Tpx2
Arpc1b, BRCA1,CENP-A, CPEB, Eg5,
Histone H3, LATS2, Ndel1, N-Myc,
p53, TACC
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
Cdk2
Actopaxin, adenomatous polyposis coli,
Aki1 Amphiphysin 1, Anaphase
Promoting Complex, Ase1, BARD1,
Bcl-2, caldesmon, caspase-2,
caspase-9, Cdc7, Cdc20, Cdc25A,
Cdc25 C, Cdh1, Cdk7, C/EBP␤, CK
II, CtIP, dynein, dystrophin, EF-1,
Eg5, EGFR, ERK-3, FANCG, Fos,
FoxM1B, FoxO1, GBF-1, GFAP,
GM130, GRASP65, histone H1,
hHR6A, HMG-I(Y), IFAP300, KRC,
lamins A, B, and C, lamin B
receptor, Lats1, MAP1B, MAP4,
Map205, Marcks, MCM2, MCM4,
MKLP1, Myb, Nedd1, NBP60,
neurofilament H, NF-I, Nir2, NO38,
nuclear pore complex, nucleolin,
Nucks, numatrin, Orc1, p18, p47,
p53, p54NRB, PAP, PHF8, plectin,
PP1-I2, pRb, R2, Rab4, Rap1GAP,
Raptor, RCC1, RIIalpha, RunX2,
S6K1, Sam68, Securin, Separase,
SIRT1, Ski, survivin, mSTI1, Tau,
TMAP(CKAP2), vimentin, Vsp34,
thymidine kinase, 53BP1
ATRIP, BARD1, B-Myb, BRCA1, CBP/
p300, Cdc6, Cdc7, Cdk7, Cdt1, C/
EBP␤, DP1, hHR6A, HIRA, Ku70,
Marcks, MCM2, MCM4, MyoD,
NPAT, nucleophosmin (B23), p107,
p21Cip1, p27Kip1, p53, pRb, R2,
RPA, Smad3, thymidine kinase
Cables 1, c-Jun
CELL CYCLE KINASES
Table 1—Continued
Symbol
AurkB
AurkC
Alias
Function
Regulatory Partners
Aik2, AIM-1,
Chromosomal passenger
Ark2, Stk12,
complex (CPC) kinase;
Stk5
Chromosome attachment
and cytokinesis
Ark3, Stk13
CPC kinase, meiosis
Substrates (Vertebrates)
INCENP, Borealin,
Survivin
Borealin, CENP-A, Hec1, Histone
H3, MCAK, MYBBP1A
INCENP, Borealin,
Survivin?
Borealin, CENP-A
Polo-like kinases
Plk1
Plk2
Snk
Plk4
Plk5
Sak
AC104852,
LOC126520
Substrates need to be
primed by Cdks
Substrates need to be
primed by Cdks
␣-Synuclein, ␤-catenin, FoxM1B,
Nedd1, NudC, 53BP1
SPAR, ␣-synuclein
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
Plk3
Centrosome biology and
mitosis
G1/S progression?, neuron
function
G1/S progression, neuron
function
Centriole biology
Neurite growth
Vrk1, ␣-synuclein
No substrates identified
Checkpoint kinases
Bub1
BubR1
Mps1
Bub1b
Ttk
Spindle assembly checkpoint
Spindle assembly checkpoint CENP-E
Spindle assembly checkpoint
Cdc20, Mad1, Bub3
p53, BLM, Dam1
Replication kinases
Cdc7
DNA replication
ASK, Dbf4, Drf1
Mcm2, Mcm4, Mcm6
NIMA-related kinases
Nek2
Nek6
Nek7
Nek9
Mitosis
Mitosis
Mitosis
Activated by Nek9
Activated by Nek9
c-Nap1, rootletin, PP1, Nlp,
centrobin, HMGA2
Eg5 S1033
No substrates identified
Nek6, Nek7
Phosphatase-inhibiting kinases
Mastl
Greatwall,
FLJ14813,
Thc2
Inhibition of PP2A, mitosis
sors for cell cycle entry by inactivating the pRb-dependent
repression machinery commonly present in adult cells. Why
are there three different D-type cyclins and two different
D-type cyclin-associated kinases? As we will see later, the
different combinations of D-type cyclins and Cdks are likely
to provide additional flexibility in different cell types or in
response to different mitogenic signals.
Cdk2 and Cdk3 are highly similar to Cdk1 but do not
share its mitotic functions. Both proteins associate to E- and
A-type cyclins, and their activities may be involved in G1
progression, entry into S phase, and DNA repair. Cdk3 is
expressed at low levels in mammals, and its function remains to be clearly established (211). Cdk2 is also able to
Activated by Cyclin
B/Cdk1
No substrates identified
phosphorylate pRb, and it may perform similar functions to
Cdk4 in the control of cell cycle entry (212). In addition, it
may participate in DNA damage and DNA repair, although
many of these functions are also shared by Cdk1 (49, 69,
74, 142, 241).
Cdk5, the mammalian Cdk with the highest similarity
to yeast Pho85, is a very particular protein as it is activated
by noncyclin proteins, p35 and p39, that are almost
uniquely expressed in brain. Cdk5 can also bind D-type and
E-type cyclins, although the activity of these complexes is
unclear. Cdk5 has multiple roles in neuron biology including neuronal migration and survival, dendrite extension,
and synapsis (76, 156). Cdk5 also display additional func-
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
977
MARCOS MALUMBRES
tions in cell adhesion (327) and cellular senescence in nonneuronal cells (219).
3. Cdk-activating kinases and transcriptional Cdks
Mammalian Cdk7 is a component of the Cdk-activating kinase (CAK) which phosphorylates and activates several cell cycle Cdks. In addition, CAK is part of the general
transcription factor TFIIH involved in promoter clearance
and progression of transcription (94). Cdk20 (Ccrk) is
highly related to Cdk7 both in sequence and function, and it
may also phosphorylate and activate other Cdks such as
Cdk2 (7, 244). It may regulate primary cilium in some
model organisms (175).
B. Aurora Kinases
Early work in Drosophila led to the identification of aurora
mutants, which carry a loss-of-function mutation in a serine/threonine kinase essential for centrosome separation
and the formation of bipolar spindles (108). A single Aurora protein exists in budding (increase-inploidy 1; Ipl1) or
fission (Ark1) yeast, whereas two family members, Aurora
A and Aurora B, are present in worms, flies, and frogs.
Three different Aurora family members, known as Aurora
A, B, and C, exist in mammals (245). These kinases contain
a conserved catalytic domain and NH2-terminal domains
that vary in sequence and in length. Aurora B and C are
close paralogues that probably arose from a relatively recent common ancestor (34).
Aurora kinases participate in multiple processes during the
mammalian cell cycle (45). Aurora A, the ortholog to the
original Drosophila kinase, localizes on duplicated centrosomes from the end of S phase to the beginning of the
following G1 phase, when this kinase is degraded by the
proteasome in an APC/C-Cdh1-dependent manner. Aurora
A participates in several processes required for building a
bipolar spindle including centrosome separation and microtubule dynamics (17, 106) (FIGURE 1). Aurora B, on the
other hand, belongs to the chromosome passenger complex
(CPC) that localizes to the kinetochores from prophase to
metaphase and to the central spindle and midbody in cyto-
978
Less is known about Aurora C, which is expressed at high
levels in the testis (45). Aurora C can bind members of the
CPC (191), and its ectopic expression can rescue Aurora B
loss of function in cultured cells (291, 307, 359), suggesting
a potential function as a regulator of microtubule-kinetochore interactions, at least in some cell types. Although
Aurora C is known to have a specific role in spermatogenesis (77, 172, 321), its relevance in the regulation of mitosis
is not well understood.
C. Polo-Like Kinases
Polo was originally identified in Drosophila as a mutant
with mitotic and meiotic defects in the microtubule spindle
(317). This mutation was later mapped to a serine-threonine protein kinase specifically concentrated in dividing
cells (204). Polo-like kinases (Plks) are found in all eukaryotes and are characterized by a highly related kinase
domain, and one or two COOH-terminal polo box domains (PBDs), involved in subcellular localization and partner interaction (83, 338). These include the Plk1 subfamily,
containing Drosophila polo and mammalian Plk1, the SAK
subfamily, containing Drosophila SAK and mammalian
Plk4, both of which are widely distributed across the eukaryotes, and the Plk2 subfamily, containing vertebrate
Plk2 and Plk3, and also including homologs from echinoderms (15, 18, 218). The mammalian genome contains a
fifth member of the Plk family, Plk5, initially described as a
pseudogene (39) and recently linked to DNA damage (9)
and neuron biology (72). Although mouse cells express a
full-length Plk5 similar in size to Plk2 or Plk3, human cells
express a shorter Plk5 form in which the kinase domain is
disrupted due to a stop mutation in exon 6 which is followed by an in-frame ATG codon immediately down-
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
Cdk7–11 also function as transcriptional regulators, in
some cases with direct links to cell cycle control (211). Thus
Cdk7 is a component of the general transcription factor
TFIIH, whereas Cdk8, Cdk9, and Cdk11 regulate RNA
polymerase II, among other functions (211). The Cdk8highly related kinase Cdk19 is likely to have similar functions as a component of the mediator complex (213, 292).
No clear function has been assigned to Cdk10. Similarly,
Cdk12–Cdk18 play diverse functions in the control of diverse cellular processes, including the regulation of the retinoblastoma pathway, although the relevance of these kinases is mostly unknown (213).
kinesis (45, 279). The CPC is responsible for the recruitment to the kinetochore and centromere of a growing number of proteins including inner centromeric proteins, regulators of the microtubule-kinetochore, or proteins involved
in the SAC (168). Some of these molecules, such as the
depolymerizing factor MCAK, are Aurora B substrates,
suggesting a critical role for the CPC in the destabilization
of aberrant microtubule-to-kinetochore attachments and
the SAC-dependent delay in mitotic progression until these
defects are corrected (279). Recent data suggest that substrate phosphorylation depends on the distance of the substrate from Aurora B at the inner centromere, thus indicating that recruitment of the CPC to the kinetochore prevents
the stabilization of improper attachments and activates the
SAC to delay the metaphase to anaphase transition (195).
During cytokinesis, Aurora B is localized to the midbody
remnant where its local inactivation is crucial for completion of abscission (115, 311). Aurora B also participates in
mitotic phosphorylation of Ser-10 and, probably, Ser-28 in
histone H3, and it may regulate cell differentiation through
these epigenetic modifications (281).
CELL CYCLE KINASES
stream, in the boundary between exons 6 and 7. However,
both the murine (long) and human (short) forms display
similar cellular functions, and the kinase domain of the
murine protein seems to be inactive in kinase assays (72).
The three Plk subfamilies have distinct functions and operate in multiple cell types. Their expression is regulated differentially in cells and tissues and in response to several
cellular processes and stimuli (352). Whereas Plk1 and Plk4
are found only in dividing cells, Plk2, Plk3, and Plk5 are
also expressed in neurons and other, nondividing, differentiated cells (72, 299, 339). Plk2 and perhaps Plk3 seem to
have a crucial function in modulating synaptic plasticity in
neuronal dendritic spines through the phosphorylation of
the spinde-associated protein SPAR (10, 298; and see below). Plk5, on the other hand, is involved in neuron differentiation and growth of neurites (72).
D. Checkpoint Kinases: Bub1, BubR1,
and Mps1
The SAC is a highly conserved cellular mechanism that
ensures chromosome segregation fidelity in all eukaryotes
by delaying anaphase onset in response to kinetochores that
are unattached to microtubules. There are more than 14
proteins that may be involved in SAC signaling, and at least
four of them are protein kinases: Bub1, BubR1, Mps1, and
Aurora B, although Aurora B may be strictly dispensable for
SAC function (240). Plk1 displays a relevant activity in
recovery to DNA damage checkpoint (340), and it may also
be involved in some aspects of the SAC, although its relevance is not clear (63). As long as there are unattached
kinetochores or improper attachments unable to produce
enough tension, the SAC is active and some SAC components such as BubR1 sequester and inhibit Cdc20, the activatory subunit of the APC/C. Upon complete attachment
and biorientation of chromosomes, the SAC is satisfied and
APC/C-Cdc20 becomes active, resulting in the ubiquitination of securin and cyclin B that are subsequently degraded
in a proteasome-dependent manner (216, 240).
The budding uninhibited by benzimidazole (Bub) proteins were originally characterized in S. cerevisiae screens
for mutants that were unable to recover from a transient
treatment with a microtubule inhibitors (131). Bub1 is a
protein kinase that first localizes at the forming kinetochore
during prophase, and it is required for the recruitment of
other proteins to the kinetochore. Bub1 plays several roles
in regulating kinetochore assembly, spindle function, as
well as sister chromatid separation (220). Bub1 monitors
microtubule attachment to the kinetochores by phosphorylating Mad1 or Bub3, thus modulating the availability of
Mad2 to inhibit APC/C-Cdc20. Cdc20 is also a direct target
of Bub1 resulting in APC/C inhibition. Bub1 also regulates
centromeric cohesion by direct phosphorylation of threonine 120 (serine 121 in fission yeast) of the conserved C-tail
of human H2A. This phosphorylation is crucial for centromeric localization of shugoshin, since most defects observed
after inhibition of Bub1 are phenocopied in H2A mutants in
which this residue has been changed to alanine, and these
defects are suppressed by tethering shugoshin proteins at
centromeres (166). The shugoshin-PP2A complex protects
centromeric cohesin during mitotic prophase by avoiding
excessive phosphorylation and premature release of cohesins. Bub1 is therefore crucial for establishing a centromeric mark for shugoshin localization and the proper control of sister chromatid separation (166).
In general, Bub1 seems to regulate the switch from
lateral to end-on attachment, while BubR1 is required for
stabilization of kinetochore-microtubule attachments
(220). Aurora B has an additive effect on the misaligment
phenotype of Bub1-depleted cells but a suppressing effect in
the BubR1 phenotype, suggesting that the defective attachments in Bub1-deficient cells are detected by active
Aurora B, which acts to destabilize them, thereby creating the possibility for new correct attachments to be established.
2. Mps1 (Ttk)
Mps1, from the monopolar spindle phenotype in the
yeast (351) (also known as Ttk in mammals), is a dualspecific protein kinase that may play specific roles in
centrosome duplication and cytokinesis (95). However,
the kinetochore functions of Mps1 have been studied the
most extensively. Mps1 is required for the SAC due to its
requirements for kinetochore recruitment of several
checkpoint proteins, including Mad1 and Mad2 (2, 96,
126, 198, 207, 221, 287, 314, 324). In the absence of
Mps1, the SAC is not functional, and cells rapidly exit
from mitosis even in the presence of microtubule poisons.
Mps1 may also play additional roles in the regulation of
p53 (139) and Abl (246).
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
979
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
The founding member of the family, Plk1, localizes to the
cytoplasm and centrosomes in interphase and concentrates
to the kinetochores and the cytokinesis bridge during cell
division. This protein has major functions in centrosome
maturation, mitotic entry, and cytokinesis (15, 18, 261,
320). The other members of the family are less studied. Plk4
(Sak) is a critical regulator required for centriole duplication both in Drosophila and mammals (25, 116). Plk2 (also
known as Snk) localizes to the centrosome and may also
participate in centrosome biology and S-phase checkpoints
(227). Plk3 (Fnk or Prk) activity peaks in G1 and localizes to
the nucleolus in interphase. This protein may function in
S-phase entry (374), and it is activated in response to replicative stress and genotoxic insults leading to apoptosis in a
p53-dependent manner (345, 356, 357).
1. Bub1 and BubR1
MARCOS MALUMBRES
E. Additional Cell Cycle Kinases: Cdc7,
Neks, and Mastl
Chromosome replication is a highly complex process that
occurs once in every cell cycle in most cells. A conserved
kinase called Cdc7 cooperates with Cdks in establishing
replication forks during the initiation of chromosome replication. Cdc7 is required for efficient S phase progression
by phosphorylating the Mcm2–7 helicase and relieving an
inhibitory activity residing within the Mcm4 NH2-terminal
domain (35, 68, 98, 301, 302). Cdc7 may also have additional roles in the DNA damage response, mitosis, or meiosis (162, 170, 225, 231, 330), although these putative
functions have not been fully studied in mammals.
Neks represent a family of serine/threonine kinases named
after the NIMA gene originally cloned in Aspergillus nidulans. Eleven mammalian family members (Nek1-Nek11)
maintain significant homology with the A. nidulans NIMA
protein, although the COOH-terminal noncatalytic region
is highly divergent, suggesting that each family member
may have distinct functions (249). Only four of these proteins, Nek2, Nek6, Nek7, and Nek9, have been shown to
play relevant roles in mitotic progression. Nek2, the closest
relative to NIMA, localizes to the centrosome and plays a
role in establishing the bipolar spindle through initiating the
separation of centrosomes and contributing to microtubule
organization at the G2/M transition by phosphorylating
several centrosomal substrates (TABLE 1) (249). Nek2 may
also play additional roles in chromosome condensation and
the SAC, through its interaction with Hec1 and Mad1.
980
Recently, a new kinase known as Mastl in mammals and
Greatwall in Xenopus and Drosophila has been shown to
be critical for maintaining the mitotic state. Greatwall was
originally identified as a kinase required for chromosome
condensation (365). Recent studies indicate that Mastl/
Greatwall inhibits PP2A in complex with the B55␦ regulatory subunit, a complex that can remove the phosphoresidues established by Cdk1 during mitosis. However,
the activiy of Mastl inhibits PP2A, ensuring that Cdk1
substrates remain phosphorylated during mitosis (38, 48,
341). Interestingly, the human MASTL gene is mutated in
a novel form of autosomal dominant inherited thrombocytopenia (102).
III. CELL CYCLE KINASES IN
DEVELOPMENT AND STEM CELL
FUNCTION
A. Development
Given the strong requirements for cell division during
development, it is not surprising that many cell cycle
kinases are critical for the formation of adult mammals.
The generation of mouse models with loss-of-function
mutations in specific genes has produced in the last years
a significant amount of data on the requirements for these
proteins in different stages of development or in different
tissues (TABLE 2).
1. G1/S kinases: reentering the cell cycle in the
embryo
Perhaps the most unexpected result in the late 1990s
and early 2000s was the relative dispensability of the major
G1/S kinases: Cdk4, Cdk2, and Cdk6 during mouse development (23, 50, 215, 251, 270, 332). Even the combined
ablation of two or the three of these genes only results in
specific phenotypes in the fetal liver or in the heart, indicating that these proteins are not required for most cell divisions during development (209, 288). Given the high number of mammalian Cdks, it is still possible that the activity
of these proteins is compensated by Cdk1 (288) or other
non-well-characterized Cdks, such as the Cdk14 subfamily,
that also bind D-type cyclins (213). However, the most
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
Progression throughout the cell cycle involves multiple molecular and cellular processes, and a number of additional kinases
are involved in the control of different aspects of the mammalian cell cycle. For instance, more than 40 human kinases result
in specific mitotic phenotypes when repressed by RNA interferences as reported by the MitoCheck Consortium (243)
(http://www.mitosys.org/cgi-bin/mtc?query⫽kinase&
query_type⫽genes). These include Aak1, Acvr1C, Cdc2L5,
Cdkl5, Cit, Dak, Gak, Grk5, Kalrn, Lck, Limk1, Lmtk3,
Map2k5, Map3k2, Mastl, Mst4, Nek3, Nek10, Nek9, Nttrk3, Pak2, Pask, Pdk1, Pink1, Pkn3, Prkab1, Prkacb, Prkce,
Prkcq, Prkg1, Prky, Ptk7, Ret, Ripk4, Rps6ka2, Ryk, Sgk223,
Stk16, Stk39, Tesk1, Tssk3, Ulk4, Vrk1, Vrk2, Wee1, and
Wnk4. Other kinases with certain relevance in the cell cycle
include the replication kinase Cdc7 (see below) or other proteins such as Tousled-like kinases (Tlk1 and Tlk2), Lats kinases, and the Cdk inactivating kinases Wee1/Myt1 or Haspin
(Gsg2) that have been reviewed elsewhere (127, 167, 208,
275, 333). In some cases, the link between these kinases and
the cell cycle may be indirect or we do not have a clear picture
of how their function modulates cell cycle progression. However, a few of these kinases, such as Cdc7, Neks, or Mastl,
have a clear direct role in the cell cycle, and they are also
known to have physiological relevance in some specific tissues
in vivo.
Nek9, Nek6, and Nek7 function in a kinase cascade that
participates in the formation and/or maintenance of the
mitotic spindle (20). Nek9 phosphorylates both Nek6 and
Nek7, relieving an inhibitory signal and thus activating
these two kinases (274). In general, Nek kinases seem to
play a critical role in microtubule organization, not only
during mitosis but also in cilia (253, 268). In fact, Nek1 and
Nek8 have been implicated in cilia function, since these
genes are mutated in mouse models of polycystic kidney
disease (197, 336).
CELL CYCLE KINASES
Table 2
Symbol
Representative mouse models of cell cycle kinases
Genotype
Phenotype
Reference Nos.
Cyclin-dependent kinases
Cdk1
Cdk2
Cdk3
Cdk4
mut
Cdk1
(gene trap)
Cdk1Cdk2KI (Cdk2 cDNA into
Cdk1 locus)
Cdk2(⫺/⫺)
E␮-Myc; Cdk2(⫺/⫺)
Cdk3(Stop/Stop) point
mutation)
Cdk4(⫺/⫺)
K-Ras V12; Cdk4(⫺/⫺)
Cdk6
Cdk11
Cdk6(⫺/⫺)
Cdk11(⫺/⫺)
Cdk2/4/6
Cdk2(⫺/⫺); Cdk4(⫺/⫺);
Cdk6(⫺/⫺)
288
293
Viable. Male and female sterility.
Cdk2 is required for Myc-induced
lymphomas
Spontaneous strain. No phenotype
23, 251
43
Viable. Diabetes and hypopituitarism
due to defective proliferation of
endocrine cells. Delayed entry into
S phase in MEFs
Cdk4 is required for H-Ras-induced
breast tumors
Cdk4 is required for K-Ras-induced
lung tumors
Viable. Mild anemia
Embryonic lethality (blastocyte stage).
Mitotic arrest and apoptosis.
Haploinsufficient for skin tumor
suppression
Embryonic lethal (E13.5–E15.5) due
to hematoipoietic defects
270, 332
362
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
MMTV-Ras; Cdk4(⫺/⫺)
Early embryonic lethality (2-cell stage)
Early embryonic lethality
367
266
215
57, 190
288
Aurora kinases
AurkA
Aurka(⫺/⫺)
AurkB
Aurkb(⫺/⫺)
AurkC
Aurkc(⫺/⫺)
Embryonic lethality (blastocyte stage).
Mitotic arrest and monopolar
spindle formation
Lethality in postimplantation embryos
due to rapid mitotic exit and
apoptotic cell death
Viable. Minor defects in sperm
functionality (note that multiple
AurkC loci may exist in the mouse
genome)
53
Fernandez-Miranda et al.,
unpublished observations
172
Polo-like kinases
Plk1
mut
Plk1
(gene trap)
Plk1(⫺/⫺) and Plk1mut
(gene trap)
Plk2
Plk2(⫺/⫺)
Plk3
Plk3(⫺/⫺)
Early embryonic lethality (morula
stage) due to interphase arrest.
Happloinsufficient for tumor
formation
Early embryonic lethality (morula
stage) due to mitotic arrest and
the formation of monopolar
spindles. Happloinsufficient for
tumor formation
Viable. Retarded growth and skeletal
development. Delayed entry into S
phase in MEFs
Viable. Increased weight and
increased susceptibility to tumor
formation
203
Wachowicz et al., unpublished
observations
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
205
361
981
MARCOS MALUMBRES
Table 2—Continued
Symbol
Plk4
Genotype
Plk4(⫺/⫺)
Phenotype
Mitotic arrest and postgastrulation
(E7.5) defects during embryonic
development. Haploinsufficient for
suppression of liver tumors
Reference Nos.
141, 176
Checkpoint kinases
Bub1
Bub1(⫺/⫺)
Bub1hypomorph
Bub1b(⫺/⫺)
Bub1bhypomorph
257
154
346
16, 70, 271
Replication kinases
Cdc7
Cdc7(⫺/⫺)
Embryonic lethality between E3.5 and
E6.5 due to S-phase defects.
Partially rescued in a p53
background
171
Nima-related kinases
Nek1
Nek7
Nek8
Spontanous loss-of-function
mutations
Nek7(⫺/⫺)
Spontanous loss-of-function
mutation
Polycystic kidney disease
336
Late embryonic development of
perinatal lethality. Increased ploidy
in MEFs.
Polycystic kidney disease
282
likely explanation for the lack of embryonic phenotype in
these models is that early embryonic cell cycles do not require interphase Cdk activity at all. Mammalian stem cells
display a short G1 phase and a rapid alternation between S
and M phases (250, 349), suggesting that early embryonic
cells do not require the G1/S machinery. In fact, pRb is not
expressed until midgestation, thus leading to a model where
early cell divisions do not have an active repression machinery and G1 kinases are therefore not required for
entering into the cell cycle (209). These kinases would
only be required in those tissues where differentiation
and the acquisition of a regulated cell cycle exit and entry
is required. No wonder, the hematopoietic system is one
of such systems in which proliferation and differentiation
are tightly regulated to produce all types of hematopoietic cells. Embryos devoid in Cdk4/6 or in the three G1
Cdks die during midgestation due to the inability of the
fetal liver to form all hematopoietic cells required for
embryo survival (215, 288).
982
197
Although the information is not as detailed for other
interphase proteins, the observations made with Cdks suggest that other interphase kinases should also be dispensable for early cell divisions. Plk2, a member of the Polo-like
kinase family with no role in mitosis, is also to be dispensable for embryonic development, although genetic ablation
of Plk2 results in retarded growth and skeletal development
late in gestation (205). Similarly, Plk3 is dispensable for
embryonic development, although Plk3-deficient mice display increased susceptibility to tumor development (361).
On the other hand, the replication protein Cdc7 is essential
for embryonic development, and Cdc7-null embryos die
between E3.5 and E6.5 due to cessation of DNA synthesis
within S phase (171).
2. Mitotic kinases
Most kinases involved in centrosome biology or mitosis seem to be required for embryonic development. Genetic
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
BubR1
Embryonic lethality (E3.5) due to
proliferative arrest and apoptosis
Increased aneuploidy and
susceptibility to spontaneous
tumors (liver and lung tumors,
sarcoma and lymphoma)
Embryonic lethality (E8.5). Abnormal
megakaryopoiesis in heterozygous
mutants
Prone to aneuplody, premature
ageing, infertility, increased
susceptibility to induced tumors
CELL CYCLE KINASES
ablation of Cdk1, the master mitotic kinase, results in a
dramatic arrest at the two-cell stage, indicating the strong
requirement for de novo synthesis of this kinase during
embryonic development (FIGURE 2). Cdk11 deficiency also
results in early embryonic lethality due to mitotic arrest and
apoptosis of the blastocyst (190). Aurora A and Plk1 are
also required for early divisions as their absence results in
arrest at the morula or eary blastocyst stage [about embryonic day (E)3.5; Refs. 53, 203]. In both cases, the absence of
these kinases results in mitotic arrest (53; P. Wachowicz, G.
de Carcer, and M. Malumbres, unpublished information),
suggesting the essentiality of these two proteins in mitotic
progression. Genetic disruption of Plk4 results in embryonic lethality by E7.5, leading to an accumulation of mitotic
and apoptotic cells during gastrulation (141).
bryonic cell divisions in the absence of Aurora B. Interestingly, Aurora C is highly expressed during the early cell
divisions, probably due to maternal contribution, and it
seems to be responsible for CPC function in these preimplantation embryos (G. Fernández-Miranda, M. Trakala, I.
Pérez de Castro, and M. Malumbres, unpublished data).
Despite the crucial role of Aurora C during these early cell
divisions, the expression of this protein is restricted to germ
cells after implantation, and it seems to be dispensable for
the rest of the embryonic development (172).
In mammals, the CPC seems to be also required for
early embryonic development before implantation. Degeneration of embryos is apparent by E2.5-E3.5 in the absence
of the CPC components Survivin (337), Incenp (56), or
Borealin (358). In these models, several mitotic defects are
observed including abnormal mitotic spindles and variable
nuclear sizes as a consequence of defective cytokinesis.
However, Aurora B-null embryos develop normally during
the early cell divisions and die only after implantation, suggesting the presence of normal cell cycles in the early em-
3. Checkpoint kinases and genomic instability
Genetic disruption of the mitotic kinase Nek7 leads to
lethality at late embryonic stages or perinatally (282).
Nek7-null newborns die within the first 2 wk, although the
defects behind this phenotype are not clear at present.
FIGURE 2 Requirements for cell cycle kinases during embryonic development in the mouse. The embryonic stage mostly affected by the genetic ablation of single kinases is indicated. Some kinases dispensable
for embryonic development display specific defects in adult tissues or in tumor development (see text and
TABLE 2 for details).
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
983
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
The SAC is not essential in budding yeast or in Drosophila probably because chromosome attachment to microtubules is very rapid and efficient (37, 107). However,
all SAC genes studied to date are essential in mice, including
Bub1 and BubR1 (FIGURE 2). Bub1-null mice die shortly
after day E3.5, and this protein is required at all stages
analyzed during embryonic development (257, 325). On
the other hand, embryos homozygous null for Bub1b (the
MARCOS MALUMBRES
gene encoding BubR1) die by E8.5 in utero (346). Although
the molecular and cellular phenotype has not been characterized in detail in these embryos, this lethality is accompanied by proliferation defects and massive apoptosis. Genetic
disruption of the murine Ttk (Mps1) locus has not been
reported yet. However, Mps1 is required for development
in zebrafish, and a hypomorphic mutation in the Mps1 gene
in this organism results in frequent developmental aneuploidy as a consequence of impaired checkpoint activity in
germ cells (262, 263).
B. Stem Cell Function and Asymmetric
Cell Division
1. Regulation of G1 phase in stem/progenitor cells
Embryonic stem cells (ESCs) exhibit a short G1 phase
that significantly lengthens as cells differentiate during development. In the embryonic epiblast, the mean generation
time has been estimated to be as low as ⬃5 h and correlates
with the high Cdk activity observed in cultured ESCs (349).
These early embryos are likely to lack a functional pRb
pathway and cell-cycle-dependent transcription as observed
in ESCs (310, 349). As embryonic cells differentiate, the cell
cycle is likely to become dependent on specific transcriptional waves required for expressing S phase and mitotic
regulators, resulting in a prominent G1 phase or in a quiescent (G0) state.
Less information is available on how adult stem cells
regulate the entry into the cell cycle upon proper stimulation. These cells are typically quiescent or slow-proliferating and are therefore quite different from ESCs under a cell
984
All together, these studies suggest that the G1 phase is a
sensitive period during which cell-fate decisions are made
with the help of crucial signals from the microenvironmental niche of the adult stem cell population (250). G1 Cdks
and their regulatory subunits may play a critical role in
maintaining stem cell function through life, and the alteration in this control is likely to lead to multiple pathological
abnormalities (FIGURE 3).
2. Asymmetric versus symmetric cell division in
stem/progenitor cells
Neural stem cells are a good model to study the
relevance of symmetric versus asymmetric cell division in
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
From the previous section, it may be concluded that some
cell cycle kinases, such as Cdk1, Plk1, or Aurora A, are
essential for cell division in every cell type analyzed (including early embryonic cells), whereas checkpoint kinases such
as Bub1, BubR1, and Mps1 may be dispensable within a
few cell cycles but their inhibition results in chromosomal
instability and apoptotic cell death. Although not tested
directly yet, these essential roles are supposed to apply similarly to stem cells. G1/S kinases, however, may have special
relevance in stem cell biology, since the presence or not of
G1 or the length of this phase may be a major regulatory
factor in adult stem cell function. Adult stem cells maintain
tissue function and integrity throughout an organism’s lifespan by replacing differentiated cells as they are lost because
of attrition or damage. To perform this function, stem cells
are endowed with a unique combination of pluri-lineage
developmental potential and the capacity to enter the cell
cycle when required. In addition, these cells usually have the
ability to perform two different cell divisions: symmetric, to
produce two identical stem cells; or asymmetric, in which
cell division results in a stem cell and a differentiated (or
committed to differentiation) cell.
cycle perspective. In fact, recent genetic studies in the mouse
have revealed the importance of stem cell quiescence in the
maintenance of stem cell function during adulthood (250).
Some cell cycle kinases are likely to participate in this regulation. In fact, the phenotype of hematopoietic stem cells
(HSCs) deficient in the Cdk inhibitor p21Cip1 was one of the
first indications suggesting the relevance of cell proliferation in stem cell exhaustion. In p21-null mice, the percentage of HSCs in G0 is reduced in agreement with increased
proliferative potential of these cells. As a consequence, the
bone marrow in these animals is rapidly exhausted after
serial transplantation or myelotoxic agents (62). Similar
results in the increased reduction of p21-null neurosphereinitiating cells with ageing (174) suggest a general mechanism by which stem cells need to maintain under tight control the number of cell divisions throughout life. The fact
that p21Cip1 is a major Cdk inhibitor suggests that Cdks are
major players in controlling the balance between stem cell
quiescence and proliferation. In fact, similar results have
been obtained after genetic disruption of other unrelated
Cdk inhibitor, p16Ink4a, when depleted in young HSCs
(153). Interestingly, ablation of p16Ink4a in old HSCs displays the opposite effect and improves the regenerative potential of these cells, as well as neuronal or pancreatic stem/
progenitor cells (153, 179, 232). Similarly, genetic ablation
of p18Ink4c results in increased number and function of
HSCs (364, 368). These results are difficult to conciliate in
a single model at this moment, although they may indicate
different functions of the target kinases (Cdk1/2 for p21Cip1
and Cdk4/6 for Ink4 inhibitors) in ageing or the response to
stress (250). For instance, Cdk2-null cells from the subventricular zone (SVZ) display decreased self-renewal capacity
and enhanced differentiation (149). Cdk4 may compensate
for the lack of Cdk2 in young animals, but not in old mice
(149), in agreement with the age-related increase of Ink4
inhibitors that may limit Cdk4 function with age. Cdk4 is
also a central kinase in triggering cell division in skin stem
cells. In quiescent hair follicle stem cells, Cdk4 is repressed
by the nuclear factor of activated T cells c1 (NFATc1). As
stem cells become activated during hair growth, NFATc1 is
downregulated, relieving Cdk4 repression and activating
proliferation of these cells (130).
CELL CYCLE KINASES
mammals. As development proceeds, an increasing proportion of neural stem cells start to switch from divisions
that generate additional stem cells (symmetric cell divisions) to divisions that generate committed progenitors
or postmitotic cells (asymmetric cell divisions) (294,
372). This switch leads to the generation of neurons and
intermediate progenitors that leave the ventricular zone
and form a second germinal region, the SVZ, which is
thought to be important for increasing cortical surface.
It has been recently proposed that the length of the
G1 phase plays a central role in the switch from symmetric to asymmetric cell division in these neural precursors.
Overexpression of Cdk4/cyclin D1 in neural progenitors
shortens G1 by 30% inhibiting neurogenesis (asymmetric
cell divisions that generate one stem/progenitor cells plus
a differentiated neuron) and promotes the expansion of
basal progenitors through symmetric cell divisions (185).
On the other hand, partial inhibition of Cdks induces
premature neurogenesis (42). Although formal demon-
stration of this hypothesis remains to be provided, these
results suggest that the observed lengthening of G1 is not
only a consequence of differentiation but may also play
causal roles in inducing neurogenesis and differentiation
(283).
In addition to the role of interphase Cdks in regulating G1, the balance between symmetric and asymmetric
cell divisions may be also modulated by other cell cycle
kinases involved in centrosome or spindle function. In
vivo, the decision between symmetric or asymmetric cell
divisions is likely to be modulated by external signals
from the stem cell niche that determine the orientation of
the cell division. In general, daughter stem cells will remain in the niche, whereas the differentiated cell will
migrate out of the niche. This has been well documented
at least for two mammalian systems: the skin and the
nervous tissue. In the skin, the basal epidermal cells can
divide asymmetrically by orientating the spindle perpendicularly to the basement membrane, a process in which
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
985
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
FIGURE 3 Adult stem/progenitor cell function and its control by G1 kinases. In normal tissues, stem cell
self-renewal is tightly controlled to ensure proper tissue homeostasis and regeneration throughout life.
Upon hyperactivation of G1 Cdks (e.g., Cdk2, Cdk4, or Cdk6) mediated by cyclin overexpression of loss of
the corresponding inhibitors (Ink4 or Cip/Kip families), proliferation of stem cells is increased possibly
cooperating with tumor formation. In addition, this increased proliferation may lead to stem cell exhaustion
and inefficient responses to stress or ageing. This model is mostly generated from evidence obtained from
mouse models with specific mutations in Cdk inhibitors, and further experimental work is required to
directly test the requirements for Cdk activity in stem/progenitor cell function in vivo.
MARCOS MALUMBRES
integrins and cadherins are essential for the apical localization of atypical protein kinase C (aPKC), the Par3Lgn-Inscuteable (Ins) complex, and NuMA-dynactin to
align the spindle (186).
FIGURE 4 A model for the control of neuroblast proliferation and asymmetric cell division by cell cycle
kinases. In the embryonic neuroepithelium, apical neuroblasts divide symmetrically to produce two progenitors
(left) or asymmetrically to generate one progenitor and one differentiated neuron (right). The decision may be
modulated by Cdk4 through the control of the length of the G1 phase of the cell cycle, by several microcephaly
proteins (such as Aspm and Cdk5Rap2) that regulate centrosome function, and by mitotic kinases by
regulating the localization of apical (green area) or basal (orange) markers. The involvement of mitotic kinases
has not been demonstrated in mammals and comes from studies in flies. Aspm, Cdk5Rap2, and the kinase
Cdk19 are mutated in human microcephaly syndromes.
986
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
However, as indicated above, most information on
asymmetric cell division comes from the study of neuroblasts in flies (90, 111, 113, 144, 265). The initial evidence
of a direct link between cell cycle kinases and asymmetric
cell division comes from the functional analysis of Cdk1 in
Drosophila. An original screen identified defects in asymmetric cell division in neuroblasts caused by a specific mutation (E51Q) in Cdk1 (326). The premature attenuation of
Cdk1 activity in this mutant results in mislocalization of
both apical (Ins, partner of Ins/Lgn and Bazooka/Par3) and
basal (Prospero, Brat, and Miranda) asymmetric markers
(FIGURE 4). The second mitotic kinase implicated in asymmetric divisions was Aurora A (21, 344). A hypomorphic
allele of Aurora A impairs asymmetric localization of the
basal asymmetric marker Numb and increases the number
of symmetric cell divisions. These defects are thought to be
caused by altered dynein-dependent spindle orientation and
delocalization of specific cortical markers such as aPKC or
Numb recruited through the Aurora A-dependent phosphorylation of Dlg(Pins), Par-3, and Par-6 (158, 169, 187,
353). Aurora B may also play a role in asymmetric cell
division as its CPC partner INCENP is required for the
asymmetric segregation of Prospero during asymmetric
neuroblast division in Drosophila (58). Finally, the Drosophila Polo has been shown to directly phosphorylate partner of Numb (Pon), a Drosophila-specific adaptor protein
that regulates the asymmetric distribution of Numb (343).
In Polo mutants, the asymmetric distribution of Pon,
Numb, and aPKC are disrupted resulting in the expansion
of neuroblasts at the expense of neurons. Despite the relevance of these studies in flies, the relevance of cell cycle
kinases in neural stem cells in mammals remains mostly
unexplored (36).
CELL CYCLE KINASES
IV. AN INTEGRATIVE VIEW OF CELL
CYCLE KINASES IN TISSUE FUNCTION
AND DISEASE
A. Endocrine Tissues, Adipogenesis, and the
Control of Metabolism
One of the first links between cell cycle regulation and the
homeostasis of different tissues in vivo was provided by
heterozygous mice with a targeted mutation in the gene
encoding pRb. Whereas complete ablation of pRb results in
embryonic lethality due to placental, hematopoietic, and
neuronal defects, pRb(⫹/⫺) mice develop frequent pituitary tumors as well as other endocrine hyperplasias and
neoplasias (150). As expected, many of these phenotypes
were reproduced in Cdk4R24C knockin mice expressing a
hyperactive form of Cdk4 that results in increased pRb
inactivation (270, 309). These mice develop pituitary tumors as well as other endocrine pathologies such as insulinomas or Leydig cell tumors. Conversely, Cdk4 deficiency
results in specific defects in endocrine tissues, mostly endocrine pancreas, the pituitary, and Leydig cells in the testis,
whereas the rest of the tissues are mostly unaffected in the
absence of Cdk4 (270, 332) (FIGURE 5). In addition, endocrine tissues are frequently altered in most mouse models
with specific mutations in G1/S regulators such as cyclins or
Cdk inhibitors such as p27Kip1 or p18Ink4c (269). The reason for the special sensitivity of endocrine tissues to the
alteration of cell cycle regulators is unclear, although it may
be somehow related to relevance of G1 regulation in maintaining the proliferative potential of endocrine progenitors.
FIGURE 5 Specific requirements for interphase Cdks in adult tissues. Multiple evidences
in cultured cell lines and mouse models suggest specific roles for the indicated kinases in
different tissues. A question mark has been
added to Cdk6 in endocrine pancreas due to
the differences in the expression of this protein
in humans and mouse (see text).
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
987
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
From the original studies in yeast or invertebrates, it is
obvious that cell cycle kinases are critical regulators required for cell cycle progression in cultured cells. Their
relevance in mammalian development is also expected, and
their putative roles in stem cells further support the relevance of these kinases for proliferation and homeostasis of
adult tissues. However, despite the critical importance of
proper cell cycle regulation in establishing the correct morphology of tissues during development, little is known
about how the cell cycle is regulated in a tissue-specific
manner. In the next sections, we will focus on several tissues
whose function is known to be modulated by specific cell
cycle kinases. The wide variety of cell types within an adult
mammal requires important variations in the cell cycle,
from differentiated cells that maintain certain potential to
proliferate (such as endocrine cells or certain hematopoietic
cells at various stages of maturation), to specific tissues that
required giant cells generated by endoreduplication or lack
of cytokinesis (e.g., megakaryocytes) or by hypertrophic
growth (cardiac cells). In some cases, cell cycle kinases
play critical roles independent of the cell cycle function as
it is clearly the case in specific postmitotic neurons. Some
clinical data also suggest that specific human diseases
may be caused by alterations in the function of specific cell
cycle kinases, and these include specific pathologies in the
indicated tissues as well as the generation of aneuploidy in
the germ cells due to the alteration of checkpoint kinases
during meiosis. The role of cell cycle regulators in other
tissues or cell types not considered here, e.g., muscle (44,
342) or vascular cell function and lesions (8, 101), has been
previously reviewed.
MARCOS MALUMBRES
In agreement with this hypothesis, most spontaneous endocrine tumors display aberrations in cyclins, Cdks, or Cdk
inhibitors, in addition to the inactivation of pocket proteins
(269). In addition, a germ line nonsense mutation on the
human CDKN1B gene encoding p27Kip1 has been associated with the development of a multiple endocrine neoplasia-like syndrome (255).
Is the relevance of the Cdk4-E2F pathway in pancreatic
␤-cells exclusively due to their effect on proliferation? A
recent study suggests that this is not the case. Cdk4, cyclin
D1, and E2F1 proteins are highly expressed in nonproliferating pancreatic ␤-cells and may control insulin secretion
through transcriptional regulation of Kir6.2 (12). Kir6.2 is
a direct E2F1 target gene and plays a major role in the
regulation of insulin secretion by controlling membrane polarization. Upon high blood glucose levels, Cdk4 is activated resulting in pRb phosphorylation, activation of E2F1,
transcriptional induction of Kir6.2, and secretion of insulin
(12). Since glucose is required for proliferation of most cell
types, this mechanism suggests a “obligatory” link between
cell cycle molecules and control of metabolism (27).
The general implications of Cdk4 in the control of glucose
homeostasis and oxidative glycolysis have been recently reviewed (27). However, these connections are likely to affect
other cell cycle kinases. When the cell enters the cell cycle,
enormous changes take place in catabolic and anabolic processes to facilitate duplication of the genome and biosynthesis of cellular structures and organelles. It is therefore
expected that cell cycle kinases may have direct or indirect
roles in controlling enzymes required for biosynthesis. As
an example, the yeast Cdk1 phosphorylates Pho2, a transcription factor involved in the expression of purine and
histidine biosynthesis genes, as well as Tgl4 and Smp2, two
proteins involved in fatty acid synthesis (181, 194, 289). In
988
B. Hematopoiesis
Hematopoiesis is a durable process throughout the lifespan
of an animal. As discussed above, the proliferative potential
of hematopoietic stem and progenitor cells must be tightly
regulated to maintain the capacity of producing the proper
cell populations upon a variety of conditions. The control
of proliferation by G1/S regulators during hematopoiesis
has been deeply reviewed (312). In general, maturation and
terminal differentiation are accompanied by an increase in
Cdk inhibitors and an overall falloff in Cdk activities. In
many cases, this is required for pRb-mediated terminal differentiation through its effects on tissue-specific transcription factors such as GATA-1, the master transcription factor of erythropoiesis (161, 273), or in mitochondrial biogenesis (284).
Among the Cdks, Cdk6 seems to play specific roles in the
hematopoietic system (FIGURE 5). Cdk6-deficient mice display specific alterations in erythropoiesis and T-cell function, whereas all other tissues display normal morphology
and function (135, 215). Conversely, knockin mice expressing a hyperactive Cdk6 mutant (Cdk6R31C) insensitive to
Ink4 inhibitors develop T-cell hyperplasia and lymphoma
(E. Rodriguez, V. Quereda, and M. Malumbres, unpublished information). Cdk6 has been proposed to play specific roles in preventing hematopoietic differention that are
not shared by Cdk4 (114). In fact, Cdk6 may directly inhibit transcriptional activation by Runx1, a transcription
factor required for the opening of chromatin of important
hematopoietic regulator genes, thus inhibiting myeloid lineage-specific gene expression and terminal differentiation.
Interestingly, this function does not require Cdk6 kinase
activity and is therefore independent on pRb function
(100).
Not only G1 kinases are able to modulate the hematopoietic
system. The inhibition of mitotic kinases, which is lethal in
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
Cdk4-deficient mice die of diabetes due to defective proliferation of postnatal pancreatic beta cells, whereas the expression of the hyperactive Cdk4R24C results in insulinoma
(270). Cyclin D1 or D2 specifically activate Cdk4 to promote proliferation of pancreatic beta cells and to facilitate
the activation of the proper progenitors in the ductal epithelium (182, 188). This function is probably mediated by
the pRb-E2F pathway as E2f1/E2f2-double knockout mice
display similar insulin-deficient diabetes accompanied by
reduction in the number and size of pancreatic islets (147).
Cdk6 is not expressed in these cells in the mouse (thus
explaining the strong phenotype in Cdk4-deficient mice;
Ref. 222), whereas it seems to be a major component of the
G1/S machinery in human pancreatic ␤-cells (92). Reexpression of Cdk6 in mouse pancreatic ␤-cells using transgenic
mice mostly rescues the pancreatic defects in Cdk4-null
mice (J. Martín and S. Ortega, personal communication),
thus suggesting the compensatory role between these two
kinases.
mammals, the Cdk4/pRb/E2F pathway is also known to
regulate adipogenesis through complementary mechanisms. Cdk4 directly promotes adipogenesis by phosphorylating pRb and activating E2F function (1). E2F transcription factors regulate adipogenesis through modulation of
the expression of the nuclear receptor PPAR␥, which is a
well-established master regulator of adipogenesis (88).
PPAR␥ and pRb form a repressor complex with the histone
deacetylase HDAC3, and this complex is dissociated after
phosphorylation of pRb by Cdks, resulting in adipocyte
differentiation (87). At least Cdk9, Cdk4, and its regulator
cyclin D3 are adipogenic factors with strong effects on metabolism through modulation of PPAR␥ activity (1, 146,
290). In addition, the direct phosphorylation of PPAR␥ by
Cdk5 leads to dysregulation of a large number of genes
whose expression is altered in obesity, and it may be therefore involved in the pathogenesis of insulin resistance (64).
CELL CYCLE KINASES
How cells regulate polyploidization or endomitosis is not
clear at present, although several evidences suggest that
specific mitotic kinases may be inhibited to allow normal S
phases without concomitant mitosis or without cytokinesis.
As described above, most of these evidences come from in
vitro assays, and further in vivo information from mouse
models will be required. The only addition to this scenario
from human disease comes from a syndrome of thrombocytopenia chraracterized by abnormal platelet numbers in
affected patients. This syndrome has been recently linked to
a mutation in Mastl (102), a kinase involved in the maintenance of mitotic Cdk-dependent phosphosites through inhibition of the Cdk-counteracting PP2A (48, 341). In fact,
in vivo inactivation of Mastl in zebrafish results in deficiency of circulating thrombocytes (157), although the putative links between the cell cycle-dependent function of
Mastl and its role in thrombocytopenia remain to be established.
C. Cardiac Function and Related Pathologies
The control of the cell cycle in cardiac cells is of considerable interest, given the high prevalence of cardiac abnormalities among humans. Cell proliferation plays a key role
in heart formation during development, although adult cardiomyocytes are thought to be terminally differentiated.
Myocardial cells maintain the proliferative potential until
just after birth in mammals, when nearly all exit the cell
cycle (4, 109). Hand1, a basic-helix-loop-helix transcription factor required for establishing the correct length of the
early heart tube, promotes G1/S transition in the embryo
cardiac cells by inducing cyclin D2 and Cdk4 (276). Al-
though Cdk4-null mice do not display any obvious cardiac
phenotype, double Cdk4;Cdk2-null mice die during late
development or perinatally due to cardiac defects, suggesting compensatory roles between these two kinases in cardiac cell proliferation (19, 24) (FIGURE 5). Similarly, transgenic mice with increased Cdk4 (overexpressing cyclin D1
or D2) or Cdk2 activity result in increased cardiac myocyte
number (192, 254, 308). The relevance of other cell cycle
kinases during heart development is not well established,
although both Mps1 and Plk1 have been shown to be required for heart regeneration in zebrafish (159, 263, 264).
Whether these requirements reflect the essential roles of
these proteins during mitosis or heart-specific functions is
not clear at present.
In postnatal hearts, the predominant form of growth is not
cell division but an increase in cell size (hypertrophy). This
change in the regulation of the cell cycle is not well understood but is preceded by a round of acytokinetic mitosis in
which cardiac myocytes generate two nuclei after chromosome segregation without cytokinesis. Thus it is generally
assumed that adult cardiomyocytes have very limited potential for self-renewal, and this is a major factor that prevents proper repair of the mammalian heart after injury.
Most G1 cyclins and Cdks are not expressed in adult cardiomyocytes and, conversely, several Cdk inhibitors are present in these cells (4). Entry into the cell cycle after injury or
re-expression of cell cycle proteins frequently leads to DNA
replication and increase in ploidy. However, cytokinesis is
not observed under these circumstances. The molecular basis for this defect is not well understood, and the activity of
cytokinesis kinases (FIGURE 1) has not been properly tested in
these cells. Only Plk1 has been shown to be downregulated in
the adult heart (105). The decrease in activation of the Rho
GTPase pathway, a target of Plk1 and Aurora B during cytokinesis, may also be responsible for the defects in the formation of the actomyosin ring in these adult cells (4).
These data may have relevance in the clinic as hypertrophic
growth is a common pathology in humans. This hypertrophic growth is commonly accompanied by the upregulation
of G1 cyclins and Cdks and the cyclin D-Cdk4/2-pRB pathway is likely to regulate cardiac myocyte size and hypertrophic growth (11, 193, 373). Interestingly, this process is
also accompanied by the activation of the other class of
Cdks, the transcriptional Cdks such as Cdk9. Cdk9 phosphorylated the COOH-terminal domain of RNA polymerase II, and its activity is derepressed in a number of models
of cardiac hypertrophy conferring a predisposition to heart
failure (285, 286).
The therapeutic application of all this information is still in
its infancy. On one hand, the overexpression of cyclin D2,
but not D1 or D3, in a mouse model of myocardial infraction promotes cell cycle entry and cardiac function (121,
254), suggesting that cell cycle-based strategies aimed to
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
989
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
most other cells, has been proposed to mediate the physiological increase in ploidy in specific cells such as megakaryocytes. These cells undergo polyploidization, which is characterized by DNA duplication without concomitant cell division. This process affects multiple cell types also during
development; for instance, trophoblast giant cells are
thought to be produced in the early embryo due to p57Kip2specific inhibition of Cdk1 (335). Megakaryocytic polyploidization was initially thought to be accompanied by
repression and/or mislocalization of Aurora B kinase (165,
371). Recent data, however, suggest that Aurora B is dispensable for polyploidization but contributes to endoreplication in these cells by unknown mechanisms (200). Other
cell cycle kinases such as Plk3, Aurora A, and BubR1 are
also thought to modulate polyploidization (138), although
the molecular pathways regulating this special cell cycle are
poorly understood. BubR1 protein levels decrease during
polyploidization (138) and, in fact, BubR1(⫹/⫺) mice display an increase in the number of splenic megakaryocytes
and megakaryocytic progenitors in bone marrow cells. This
enhanced megakaryopoiesis in BubR1(⫹/⫺) mice is not
completely functional due to a defect in the formation of
proplatelet-producing megakaryocytes (346).
MARCOS MALUMBRES
increase Cdk4/2 activity can be exploited to drive myocardial repair following injury. On the other hand, the overactivation of some of these kinases, such as Cdk9 (and perhaps Cdk4/2), may lead to hypertrophic growth and, in
fact, inhibition of Cdk9 may have potential therapeutic
value (347). In addition, the CAK-related kinase Cdk20
promotes cardiac growth and has been found to be specifically downregulated in heart failure after myocardial infarction (267).
D. The Nervous System and Neuron
Function
Microcephaly is a human syndrome characterized by reduced brain size and mental retardation that may be caused
by mutations in at least five known genes (MCPH1–5)
(323). Interestingly, all proteins encoded by these genes are
centrosomal, although the significance of this finding is still
unknown. MCPH3 is also known as Cdk5Rap2 (or
Cep215), a protein that binds Cdk5 at the centrosome
(277). In addition, at least two of the MCPH proteins,
Aspm (MCPH5) and Cdk5Rap2, are regulated by Plk1 (79,
112, 118). Recently, Cdk19 has also been identified as the
target of an inversion in chromosome 6 that leads to microcephaly and mental retardation in human patients (239).
These data suggest putative functions of Cdk5 or Plk1, in
addition to Cdk19, in mammalian neuroblasts (FIGURE 4),
and the implications of these kinases in microcephaly deserve further research efforts.
In addition to the implication of cell cycle kinases as regulators of cell proliferation in the developing or regenerating
nervous system, recent observations have proposed new
roles for these regulators in neuron function that are totally
uncoupled from cell division. The pionneer work on Cdk5
led to the identification of this protein as a kinase critical for
990
Both Plk2 and Plk3, the lesser known Polo-like kinases,
participate in neuron structure and synaptic plasticity, and
the conserved Polo-box-domain (PBD) is involved in this
neuronal function (163). Plk2 and Plk3 mRNAs increase in
response to neuronal activity, and both proteins bind to
Cib, a calcium- and integrin-binding protein. Plk2 specifically controls the protein levels of Spine-associated Rap
guanosine triphosphatase activating protein (SPAR), and
this mechanism is thought to be essential for homeostatic
plasticity, i.e., the normalization of synaptic activity to
within an optimal range in the face of chronic excitation
or depression (252). As in the case of Plk1 substrates,
SPAR needs to be primed by other kinases. Whereas the
major priming kinase for Plk1 is Cdk1, Cdk5 performs a
similar role in neurons by phosphorylating SPAR and
priming it for Plk2-dependent phosphorylation (298).
Thus Plk2 is a critical kinase for plasticity of hippocampal neurons during epileptiform activity and chronically
elevated activity (298, 300). Plk2, as well as Plk1 and Plk3,
also phosphorylate the neuronal ␣-synuclein, a phosphoprotein accumulated in several neurological diseases such
as Parkinson’s and dementia with Lewy bodies (148,
228). Plks specifically colocalize with phosphorylated
␣-syn in primary neurons as well as in ␣-syn transgenic
mice, especially cortical brain areas involved in synaptic
plasticity. Furthermore, Plk2 is significantly increased in
brains of Alzheimer’s disease and Lewy body disease patients (228). The newest member of the Plk family, Plk5, is
mostly expressed in the adult murine and human brain and
may modulate neurite formation in established cell lines
and primary neurons (72). As suggested for Plk2 and Plk3,
this function is also likely to be dependent on the PBD as
human Plk5, which does not contain the kinase domain,
also modulates neurite formation. Thus it is tempting to
speculate that Plk5 has evolved as a kinase-deficient Plk-
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
The role of cell cycle kinases in the proliferation of neural
progenitors has been described above (see sect. III). Both the
G1/S machinery (Cdk2, -4, and -6) and the mitotic kinases
possibly involved in neural asymmetric cell division (Cdk1,
Aurora A, and Plk1) may modulate the development of the
nervous system and the production of new neurons from
progenitor cells. In terminally differentiated neurons, reentry into the cell cycle frequently triggers neuronal death
instead of proliferation, which may be related to some acquired and neurodegenerative disorders. In neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Niemann-Pick disease type C, some populations of neurons complete DNA
synthesis, but the cell cycle is arrested at the G2/M transition
(99). Whether inhibition of these cell cycle kinases may
protect adult neurons or progenitor cells from entering
and/or progressing through the cell cycle thus preventing
neurodegeneration is an attractive hypothesis that deserves
further research in the upcoming years.
correct migration during cortical development (55, 76).
Cdk5 is mostly expressed and active in postmitotic neurons
that express p35 and p39, the noncyclin activators of Cdk5.
Cdk5 is therefore mostly inactive in proliferating cells despite the fact that it can bind D-type cyclins and phosphorylate the pRb protein upon specific conditions. A number of
studies have uncovered critical functions for Cdk5 in neurite growth, neuronal survival, and synaptic plasticity both
in developmental and adult neurogenesis, and this protein
has been proposed as a therapeutic target in neurodegenerative diseases (156, 328). Cdk5 also suppresses the neuronal cell cycle by sequestering E2F1 into Cdk5-p35-E2F1
complexes that are transcriptionally inactive and therefore
disrupting the active E2F1-DP1 complexes (370). This anticell cycle activity is most likely a neuroprotective function
of Cdk5. Although no other Cdks have been shown to share
these functions, it is worth noting that some less-studied
Cdks, such as Cdk16 –18, may also interact with the p35
activator subunit (213), and Cdk20 is subjected to specific
epigenetic regulation in the brain (89).
CELL CYCLE KINASES
family member whose activity mostly depends on proteinprotein interactions mediated by the PBD (72).
Because many mitotic kinases regulate centrosome and
microtubule dynamics (required for the formation of the
mitotic spindle), it is possible that these proteins may also
regulate microtubule dynamics in neurons, given the relevance of this process in axon and dendrite function. It is
not surprising therefore that the single polo kinase present in yeast has evolved to form four additional paralogs,
three of which display specific neuronal functions. In addition, several Nek kinases are specifically expressed in the nervous system (14), and Nek3 seems to be especially relevant to
regulate microtubule acetylation in neurons (59).
E. Germ Cells and the Generation
of Aneuploidy
From a physiological point of view, the production of
aneuploidy in specific somatic cell types does not have
major consequences (unless these alterations are perhaps
combined with other mutations that may lead for instance to cancer; see sect. V). However, chomosome segregation fidelity is particularly important in meiosis and
during development when the embryo undergoes rapid
cellular divisions, since these defects may lead to aneuploid individuals. Aneuploidy is the most common genetic
disorder affecting human reproduction, and ⬃25% of
human zygotes generated are thought to be aneuploid
(122). These embryos are usually lost as spontaneous
abortions, and only trisomies of chromosomes 13, 18, or
21 and aneuploidies of the sex chromosomes are compatible with life. It is well known that these abnormalities
correlate with maternal age, and several cell cycle kinases
and specifically checkpoint kinases are thought to play
critical roles in preventing these defects.
The alteration of mitotic checkpoint kinases also results
in significant abnormalities during meiosis. BubR1 haploinsufficiency causes progressive aneuploidy, along with
a variety of progeroid features, and both male and female
mutant mice have defects in meiotic chromosome segregation and are infertile (16). On the other hand, perturbation of the kinetochore localization or activity of Bub1
leads to acceleration of meiosis I and increase in aneuploidy in female germ cells associated with the premature
separation of sister chromatids (189, 229). Mutation in a
single copy of Bub1 is sufficient to produce this phenotype, and these defects are stronger in female mice with
advanced age (189). Both Bub1 and Mad2 phenotypes in
aneuploidy are stronger in oocytes than in sperm. Although the molecular reason behind this observation is
not clear, these data clearly establish the relevance of
reduced SAC function in oocytes as a function of age and
the consequences in pregnancy loss in humans (220). As
described above, a hypomorphic mutation in Mps1 also
results in reduced checkpoint activity and aneuploid
progeny in zebrafish (263), although no in vivo models
for this protein have been described in mammals.
V. CELL CYCLE KINASES AND CANCER
A plethora of studies on the cyclin-Cdk-pRb pathway in
human tumors have led to the proposal that G1/S regulation
is altered in almost every human tumor. More than 80 –
90% of tumors from different origin display altered Cdk4/
6/2 kinase activity (212). As described in the previous sec-
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
991
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
Whereas Aurora B expression seems to be restricted to
proliferating cells, Aurora A is expressed in the hippocampus and is enriched at the postsynaptic compartment. The stimulation of glutamate receptors results in
Aurora A activation and phosphorylation of CPEB-1, a
protein involved in translation by direct binding to specific elements in the mRNAs. This activation leads to
increased polyadenylation and translation of ␣CaMKII,
a mechanism with potential implications in hippocampal
long-term potentiation (140). More recently, the activity
of Aurora A has also been linked to microtubule dynamics of postmitotic neurons. In dorsal root ganglia neurons, aPKC phosphorylates Aurora A resulting in increased autophosphorylation of this kinase and binding
to its activator Tpx2. Aurora A-Tpx2 complexes localize
to the spindle where Aurora A subsequently phosphorylates the peptidase Ndel1, a protein that associates with
dynein and promotes neurite outgrowth (235, 236).
All mitotic kinases discussed here (e.g., Polo, Aurora, or
checkpoint kinases) play also major roles during meiosis.
The case of Aurora C is particularly interesting as the
expression of this protein is mostly restricted to germ
cells and early developing embryos (22, 329, 360; G.
Fernández-Miranda, M. Trakala, I. Pérez, M. Malumbres, unpublished data). Genetic ablation of murine Aurora C results in partial sterility due to minor defects in
sperm morphology (172), although the interpretation of
this phenotype may been complicated by the presence of
multiple Aurora C copies in the mouse genome (134).
Microinjection of a kinase-deficient Aurora C mutant
into mouse oocytes causes multiple defects, including
chromosome misalignment, abnormal kinetochoremicrotubule attachment, premature chromosome segregation, and cytokinesis failure in meiosis I. In addition,
histone H3 phosphorylation and kinetochore localization of Bub1 and BubR1 are inhibited, suggesting a significant impairment in CPC function (360). Interestingly,
a homozygous mutation (c.144delC) in the human Aurora C gene leads to meiosis I arrest or the production of
large-headed multiflagellar polyploidy spermatozoa in
patients showing sterility (77, 78). These data suggest
that Aurora C is a critical regulator of genomic instability
during meiosis despite its limited activity in mitotic cells.
MARCOS MALUMBRES
tions, the hyperactivation of these G1 kinases may lead to
increased proliferation of differentiated cells that otherwise
divide very rarely (e.g., endocrine cells), or the increased
entry into the cell cycle of cells that were terminally differentiated. In addition, we now understand that the capacity
for self-renewal of progenitor/stem cells presents a risk to
the organism since diverse pathologies, including cancer,
may be induced if this property is not properly controlled.
A. Oncogenes or Tumor Suppressors?
3. Polo-like kinases
1. Cdks
Plk1 is also overexpressed in several tumor types
and it is currently considered as a relevant oncogene and cancer target (73, 313) (see below). However,
an interesting observation about the oncogenic or tumorsuppressor role of Polo-like kinases comes from genetic and
epigenetic studies in the other Plk family members. Loss of
heterozygosity (LOH) occurs at the Plk4 locus in 50% of
human hepatocellular carcinomas (HCC) and is present
even in preneoplastic cirrhotic liver nodules, suggesting that
Plk4 may function as a tumor suppressor gene. This alteration is associated with reduced Plk4 expression in HCC and
Plk4(⫹/⫺) cells display a high incidence of multinucleation,
supernumerary centrosomes, and a near-tetraploid karyotype, probably as a consequence of defective RhoA signaling and cytokinesis failure (176, 278). Yet, the human Plk4
gene is overexpressed in multiple neoplasias (FIGURE 6), and
Plk4 overexpression is likely to result in similar defects in
genomic stability. Plk4 may also be silenced by promoter
hypermethylation in HCC (256). Similarly, Plk2, Plk3, and
Plk5 may also be considered as tumor suppressors as they
are silenced by epigenetic means in glioblastoma as well as
hematopoietic and liver tumors (72, 256, 319). In fact,
overexpression of Plk2, -3, -4, and -5 results in cell cycle
inhibition and apoptosis in the case of Plk5, suggesting the
possible therapeutic value of reexpressing these proteins in
tumors (72, 256). In addition, Plk3-deficient mice develop
increased susceptibility to spontaneous tumors, further suggesting a tumor suppressor role for this protein (361). It is
interesting to note that only a few point mutations have
(FIGURE 6),
Extensive data on the alteration of G1 Cdks in cancer,
mostly Cdk4 and Cdk6, are already available (209, 211,
212). The causal involvement of other Cdks in cancer development is not well documented. Cdk1 is overexpressed
in multiple tumors (FIGURE 6), and it is part of the genetic
signature associated with chromosomal instability in tumors (47, 258). Some transcriptional Cdks have been proposed as cancer targets due to its relevance in transcription
(Cdk9) or in the activation of the other Cdks (Cdk7), but
they are not commonly altered in human tumors. Cdk8 has
been recently proposed as a critical oncogene in colorectal
cancer by regulating ␤-catenin activity (93, 237). Cdk8 represses E2F1 activity protecting ␤-catenin/TCF-dependent
transcription from inhibition by E2F1, thus explaining why
colorectal tumors, which depend on ␤-catenin transcription
for their abnormal proliferation, keep pRb intact (237).
Among the less studied Cdks, Cdk20 has been shown to
function as an oncogene in glioblastoma (244), ovarian carcinoma (355), and colorectal cancer (7). Cdk20, which is
highly similar to Cdk7, supports proliferation in these tissues by regulating Cdk2, cyclin E, and pRb function, probably through its Cdk-activating kinase activity.
2. Aurora
Overexpression of Aurora A and B has been observed
in several tumor types and has been linked with a poor
992
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
The involvement of centrosomal and mitotic kinases has
been controversial, since the initial studies failed to find
mutation in these genes in clinical samples. The essential
role for most of these kinases in the cell cycle indicates that
complete loss-of-function mutations (homozygous null mutations or whole gene deletions) are not likely to occur in
cancer cells as these alterations would be deleterious for
tumor growth. On the other hand, tumor-associated overexpression is common for several of these genes (73, 258),
although the causal effect of this alteration in tumor growth
is always difficult to evaluate. More recently, additional
specific point mutations or polymorphisms have been described in several cell cycle kinases (TABLE 3), and only the
most relevant or new data and its significance in cancer and
therapy will be discussed below.
prognosis of cancer patients (104, 258). Overexpression or
amplification of Aurora A has been identified in breast,
lung, head and neck, and colon cancers. Aurora B is similarly overexpressed in lung tumors, glioblastoma, and oral
squamous cell carcinoma (FIGURE 6). However, perhaps the
most interesting information about Aurora A and tumor
development was generated in a genetic screen for skin tumor susceptibility genes in the mouse. Aurora A was identified as a low-penetrance tumor susceptibility gene in
mouse and human tumors (85), and specific polymorphisms
for Aurora A have been later described in multiple tumor
types such as hepatocarcinoma and prostate, pancreas,
colorectal, lung, gastric, breast, and esophageal cancer (5,
54, 61, 86, 160, 173, 199, 224, 230, 316). A polymorphism
in Aurora B may also modulate tumor outcome in breast
tumor patients (322). Finally, a mutation in the gene encoding Aurora C has also been described in lung tumors (71).
Although the molecular basis for the effect of these polymorphisms in cell cycle progression is mostly unknown, this
information suggests that minor changes in kinase function
in critical mitotic regulators may have relevant implications
in tumor development. Typical molecular pathology techniques currently used in the clinic are not likely to identify
these alterations, and the way is now open for genetic association studies.
CELL CYCLE KINASES
Table 3
Human Gene
Human
Chromosome
Alteration of cell cycle kinases in human disease
Genetic or Epigenetic
Alteration
Disease
Reference Nos.*
Glioblastoma
Glioma
Melanoma
Several neoplasias
Melanoma and brain tumors
Hematopoietic disorders
Intestine and lung tumors
Microcephaly
Melanoma and brain tumors
Cosmic
Cosmic
354
Reviewed in Ref. 211
Cosmic
Reviewed in Ref. 211
Cosmic
239
Cosmic
Cyclin-dependent kinases
CDK2
CDK3
CDK4
12.q13.2
17q25.1
12q14.1
CDK6
7q21.2
CDK8
CDK19 (Cdc2L6)
13q12.13
6q21
Aurora kinases
AURKA
20q13.2
AURKB
AURKC
17p13.1
19q13.43
Amplification
S155R, S398L, V174M,
and ns
V57M, E274Q
c.144delC
G18E, E114Q, H210Q
Multiple neoplasias
Intestine, skin, and lung
tumors
Lung and brain tumors
Sterility
Lung tumors
26
Cosmic
Cosmic
77, 78
Cosmic
Polo-like kinases
PLK1
16p12.2
PLK2
5q11.2
PLK3
PLK4
PLK5
1p34.1
4q28.2
8q12.3
Several point mutations
R12L
Hypermethylation
G92S, S14T, and fs
Hypermethylation
LOH, hypermethylation
Hypermethylation
Carcinoma cell lines
Lung tumor
Hematopoietic, liver tumors
Lung and ovary tumors
Liver tumors
Hepatocellular carcinoma
Glioblastoma
Simizu et al., 2000
Cosmic
319
Cosmic
256
176, 256
72
Checkpoint kinases
BUB1
BUB1B (BubR1)
TTK (Mps1)
2q13
Several point mutations
and hypermethylation
15q15.1
6q14.1
Point mutations
Hypermethylation
fs mutations in A9 and
A7 repeats
Several tumor
types(colorectal, lung
thyroid, T cell leukemia)
Mosaic variegated
aneuploidy and premature
chromatid separation
syndromes
Colon carcinoma
Gastric, pancreas, ovary
and colorectal tumors
303 Reviewed in Ref.
258. Cosmic
117, 226
303
3, 46 Cosmic
Replication kinases
CDC7
1p22.2
G119E and fs
Spontanous mutations in
stomach, intestine and
brain tumors
Cosmic
Nima-related kinases
NEK6
9q33.3
I99S
NEK7
1q31.3
I275M and ns
Spontanous mutations in
kidney tumors
Spontanous mutations in
lung and ovary tumors
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Cosmic
Cosmic
993
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
P45L
S106N
R24C, R24H, N41S
Amplification
P199L and fs
translocation
R424C; D189N
Inversion
G175S, A395V
MARCOS MALUMBRES
Table 3—Continued
Human Gene
Human
Chromosome
Genetic or Epigenetic
Alteration
NEK8
17q11.2
L621F, R282Q and fs,
NEK9
14q24.3
P870S and fs
Disease
Spontanous mutations in
ovary, skin and stomach
tumors
Spontanous mutations in
lung and ovary tumors
Reference Nos.*
Cosmic
Cosmic
Phosphatase-inhibiting kinases
MASTL
10q12.1
CHECK
D854N and fs
Thrombocytopenia;
Spontaneous mutations in
stomach and lung tumors
Cosmic
been found in the Plk1 locus in tumor cells. Interestingly,
these mutations result in increased Plk1 protein instability
(306). Plk1(⫹/⫺) mice also display increased susceptibility
to tumor development (203; P. Wachowicz, G. de Cárcer,
and M. Malumbres, unpublished information), thus raising
the question whether Plk1 may also function as a tumor
suppressor.
4. Mitotic checkpoint kinases
All the three mitotic checkpoint kinases, Bub1,
BubR1, and Mps1, are overexpressed in multiple tumor
types (FIGURE 6). Yet, all these three kinases display lossof-function mutations in human tumors. Bub1 mutations
were originally found in a pioneer analysis of mitotic checkpoint genes in tumors with microsatellite instability (40).
Multiple genetic and epigenetic alterations have been described in Bub1 and BubR1 in a variety of human cancers
(258). Mutations in BubR1 are associated with the cancersusceptible disorders mosaic variegated aneuploidy (MVA)
and the premature chromatid separation syndrome (117,
226). These individuals are predisposed to develop childhood cancer including rhabdomyosarcoma, Wilms tumor,
or leukemia (117). Cell lines derived from MVA patients
with biallelic mutations have an impaired mitotic checkpoint, chromosome alignment defects, and low overall
BubR1 abundance, resulting in premature sister-chromatid
separation and aneuploidy (29, 315). Both Bub1 and
FIGURE 6 Expression of cell cycle kinases in human cancer. Red cells indicate overexpression, whereas
downregulation is indicated by blue cells for each tumor type. The figures within the cells indicate the number
of studies where these changes are statistically significant (P ⬍ 0.0001) versus the total number of studies
including the corresponding probe. Cell color is determined by the best gene rank percentile for the analysis
within the cell. Data are from Oncomine (www.oncomine.org). No significant differences were found for Plk5
(LOC126520) or Nek8 under these criteria. Other kinases not indicated in the figure were not analyzed.
994
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
fs, Frameshift; ns, nonsense mutation. *Cosmic database: http://www.sanger.ac.uk/genetics/CGP/cosmic.
CELL CYCLE KINASES
BubR1 hypomorphic mice display increased susceptibility
to develop spontaneous or induced tumors (16, 70, 154,
271).
1. Inhibiting cell cycle entry or progression
The critical roles of multiple cell cycle kinases in the
progression throughout the cell cycle suggest that their inhibition may arrest tumor cell proliferation. In fact, inhibition of a number of these kinases or suppression of their
expression by a variety of techniques results in cell cycle
arrest or apoptotic cell death in culture. Those cases in
which the elimination of a cell cycle kinase resulted in no
cell-cycle defects are likely to be due to the presence of
multiple family members or compensatory roles by other
kinases.
5. Other cell cycle kinases
Cdc7 is overexpressed in some tumor types (30, 97,
180), and the corresponding locus is amplified in breast
tumors (65). Nek2, -6, and -8 are upregulated in several
cancers (33, 123, 124), and a specific mutation of Nek8
has also been proposed to drive pancreatic cancer (46).
Nek2 has been shown to mediate certain oncogenic activities of the Ras oncogenes (369), and it may contribute
to aneuploidy through its regulation of Mad2 and Cdc20
(196). Nek6 induces anchorage-independent growth and
has been show to display transforming potential in vitro
(155, 242).
B. Therapeutic Approaches
The almost obligatory alteration of the G1/S machinery in
tumors triggered an enormous interest to inhibit cell cycle
kinases in cancer therapy, even before the requirements for
these kinases were analyzed in vivo (208, 212). On the other
hand, the essential requirements that most cells, either normal or tumoral, have for mitotic kinases such as Aurora A/B
or Plk1 also led to the incorporation of these molecules to
the pipeline of major pharmaceutical companies. Both efforts respond to the necessity to impair cell proliferation,
even if the targeted molecules themselves are not a frequent
target of tumor-associated mutations, as in the case of Aurora or Plk1. Even more paradoxically, some targets such as
the checkpoint kinases are clearly tumor suppressors (upon
partial inhibition) and, yet, their further inhibition is likely
to impair proliferation of cancer cells. A second class of
therapeutic strategies is based on the abrogation of the cell
cycle checkpoints, initially proposed for selecting DNA
damage response kinases for cancer therapy (164, 280).
These strategies are based on the idea that inactivating the
checkpoints in rapidly proliferating cells may lead to the
accumulation of DNA damage and genomic instability in
these tumor cells. In both cases, kinases have been selected
In the case of the large family of mammalian Cdks,
these compensatory roles have been at least partially analyzed through the use of mouse knockout models (209,
211). Thus, although Cdk2 was initially one of the major
targets for inhibiting G1/S progression in tumor cells, the
discovery of its complete dispensability during mitosis in
mammals (23, 251) was critical to reevaluate which of
the G1 Cdks may be more relevant for cancer therapy.
The answer is likely to depend on the cell of origin of the
tumor and the genetic background that drives malignancy in these cells (214). For instance, Cdk6 is likely to
be a major target for lymphoid malignancies (135),
whereas Cdk4 may be a relevant target in multiple epithelial tumors (214). The best demonstration that Cdk4
is required for specific malignancies comes from the genetic elimination of this protein in several tumor types
induced by specific oncogenes. The pioneer work by P.
Sicinski group showed that cyclin D1 is required for Rasbut not Myc-induced breast tumors (366), and this requirement was later attributed to the cyclin D1-dependent kinase activity of Cdk4 (184, 210, 367). In the lung,
genetic ablation of Cdk4, but not Cdk2 or Cdk6, induces
an immediate senescence response only in oncogenic lung
cells that express an endogenous K-Ras oncogene (266).
This result demonstrates the relevance of Cdk4 to prevent senescence induced by oncogenes in vivo and the
relevance of Cdk4 to arrest tumor development induced
by Ras oncogenes. Cdk2 may play similar roles downstream of the Myc oncogene as Cdk2 ablation prevents
senescence in Myc transformed cells (43, 145). These
studies are likely to strongly contribute to the adequate
design of therapeutic strategies aimed to inhibit Cdk4 in
the right tumor cell, i.e., proper selection of the tumor
type and the initiating oncogenic alterations (214). Other
therapeutic efforts to inhibit Cdk2, Cdk1, or Cdk5 have
also resulted in promising data in different preclinical
assays (81, 91, 110), although the identity of the relevant
target in these studies is in most cases compromised due
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
995
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
More recently, these observations have been extended to
the Mps1 kinase. The human Mps1 gene contains several
mononucleotide repeats (A9 and A7 repeats in exon 5) which
harbor frequent (⬃35%) mutations in gastric and colorectal
tumors with microsatellite instability (3). All these alterations
are frameshift mutations that result in premature stops of
Mps1 protein synthesis. Mps1 mutations also have putative
driver oncogenic potential in pancreatic cancer (46). As discussed above for Plk1 or Plk4, overexpression of these checkpoint kinases in human cancer (FIGURE 6) represents either a
passenger alteration or suggest that both loss- and gain-offunction alterations in these proteins may cooperate in tumor
development.
as prime targets for these therapeutic efforts given the relative simplicity of obtaining small molecule inhibitors of the
kinase activity. Finally, we will discuss new proposals to
disrupt mitotic exit, thus leading to apoptotic cell death in
tumor cells.
MARCOS MALUMBRES
to the lack of specific compounds or the use of in vitro
systems. Similarly, transcriptional Cdks are also considered as putative cancer targets, although no data are
available on the recommended therapeutic uses of these
strategies (41, 347).
Several small molecules targeting Aurora kinases A
and B or Plk1 have been evaluated preclinically and in
early-phase trials (31, 259). Inhibition of Aurora activity
leads to failure in chromosome segregation, accumulation of tetraploid cells, and ultimately apoptosis, preferentially in cells with compromised p53 function (279).
Several Aurora inhibitors have been tested in clinical trials so far. Most of them inhibit all Aurora kinases as well
as other kinases such as Abl, Ret, Flt3, or Jak kinases.
Neutropenia is the most common toxicity, and some partial responses and stable disease have been described,
although it is currently impossible to discriminate
whether the effective targets are Aurora kinases or some
other leukemia targets such as Abl (31). Aurora A-specific inhibitors (MLN8054 and MLN8237; Millenium
Pharmaceuticals) have also shown partial stabilization of
the disease in phase I clinical trials and need to be further
analyzed in new trials. The Aurora B-specific inhibitor
AZD1152 (AstraZeneca) also showed stabilization of the
disease in ⬍50% of patients (31). Most of these treatments resulted in neutropenia, a dose-limiting side effect
of several anticancer drugs. Inhibition of Aurora kinases
does not result in thrombocytopenia, probably as a consequence of the natural downregulation of these kinases
and subsequent polyploidization during maturation of
megakaryocytes (165). In general, it is too early to evaluate the advantage of using these drugs, and further studies are required. Indeed, a plethora of additional Aurora
inhibitors have demonstrated antitumoral effects in preclinical assays but have not entered clinical trials yet.
Several Plk1 inhibitors (BI-2536, GSK-461364, ON01910, and HMN-214) have been studied in clinical trials, and some other drugs are in development (75, 296).
In general, these inhibitors showed partial antitumor activity in the first clinical trials enrolling patients with
advanced solid tumors and refractory or relapsed acute
myeloid leukemia. Adverse events included neutropenia
and other hematologic toxicities narrowing the therapeu-
996
Only preliminary in vitro studies are available for
other cell cycle kinases due to the lack of specific compounds or in vivo models. Nek kinases are putative cancer targets as suggested from multiple in vitro data (124,
177, 242, 331), and the first efforts to identify specific
inhibitors have been recently reported (125). The discovery of a new molecular mechanism of regulation of Nek2,
Nek6, and Nek7 kinases (274) has also opened the way
for the search of specific inhibitors of these proteins that
do not target other kinases.
Recent data also suggest that Mastl, the mitotic kinase that inhibits PP2A (38, 48, 341), may also be a
relevant target for anticancer therapy. Inactivation of
Mastl would be predicted to activate PP2A, a wellknown tumor suppressor (82), and to inhibit mitotic progression in dividing cells (38). Furthermore, the combination of Mastl inhibitors with Cdk1 inhibitors may be
of particular efficacy in preventing the division of cancer
cells by lowering Cdk1 activity and increasing the activity of the PP2A that remove Cdk-dependent phosphates
in critical cell cycle substrates.
2. Checkpoint abrogation
The primary function of the SAC is to prevent chromosome missegregation and genomic instability. As described above, several checkpoint proteins are mutated in
human cancer, usually as heterozygous, partial loss-offunction mutations. These abnormalities may eventually
participate in malignant transformation by allowing
chromosomal instability and the selection of malignant
chromosome arrangements. However, further disruption
of the mitotic checkpoint may also confer therapeutic
advantages by causing aberrant divisions and apoptotic
cell death in tumor cells. In fact, in the absence of a
functional checkpoint, as occurs when Bub1 or Mps1
function is lost, cells become rapidly aneuploid and subsequently die (152, 178). Thus elevating the frequency of
chromosome missegregation may be adopted as a strategy to kill tumor cells. This approach and the strong
requirements for Mps1 during the cell cycle have led to
an intense search for small molecule inhibitors for this
kinase (66, 67, 80, 183, 287, 295). Inhibiting these mitotic kinases is also likely to synergize with spindle damaging agents such as taxanes or vinca alkaloids as cells
with decreased levels of SAC proteins not only will experience defective microtubule-kinetochore attachments
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
Cdc7 cooperates with Cdks in the regulation of DNA
replication from licensed chromosomes and is completely
required for efficient S-phase progression (302). Multiple
recent studies have led to the proposal of Cdc7 as a new
important cancer target. Inhibition of Cdc7 kinase activity
results in a decrease of Mcm2 phosphorylation, restricts
DNA replication, and induces apoptotic cell death (60,
234). Several Cdc7 inhibtors have been analyzed in preclinical studies, and two of these inhibitors are currently in
phase I clinical development (233, 318).
tic index in these trials (75, 238, 297, 348). In the case of
Plks, additional efforts are ongoing to identify and validate small molecules that bind to the PBD to inhibit the
interaction of Plk1 with its partners (259). All these efforts, however, must take into account that inhibition of
Plk2, Plk3, Plk4, or Plk5 may lead to tumor development
as these less-known Plks may function as tumor suppressors in specific cell types as described above.
CELL CYCLE KINASES
but will also be unable to sense the errors, being thereby
highly prone to genetic instability. The clinical impact of
these proposals remains to be tested, but it is likely to
promote an intense research in the field in the next few
years.
3. Inhibiting cell cycle exit
The intense research on the regulation of the cell division
cycle has led to the discovery of a significant number of
genes and molecular complexes involved in cell cycle regulation (143, 243). For instance, ⬃600 human genes result in
mitotic phenotypes when inhibited by RNAi (243), and the
number of proteins potentially affecting G1/S regulation
(e.g., mitogenic pathways) is much higher. As an example,
7,161 gene products are classified as “cell cycle” molecules
in the Gene Ontology database (GO:0007049; http://www.
geneontology.org/). Similarly, multiple protein kinases are
likely to affect cell cycle progression at different levels. In
this review, we have selected those kinases whose main
function is to regulate the cell cycle by direct phosphorylation of critical components of the cell cycle machinery.
As a first conclusion from this review, three major groups of
cell cycle kinases can be established based on their function,
cellular requirements, and even therapeutic use: 1) kinases
required for cell cycle entry, 2) kinases required for cell
cycle progression, and 3) checkpoint kinases (FIGURE 7).
Cell cycle entry kinases (e.g., Cdk4/6) are typically inhibited
in quiescent cells, and their reactivation is responsible for
entry into the cell cycle in response to proper mitogenic
signals. These kinases are not required for the basic cell
cycle, for instance, in embryonic cells as these cells express
all the other regulators required for cell cycle progression
but do not express the repression machinery required for
differentiation. Thus, as suggested by Boveri more than a
century ago (32), cell division is part of the nature of the
cells, and the repression/derepression machinery is only required for regulating this intrinsic proliferative potential of
cells. Therefore, these kinases are likely to be crucial regu-
FIGURE 7 Essential roles and therapeutic
uses of cell cycle kinases in human cancer.
Inhibition of cell-cycle-entry kinases may arrest
tumor cells in G0/G1 without major damage,
although apoptosis is observed in some cases,
probably as a consequence of the survival function of E2F factors. Inhibition of core kinases
should prevent cell cycle progression as long
as all compensatory or related kinases are inhibited. This arrest is likely to lead to aberrant
ploidy or apoptosis as these cells already
started S phase. Checkpoint abrogation should
lead to genomic instability and apoptosis upon
continuous treatments. Other kinases or pathways not discussed in the main text (such as
DNA damage) are not considered here.
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
997
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
Many therapeutic strategies aimed to inhibit the cell
cycle result in arrested tumor cells that may eventually
reenter the cell cycle. A new therapeutic strategy has been
suggested in which tumor cells are allowed to progress
throughout the cell cycle, but mitotic exit is prevented by
impairing the APC/C-Cdc20-dependent degradation of
cyclin B (137). Thus elimination of Cdc20 by RNAi or
genetic ablation results in a dramatic metaphase arrest
that is followed by p53-independent apoptotic cell death
in every cell tested (137, 217). In fact, genetic ablation of
Cdc20 results in a dramatic elimination of epithelial or
mesenchymal tumors in vivo, whereas similar treatments
with other mitotic drugs (microtubule poisons or Plk
inhibitors) only result in partial arrest of tumor growth
(217). Although this strategy requires further refinement
to discriminate between normal and tumor cells, it may
provide therapeutic advantages when putative APC/CCdc20 inhibitors are properly delivered or in combination with other therapies (e.g., microtubule poisons such
as taxol) whose efficiency correlates with the length of
mitosis. Although the molecular pathways involved in
mammalian exit are not well understood, our recent
work supports the relevance of inhibiting Mastl to allow
PP2A activity during mitotic exit. In fact, inhibiting
Cdk1 and/or Mastl may prevent cell cycle arrest and
apoptosis after Cdc20 ablation (217). Thus inhibiting
these two kinases may actually counteract the therapeutic effect of inhibiting APC/C-Cdc20 in tumor cells.
VI. SUMMARY AND FUTURE
PERSPECTIVES
MARCOS MALUMBRES
lators of stem cell function; regenerative potential of tissues
and its deregulation is a hallmark alteration in human cancer.
Checkpoint kinases (Bub1, BubR1, and Mps1) are not
strictly required for cell cycle progression but are critical to
avoid errors and to prevent genomic instability. In most
studies, the inhibition of these kinases results in lethal phenotypes, although they are not usually found within the first
cell cycle, and they may be a consequence of the inefficient
chromosome alignment in human cultured cells. Their inhibition may be used for therapeutic strategies aimed either
to inhibit cell cycle progression or to promote massive instability in tumor cells by abrogating the corresponding
checkpoints.
One aspect not covered in the previous classification is the
cell-type specificity of some of these kinases. Thus it was
initially surprising that Cdk5 function mostly affects neurons or that Cdk4-null mice are diabetic and Cdk2-null
mice are sterile, despite the absence of alterations in any
other tissue (209). In addition, the complexity of the different cell cycles in multicellular organisms requires a different
combination of kinases to coordinate cellular responses
with the rest of the cells in the tissue or with other tissues.
On one hand, the variety of mitogenic signals may require a
wide panel of cyclins (⬃25 in the human genome) and Cdks
(20 Cdks in humans; Ref. 211) to control reentry into the
cell cycle. On the other hand, different variants of the cell
cycle (endoreduplication, acytokinetic, or even meiosis) require specific machineries or specific regulation of the existing enzymes. As discussed above, we now have a preliminary picture of the physiological relevance of many of these
kinases in mammals.
Given that kinases are druggable targets, the physiological
relevance of these proteins is a major issue in human disease. Cell cycle kinases are promising therapeutic targets for
multiple diseases, and their inhibition may be beneficial in
neurodegenerative diseases (Parkinson’s and Alzheimer’s
diseases; Cdk5), cardiac failure and hypertrophic cardiomyopathy (Cdk9), and cancer (multiple Cdks, Cdc7, Au-
998
ACKNOWLEDGMENTS
I am grateful to all members of my laboratory for providing
experimental data and valuable discussions.
Address for reprint and other correspondence: M. Malumbres, Cell Division and Cancer Group, Centro Nacional de
Investigaciones Oncológicas (CNIO), Melhor Fernandez
Almagro 3, E-28029 Madrid, Spain (e-mail: malumbres
@cnio.es).
GRANTS
The Cell Division and Cancer Group of the CNIO is supported
by grants from the MICINN (SAF2009-07973), ConsoliderIngenio 2010 Programme (CSD2007-00017), Comunidad de
Madrid (OncoCycle Programme; S-BIO-0283-2006), Fundación Ramón Areces, Association for International Cancer Research (AICR 08-0188), and the MitoSys project (HEALTH-F52010-241548; European Union Seventh Framework Program).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared
by the author.
REFERENCES
1. Abella A, Dubus P, Malumbres M, Rane SG, Kiyokawa H, Sicard A, Vignon F, Langin D,
Barbacid M, Fajas L. Cdk4 promotes adipogenesis through PPARgamma activation.
Cell Metab 2:239 –249, 2005.
2. Abrieu A, Magnaghi-Jaulin L, Kahana JA, Peter M, Castro A, Vigneron S, Lorca T,
Cleveland DW, Labbe JC. Mps1 is a kinetochore-associated kinase essential for the
vertebrate mitotic checkpoint. Cell 106:83–93, 2001.
3. Ahn CH, Kim YR, Kim SS, Yoo NJ, Lee SH. Mutational analysis of TTK gene in gastric
and colorectal cancers with microsatellite instability. Cancer Res Treat 41:224 –228,
2009.
4. Ahuja P, Sdek P, MacLellan WR. Cardiac myocyte cell cycle control in development,
disease, and regeneration. Physiol Rev 87:521–544, 2007.
5. Akkiz H, Bayram S, Bekar A, Akgollu E, Ozdil B. Relationship between functional
polymorphism in the Aurora A gene and susceptibility of hepatocellular carcinoma. J
Viral Hepat 17:668 – 674, 2010.
6. Aleem E, Kiyokawa H, Kaldis P. Cdc2-cyclin E complexes regulate the G1/S phase
transition. Nat Cell Biol 7:831– 836, 2005.
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
The core kinases required for the cell division cycle (e.g.,
Cdk1, Cdc7, Aurora A/B, or Plk1) are well conserved
throughout evolution and are essential for cell cycle progression. Nonessential phenotypes are only observed by
compensation by other family members that have been generated throughout evolution. The expression of these kinases is altered in some tumors, although it is not clear to
what extent this alteration reflects proliferative potential.
Its inhibition is likely to be lethal for every cell, although the
increased proliferative potential of tumor cells, as well as
other strategies that we still need to delineate (e.g., combination treatments), may allow their use as therapeutic targets.
rora, Plk1, Nek kinases etc.). On the other hand, reexpression or activation of cell cycle kinases (e.g., Cdk4 or Cdk2)
may be used to improve the regenerative potential of some
organs such as the heart after cardiac injury or in specific
hypomorphic syndromes such as hypopituitarism. In any
case, the balance between the therapeutic benefit of modulating these activities and the undesirable side effects remains as a major issue to be solved. Research efforts in the
next years are likely to improve this picture by adding new
kinases, providing a better understanding of their molecular
function and their tissue-specific requirements, and finding
synthetic lethal interactions of clinical relevance.
CELL CYCLE KINASES
7. An X, Ng SS, Xie D, Zeng YX, Sze J, Wang J, Chen YC, Chow BK, Lu G, Poon WS,
Kung HF, Wong BC, Lin MC. Functional characterisation of cell cycle-related kinase
(CCRK) in colorectal cancer carcinogenesis. Eur J Cancer 46:1752–1761, 2010.
8. Andres V. Control of vascular cell proliferation and migration by cyclin-dependent
kinase signalling: new perspectives and therapeutic potential. Cardiovasc Res 63:11–
21, 2004.
9. Andrysik Z, Bernstein WZ, Deng L, Myer DL, Li YQ, Tischfield JA, Stambrook PJ,
Bahassi EM. The novel mouse Polo-like kinase 5 responds to DNA damage and
localizes in the nucleolus. Nucleic Acids Res 38:2931–2943, 2010.
10. Ang XL, Seeburg DP, Sheng M, Harper JW. Regulation of postsynaptic RapGAP SPAR
by Polo-like kinase 2 and the SCFbeta-TRCP ubiquitin ligase in hippocampal neurons.
J Biol Chem 283:29424 –29432, 2008.
11. Angelis E, Garcia A, Chan SS, Schenke-Layland K, Ren S, Goodfellow SJ, Jordan MC,
Roos KP, White RJ, MacLellan WR. A cyclin D2-Rb pathway regulates cardiac myocyte
size and RNA polymerase III after biomechanical stress in adult myocardium. Circ Res
102:1222–1229, 2008.
13. Antoni L, Sodha N, Collins I, Garrett MD. CHK2 kinase: cancer susceptibility and
cancer therapy–two sides of the same coin? Nat Rev Cancer 7:925–936, 2007.
14. Arama E, Yanai A, Kilfin G, Bernstein A, Motro B. Murine NIMA-related kinases are
expressed in patterns suggesting distinct functions in gametogenesis and a role in the
nervous system. Oncogene 16:1813–1823, 1998.
15. Archambault V, Glover DM. Polo-like kinases: conservation and divergence in their
functions and regulation. Nat Rev Mol Cell Biol 10:265–275, 2009.
16. Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S, Kopecka A, Kumar R,
Jenkins RB, de Groen PC, Roche P, van Deursen JM. BubR1 insufficiency causes early
onset of aging-associated phenotypes and infertility in mice. Nat Genet 36:744 –749,
2004.
17. Barr AR, Gergely F. Aurora-A: the maker and breaker of spindle poles. J Cell Sci
120:2987–2996, 2007.
18. Barr FA, Sillje HH, Nigg EA. Polo-like kinases and the orchestration of cell division.
Nat Rev Mol Cell Biol 5:429 – 440, 2004.
29. Bohers E, Sarafan-Vasseur N, Drouet A, Paresy M, Latouche JB, Flaman JM, Sesboue
R, Frebourg T. Gradual reduction of BUBR1 protein levels results in premature
sister-chromatid separation then in aneuploidy. Hum Genet 124:473– 478, 2008.
30. Bonte D, Lindvall C, Liu H, Dykema K, Furge K, Weinreich M. Cdc7-Dbf4 kinase
overexpression in multiple cancers and tumor cell lines is correlated with p53 inactivation. Neoplasia 10:920 –931, 2008.
31. Boss DS, Beijnen JH, Schellens JH. Clinical experience with aurora kinase inhibitors: a
review. Oncologist 14:780 –793, 2009.
32. Boveri T. Zur Frage der Entstehung maligner Tumoren (Concerning the Origin of Malignant Tumors). Cold Spring Harbor, NY:Cold Spring Harbor Laboratory, 2008.
33. Bowers AJ, Boylan JF. Nek8, a NIMA family kinase member, is overexpressed in
primary human breast tumors. Gene 328:135–142, 2004.
34. Brown JR, Koretke KK, Birkeland ML, Sanseau P, Patrick DR. Evolutionary relationships of Aurora kinases: implications for model organism studies and the development
of anti-cancer drugs. BMC Evol Biol 4:39, 2004.
35. Bruck I, Kaplan D. Dbf4-Cdc7 phosphorylation of Mcm2 is required for cell growth. J
Biol Chem 284:28823–28831, 2009.
36. Buchman JJ, Tsai LH. Spindle regulation in neural precursors of flies and mammals. Nat
Rev Neurosci 8:89 –100, 2007.
37. Buffin E, Emre D, Karess RE. Flies without a spindle checkpoint. Nat Cell Biol 9:565–
572, 2007.
38. Burgess A, Vigneron S, Brioudes E, Labbe JC, Lorca T, Castro A. Loss of human
Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the
cyclin B-Cdc2/PP2A balance. Proc Natl Acad Sci USA 107:12564 –12569, 2010.
39. Caenepeel S, Charydczak G, Sudarsanam S, Hunter T, Manning G. The mouse kinome: discovery and comparative genomics of all mouse protein kinases. Proc Natl
Acad Sci USA 101:11707–11712, 2004.
40. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW,
Vogelstein B. Mutations of mitotic checkpoint genes in human cancers. Nature 392:
300 –303, 1998.
19. Barriere C, Santamaria D, Cerqueira A, Galan J, Martin A, Ortega S, Malumbres M,
Dubus P, Barbacid M. Mice thrive without Cdk4 and Cdk2. Mol Oncol 1:72– 83, 2007.
41. Cai D, Latham VM ,Jr, Zhang X, Shapiro GI. Combined depletion of cell cycle and
transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells.
Cancer Res 66:9270 –9280, 2006.
20. Belham C, Roig J, Caldwell JA, Aoyama Y, Kemp BE, Comb M, Avruch J. A mitotic
cascade of NIMA family kinases. Nercc1/Nek9 activates the Nek6 and Nek7 kinases.
J Biol Chem 278:34897–34909, 2003.
42. Calegari F, Huttner WB. An inhibition of cyclin-dependent kinases that lengthens, but
does not arrest, neuroepithelial cell cycle induces premature neurogenesis. J Cell Sci
116:4947– 4955, 2003.
21. Berdnik D, Knoblich JA. Drosophila Aurora-A is required for centrosome maturation
and actin-dependent asymmetric protein localization during mitosis. Curr Biol 12:640 –
647, 2002.
43. Campaner S, Doni M, Hydbring P, Verrecchia A, Bianchi L, Sardella D, Schleker T,
Perna D, Tronnersjo S, Murga M, Fernandez-Capetillo O, Barbacid M, Larsson LG,
Amati B. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat
Cell Biol 12:54 –59, 2010.
22. Bernard M, Sanseau P, Henry C, Couturier A, Prigent C. Cloning of STK13, a third
human protein kinase related to Drosophila aurora and budding yeast Ipl1 that maps on
chromosome 19q13.3-ter. Genomics 53:406 – 409, 1998.
44. Carlson ME, Hsu M, Conboy IM. Imbalance between pSmad3 and Notch induces
CDK inhibitors in old muscle stem cells. Nature 454:528 –532, 2008.
23. Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P. Cdk2 knockout mice are
viable. Curr Biol 13:1775–1785, 2003.
45. Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell
Biol 4:842– 854, 2003.
24. Berthet C, Klarmann KD, Hilton MB, Suh HC, Keller JR, Kiyokawa H, Kaldis P.
Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation. Dev Cell 10:563–573, 2006.
46. Carter H, Samayoa J, Hruban RH, Karchin R. Prioritization of driver mutations in
pancreatic cancer using cancer-specific high-throughput annotation of somatic mutations (CHASM). Cancer Biol Ther 10:582–587, 2010.
25. Bettencourt-Dias M, Rodrigues-Martins A, Carpenter L, Riparbelli M, Lehmann L,
Gatt MK, Carmo N, Balloux F, Callaini G, Glover DM. SAK/PLK4 is required for
centriole duplication and flagella development. Curr Biol 15:2199 –2207, 2005.
47. Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z. A signature of chromosomal
instability inferred from gene expression profiles predicts clinical outcome in multiple
human cancers. Nat Genet 38:1043–1048, 2006.
26. Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P,
Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ, Plowman GD. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal
cancers. EMBO J 17:3052–3065, 1998.
48. Castilho PV, Williams BC, Mochida S, Zhao Y, Goldberg ML. The M phase kinase
Greatwall (Gwl) promotes inactivation of PP2A/B55delta, a phosphatase directed
against CDK phosphosites. Mol Biol Cell 20:4777– 4789, 2009.
27. Blanchet E, Annicotte JS, Fajas L. Cell cycle regulators in the control of metabolism.
Cell Cycle 8:4029 – 4031, 2009.
49. Cerqueira A, Santamaria D, Martinez-Pastor B, Cuadrado M, Fernandez-Capetillo O,
Barbacid M. Overall Cdk activity modulates the DNA damage response in mammalian
cells. J Cell Biol 187:773–780, 2009.
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
999
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
12. Annicotte JS, Blanchet E, Chavey C, Iankova I, Costes S, Assou S, Teyssier J, Dalle S,
Sardet C, Fajas L. The CDK4-pRB-E2F1 pathway controls insulin secretion. Nat Cell
Biol 11:1017–1023, 2009.
28. Bloom J, Cross FR. Multiple levels of cyclin specificity in cell-cycle control. Nat Rev Mol
Cell Biol 8:149 –160, 2007.
MARCOS MALUMBRES
50. Ciemerych MA, Sicinski P. Cell cycle in mouse development. Oncogene 24:2877–
2898, 2005.
51. Cimprich KA, Cortez D. ATR: an essential regulator of genome integrity. Nat Rev Mol
Cell Biol 9:616 – 627, 2008.
52. Classon M, Harlow E. The retinoblastoma tumour suppressor in development and
cancer. Nat Rev Cancer 2:910 –917, 2002.
53. Cowley DO, Rivera-Perez JA, Schliekelman M, He YJ, Oliver TG, Lu L, O’Quinn R,
Salmon ED, Magnuson T, Van Dyke T. Aurora-A kinase is essential for bipolar spindle
formation and early development. Mol Cell Biol 29:1059 –1071, 2009.
71. Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G, Teague J, Butler A,
Edkins S, Stevens C, Parker A, O’Meara S, Avis T, Barthorpe S, Brackenbury L, Buck
G, Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, Gray K, Halliday K,
Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry
J, Petty R, Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts C, Varian J,
Webb A, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Green A,
Knowles M, Leung SY, Looijenga LH, Malkowicz B, Pierotti MA, Teh BT, Yuen ST,
Lakhani SR, Easton DF, Weber BL, Goldstraw P, Nicholson AG, Wooster R, Stratton
MR, Futreal PA. Somatic mutations of the protein kinase gene family in human lung
cancer. Cancer Res 65:7591–7595, 2005.
72. De Cárcer G, Escobar B, Higuero A, Garcia L, Ansón A, Pérez G, Mollejo M, Manning
G, Melendez B, Abad-Rodriguez J, Malumbres M. Plk5, a Polo-box domain-only protein with specific roles in neuron differentiation and glioblastoma suppression. Mol Cell
Biol 31:1225–1239, 2010.
55. Cruz JC, Tsai LH. A Jekyll and Hyde kinase: roles for Cdk5 in brain development and
disease. Curr Opin Neurobiol 14:390 –394, 2004.
73. De Carcer G, Perez de Castro I, Malumbres M. Targeting cell cycle kinases for cancer
therapy. Curr Med Chem 14:969 –985, 2007.
56. Cutts SM, Fowler KJ, Kile BT, Hii LL, O’Dowd RA, Hudson DF, Saffery R, Kalitsis P,
Earle E, Choo KH. Defective chromosome segregation, microtubule bundling and
nuclear bridging in inner centromere protein gene (Incenp)-disrupted mice. Hum Mol
Genet 8:1145–1155, 1999.
74. Deans AJ, Khanna KK, McNees CJ, Mercurio C, Heierhorst J, McArthur GA. Cyclindependent kinase 2 functions in normal DNA repair and is a therapeutic target in
BRCA1-deficient cancers. Cancer Res 66:8219 – 8226, 2006.
57. Chandramouli A, Shi J, Feng Y, Holubec H, Shanas RM, Bhattacharyya AK, Zheng W,
Nelson MA. Haploinsufficiency of the cdc2l gene contributes to skin cancer development in mice. Carcinogenesis 28:2028 –2035, 2007.
58. Chang CJ, Goulding S, Adams RR, Earnshaw WC, Carmena M. Drosophila Incenp is
required for cytokinesis and asymmetric cell division during development of the nervous system. J Cell Sci 119:1144 –1153, 2006.
59. Chang J, Baloh RH, Milbrandt J. The NIMA-family kinase Nek3 regulates microtubule
acetylation in neurons. J Cell Sci 122:2274 –2282, 2009.
60. Charych DH, Coyne M, Yabannavar A, Narberes J, Chow S, Wallroth M, Shafer C,
Walter AO. Inhibition of Cdc7/Dbf4 kinase activity affects specific phosphorylation
sites on MCM2 in cancer cells. J Cell Biochem 104:1075–1086, 2008.
61. Chen J, Li D, Wei C, Sen S, Killary AM, Amos CI, Evans DB, Abbruzzese JL, Frazier ML.
Aurora-A and p16 polymorphisms contribute to an earlier age at diagnosis of pancreatic cancer in Caucasians. Clin Cancer Res 13:3100 –3104, 2007.
62. Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT.
Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287:1804 –
1808, 2000.
63. Chi YH, Haller K, Ward MD, Semmes OJ, Li Y, Jeang KT. Requirements for protein
phosphorylation and the kinase activity of polo-like kinase 1 (Plk1) for the kinetochore
function of mitotic arrest deficiency protein 1 (Mad1). J Biol Chem 283:35834 –35844,
2008.
64. Choi JH, Banks AS, Estall JL, Kajimura S, Bostrom P, Laznik D, Ruas JL, Chalmers MJ,
Kamenecka TM, Bluher M, Griffin PR, Spiegelman BM. Anti-diabetic drugs inhibit
obesity-linked phosphorylation of PPARgamma by Cdk5. Nature 466:451– 456, 2010.
65. Choschzick M, Lebeau A, Marx AH, Tharun L, Terracciano L, Heilenkotter U,
Jaenicke F, Bokemeyer C, Simon R, Sauter G, Schwarz J. Overexpression of cell
division cycle 7 homolog is associated with gene amplification frequency in breast
cancer. Hum Pathol 41:358 –365, 2010.
66. Chu ML, Chavas LM, Douglas KT, Eyers PA, Tabernero L. Crystal structure of the
catalytic domain of the mitotic checkpoint kinase Mps1 in complex with SP600125. J
Biol Chem 283:21495–21500, 2008.
67. Chu ML, Lang Z, Chavas LM, Neres J, Fedorova OS, Tabernero L, Cherry M, Williams
DH, Douglas KT, Eyers PA. Biophysical and X-ray crystallographic analysis of Mps1
kinase inhibitor complexes. Biochemistry 49:1689 –1701, 2010.
75. Degenhardt Y, Lampkin T. Targeting Polo-like kinase in cancer therapy. Clin Cancer
Res 16:384 –389, 2010.
76. Dhavan R, Tsai LH. A decade of CDK5. Nat Rev Mol Cell Biol 2:749 –759, 2001.
77. Dieterich K, Soto Rifo R, Faure AK, Hennebicq S, Ben Amar B, Zahi M, Perrin J,
Martinez D, Sele B, Jouk PS, Ohlmann T, Rousseaux S, Lunardi J, Ray PF. Homozygous
mutation of AURKC yields large-headed polyploid spermatozoa and causes male
infertility. Nat Genet 39:661– 665, 2007.
78. Dieterich K, Zouari R, Harbuz R, Vialard F, Martinez D, Bellayou H, Prisant N,
Zoghmar A, Guichaoua MR, Koscinski I, Kharouf M, Noruzinia M, Nadifi S, Sefiani A,
Lornage J, Zahi M, Viville S, Sele B, Jouk PS, Jacob MC, Escalier D, Nikas Y, Hennebicq
S, Lunardi J, Ray PF. The Aurora Kinase C c.144delC mutation causes meiosis I arrest
in men and is frequent in the North African population. Hum Mol Genet 18:1301–
1309, 2009.
79. Do Carmo Avides M, Tavares A, Glover DM. Polo kinase and Asp are needed to
promote the mitotic organizing activity of centrosomes. Nat Cell Biol 3:421– 424,
2001.
80. Dorer RK, Zhong S, Tallarico JA, Wong WH, Mitchison TJ, Murray AW. A smallmolecule inhibitor of Mps1 blocks the spindle-checkpoint response to a lack of tension
on mitotic chromosomes. Curr Biol 15:1070 –1076, 2005.
81. Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, Huber WE, Nishimura EK,
Golub TR, Fisher DE. Critical role of CDK2 for melanoma growth linked to its
melanocyte-specific transcriptional regulation by MITF. Cancer Cell 6:565–576, 2004.
82. Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits
and cancer. Biochim Biophys Acta 1795:1–15, 2009.
83. Elia AE, Rellos P, Haire LF, Chao JW, Ivins FJ, Hoepker K, Mohammad D, Cantley LC,
Smerdon SJ, Yaffe MB. The molecular basis for phosphodependent substrate targeting
and regulation of Plks by the Polo-box domain. Cell 115:83–95, 2003.
84. Enserink JM, Kolodner RD. An overview of Cdk1-controlled targets and processes.
Cell Div 5:11, 2010.
85. Ewart-Toland A, Briassouli P, de Koning JP, Mao JH, Yuan J, Chan F, MacCarthyMorrogh L, Ponder BA, Nagase H, Burn J, Ball S, Almeida M, Linardopoulos S, Balmain
A. Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility
gene in mouse and human. Nat Genet 34:403– 412, 2003.
69. Chung JH, Bunz F. Cdk2 is required for p53-independent G2/M checkpoint control.
PLoS Genet 6:e1000863, 2010.
86. Ewart-Toland A, Dai Q, Gao YT, Nagase H, Dunlop MG, Farrington SM, Barnetson
RA, Anton-Culver H, Peel D, Ziogas A, Lin D, Miao X, Sun T, Ostrander EA, Stanford
JL, Langlois M, Chan JM, Yuan J, Harris CC, Bowman ED, Clayman GL, Lippman SM,
Lee JJ, Zheng W, Balmain A. Aurora-A/STK15 T⫹91A is a general low penetrance
cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis
26:1368 –1373, 2005.
70. Dai W, Wang Q, Liu T, Swamy M, Fang Y, Xie S, Mahmood R, Yang YM, Xu M, Rao
CV. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1
haploinsufficiency. Cancer Res 64:440 – 445, 2004.
87. Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K, Debril MB, Miard S, Auwerx J. The
retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte
differentiation. Dev Cell 3:903–910, 2002.
68. Chuang LC, Teixeira LK, Wohlschlegel JA, Henze M, Yates JR, Mendez J, Reed SI.
Phosphorylation of Mcm2 by Cdc7 promotes pre-replication complex assembly during cell-cycle re-entry. Mol Cell 35:206 –216, 2009.
1000
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
54. Cox DG, Hankinson SE, Hunter DJ. Polymorphisms of the AURKA (STK15/aurora
kinase) gene and breast cancer risk (United States). Cancer Causes Control 17:81– 83,
2006.
CELL CYCLE KINASES
88. Fajas L, Landsberg RL, Huss-Garcia Y, Sardet C, Lees JA, Auwerx J. E2Fs regulate
adipocyte differentiation. Dev Cell 3:39 – 49, 2002.
109. Goetz SC, Conlon FL. Cardiac progenitors and the embryonic cell cycle. Cell Cycle
6:1974 –1981, 2007.
89. Farcas R, Schneider E, Frauenknecht K, Kondova I, Bontrop R, Bohl J, Navarro B,
Metzler M, Zischler H, Zechner U, Daser A, Haaf T. Differences in DNA methylation
patterns and expression of the CCRK gene in human and nonhuman primate cortices.
Mol Biol Evol 26:1379 –1389, 2009.
110. Goga A, Yang D, Tward AD, Morgan DO, Bishop JM. Inhibition of CDK1 as a potential
therapy for tumors over-expressing MYC. Nat Med 13:820 – 827, 2007.
90. Farkas LM, Huttner WB. The cell biology of neural stem and progenitor cells and its
significance for their proliferation versus differentiation during mammalian brain development. Curr Opin Cell Biol 20:707–715, 2008.
91. Feldmann G, Mishra A, Hong SM, Bisht S, Strock CJ, Ball DW, Goggins M, Maitra A,
Nelkin BD. Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer
formation and progression through the suppression of Ras-Ral signaling. Cancer Res
70:4460 – 4469, 2010.
92. Fiaschi-Taesch N, Bigatel TA, Sicari B, Takane KK, Salim F, Velazquez-Garcia S, Harb
G, Selk K, Cozar-Castellano I, Stewart AF. Survey of the human pancreatic beta-cell
G1/S proteome reveals a potential therapeutic role for cdk-6 and cyclin D1 in enhancing human beta-cell replication and function in vivo. Diabetes 58:882– 893, 2009.
94. Fisher RP. Secrets of a double agent: CDK7 in cell-cycle control and transcription. J
Cell Sci 118:5171–5180, 2005.
95. Fisk HA, Mattison CP, Winey M. A field guide to the Mps1 family of protein kinases.
Cell Cycle 3:439 – 442, 2004.
96. Fisk HA, Mattison CP, Winey M. Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression. Proc Natl Acad Sci USA 100:14875–
14880, 2003.
97. Fluge O, Bruland O, Akslen LA, Lillehaug JR, Varhaug JE. Gene expression in poorly
differentiated papillary thyroid carcinomas. Thyroid 16:161–175, 2006.
98. Francis LI, Randell JC, Takara TJ, Uchima L, Bell SP. Incorporation into the prereplicative complex activates the Mcm2–7 helicase for Cdc7-Dbf4 phosphorylation. Genes
Dev 23:643– 654, 2009.
99. Frank CL, Tsai LH. Alternative functions of core cell cycle regulators in neuronal
migration, neuronal maturation, and synaptic plasticity. Neuron 62:312–326, 2009.
100. Fujimoto T, Anderson K, Jacobsen SE, Nishikawa SI, Nerlov C. Cdk6 blocks myeloid
differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. EMBO J 26:2361–2370, 2007.
101. Fuster JJ, Fernandez P, Gonzalez-Navarro H, Silvestre C, Nabah YN, Andres V.
Control of cell proliferation in atherosclerosis: insights from animal models and human
studies. Cardiovasc Res 86:254 –264, 2010.
102. Gandhi MJ, Cummings CL, Drachman JG. FLJ14813 missense mutation: a candidate
for autosomal dominant thrombocytopenia on human chromosome 10. Hum Hered
55:66 –70, 2003.
103. Gautier J, Norbury C, Lohka M, Nurse P, Maller J. Purified maturation-promoting
factor contains the product of a Xenopus homolog of the fission yeast cell cycle control
gene cdc2⫹. Cell 54:433– 439, 1988.
104. Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN ,Jr, Gandara DR. Aurora
kinases as anticancer drug targets. Clin Cancer Res 14:1639 –1648, 2008.
105. Georgescu SP, Komuro I, Hiroi Y, Mizuno T, Kudoh S, Yamazaki T, Yazaki Y. Downregulation of polo-like kinase correlates with loss of proliferative ability of cardiac
myocytes. J Mol Cell Cardiol 29:929 –937, 1997.
106. Giet R, Petretti C, Prigent C. Aurora kinases, aneuploidy and cancer, a coincidence or
a real link? Trends Cell Biol 15:241–250, 2005.
107. Gillett ES, Espelin CW, Sorger PK. Spindle checkpoint proteins and chromosomemicrotubule attachment in budding yeast. J Cell Biol 164:535–546, 2004.
108. Glover DM, Leibowitz MH, McLean DA, Parry H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81:95–105,
1995.
112. Gonzalez C, Sunkel CE, Glover DM. Interactions between mgr, asp, and polo: asp
function modulated by polo and needed to maintain the poles of monopolar and
bipolar spindles. Chromosoma 107:452– 460, 1998.
113. Gotz M, Huttner WB. The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6:777–
788, 2005.
114. Grossel MJ, Hinds PW. Beyond the cell cycle: a new role for Cdk6 in differentiation. J
Cell Biochem 97:485– 493, 2006.
115. Guse A, Mishima M, Glotzer M. Phosphorylation of ZEN-4/MKLP1 by aurora B
regulates completion of cytokinesis. Curr Biol 15:778 –786, 2005.
116. Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA. The Polo kinase Plk4 functions in
centriole duplication. Nat Cell Biol 7:1140 –1146, 2005.
117. Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D, Kidd A, Mehes K, Nash R,
Robin N, Shannon N, Tolmie J, Swansbury J, Irrthum A, Douglas J, Rahman N. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in
BUB1B. Nat Genet 36:1159 –1161, 2004.
118. Haren L, Stearns T, Luders J. Plk1-dependent recruitment of gamma-tubulin complexes to mitotic centrosomes involves multiple PCM components. PLoS One
4:e5976, 2009.
119. Hartwell LH. Saccharomyces cerevisiae cell cycle. Bacteriol Rev 38:164 –198, 1974.
120. Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle
events. Science 246:629 – 634, 1989.
121. Hassink RJ, Pasumarthi KB, Nakajima H, Rubart M, Soonpaa MH, de la Riviere AB,
Doevendans PA, Field LJ. Cardiomyocyte cell cycle activation improves cardiac function after myocardial infarction. Cardiovasc Res 78:18 –25, 2008.
122. Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy.
Nat Rev Genet 2:280 –291, 2001.
123. Hayward DG, Clarke RB, Faragher AJ, Pillai MR, Hagan IM, Fry AM. The centrosomal
kinase Nek2 displays elevated levels of protein expression in human breast cancer.
Cancer Res 64:7370 –7376, 2004.
124. Hayward DG, Fry AM. Nek2 kinase in chromosome instability and cancer. Cancer Lett
237:155–166, 2006.
125. Hayward DG, Newbatt Y, Pickard L, Byrne E, Mao G, Burns S, Sahota NK, Workman
P, Collins I, Aherne W, Fry AM. Identification by high-throughput screening of viridin
analogs as biochemical and cell-based inhibitors of the cell cycle-regulated Nek2
kinase. J Biomol Screen 15:918 –927, 2010.
126. Hewitt L, Tighe A, Santaguida S, White AM, Jones CD, Musacchio A, Green S, Taylor
SS. Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1-CMad2 core complex. J Cell Biol 190:25–34, 2010.
127. Higgins JM. Haspin: a newly discovered regulator of mitotic chromosome behavior.
Chromosoma 119:137–147, 2010.
128. Hochegger H, Takeda S, Hunt T. Cyclin-dependent kinases and cell-cycle transitions:
does one fit all? Nat Rev Mol Cell Biol 9:910 –916, 2008.
129. Holt LJ, Tuch BB, Villen J, Johnson AD, Gygi SP, Morgan DO. Global analysis of Cdk1
substrate phosphorylation sites provides insights into evolution. Science 325:1682–
1686, 2009.
130. Horsley V, Aliprantis AO, Polak L, Glimcher LH, Fuchs E. NFATc1 balances quiescence and proliferation of skin stem cells. Cell 132:299 –310, 2008.
131. Hoyt MA, Totis L, Roberts BT. S. cerevisiae genes required for cell cycle arrest in
response to loss of microtubule function. Cell 66:507–517, 1991.
132. Hu D, Mayeda A, Trembley JH, Lahti JM, Kidd VJ. CDK11 complexes promote premRNA splicing. J Biol Chem 278:8623– 8629, 2003.
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
1001
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
93. Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, Freed E, Ligon AH, Vena N,
Ogino S, Chheda MG, Tamayo P, Finn S, Shrestha Y, Boehm JS, Jain S, Bojarski E,
Mermel C, Barretina J, Chan JA, Baselga J, Tabernero J, Root DE, Fuchs CS, Loda M,
Shivdasani RA, Meyerson M, Hahn WC. CDK8 is a colorectal cancer oncogene that
regulates beta-catenin activity. Nature 455:547–551, 2008.
111. Gonzalez C. Spindle orientation, asymmetric division and tumour suppression in
Drosophila stem cells. Nat Rev Genet 8:462– 472, 2007.
MARCOS MALUMBRES
133. Hu D, Valentine M, Kidd VJ, Lahti JM. CDK11(p58) is required for the maintenance of
sister chromatid cohesion. J Cell Sci 120:2424 –2434, 2007.
134. Hu HM, Chuang CK, Lee MJ, Tseng TC, Tang TK. Genomic organization, expression,
and chromosome localization of a third aurora-related kinase gene, Aie1. DNA Cell
Biol 19:679 – 688, 2000.
135. Hu MG, Deshpande A, Enos M, Mao D, Hinds EA, Hu GF, Chang R, Guo Z, Dose M,
Mao C, Tsichlis PN, Gounari F, Hinds PW. A requirement for cyclin-dependent kinase
6 in thymocyte development and tumorigenesis. Cancer Res 69:810 – 818, 2009.
136. Huang D, Friesen H, Andrews B. Pho85, a multifunctional cyclin-dependent protein
kinase in budding yeast. Mol Microbiol 66:303–314, 2007.
137. Huang HC, Shi J, Orth JD, Mitchison TJ. Evidence that mitotic exit is a better cancer
therapeutic target than spindle assembly. Cancer Cell 16:347–358, 2009.
138. Huang X, Ruan Q, Fang Y, Traganos F, Darzynkiewicz Z, Dai W. Physical and functional interactions between mitotic kinases during polyploidization and megakaryocytic differentiation. Cell Cycle 3:946 –951, 2004.
140. Huang YS, Jung MY, Sarkissian M, Richter JD. N-methyl-D-aspartate receptor signaling
results in Aurora kinase-catalyzed CPEB phosphorylation and alpha CaMKII mRNA
polyadenylation at synapses. EMBO J 21:2139 –2148, 2002.
141. Hudson JW, Kozarova A, Cheung P, Macmillan JC, Swallow CJ, Cross JC, Dennis JW.
Late mitotic failure in mice lacking Sak, a polo-like kinase. Curr Biol 11:441– 446, 2001.
142. Huertas P, Cortes-Ledesma F, Sartori AA, Aguilera A, Jackson SP. CDK targets Sae2
to control DNA-end resection and homologous recombination. Nature 455:689 –
692, 2008.
143. Hutchins JR, Toyoda Y, Hegemann B, Poser I, Heriche JK, Sykora MM, Augsburg M,
Hudecz O, Buschhorn BA, Bulkescher J, Conrad C, Comartin D, Schleiffer A, Sarov
M, Pozniakovsky A, Slabicki MM, Schloissnig S, Steinmacher I, Leuschner M, Ssykor A,
Lawo S, Pelletier L, Stark H, Nasmyth K, Ellenberg J, Durbin R, Buchholz F, Mechtler
K, Hyman AA, Peters JM. Systematic analysis of human protein complexes identifies
chromosome segregation proteins. Science 328:593–599, 2010.
144. Huttner WB, Kosodo Y. Symmetric versus asymmetric cell division during neurogenesis in the developing vertebrate central nervous system. Curr Opin Cell Biol 17:648 –
657, 2005.
145. Hydbring P, Bahram F, Su Y, Tronnersjo S, Hogstrand K, von der Lehr N, Sharifi HR,
Lilischkis R, Hein N, Wu S, Vervoorts J, Henriksson M, Grandien A, Luscher B, Larsson
LG. Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence
in cotransformation. Proc Natl Acad Sci USA 107:58 – 63, 2010.
146. Iankova I, Petersen RK, Annicotte JS, Chavey C, Hansen JB, Kratchmarova I, Sarruf D,
Benkirane M, Kristiansen K, Fajas L. Peroxisome proliferator-activated receptor
gamma recruits the positive transcription elongation factor b complex to activate
transcription and promote adipogenesis. Mol Endocrinol 20:1494 –1505, 2006.
147. Iglesias A, Murga M, Laresgoiti U, Skoudy A, Bernales I, Fullaondo A, Moreno B,
Lloreta J, Field SJ, Real FX, Zubiaga AM. Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice. J Clin Invest 113:1398 –1407, 2004.
148. Inglis KJ, Chereau D, Brigham EF, Chiou SS, Schobel S, Frigon NL, Yu M, Caccavello RJ,
Nelson S, Motter R, Wright S, Chian D, Santiago P, Soriano F, Ramos C, Powell K,
Goldstein JM, Babcock M, Yednock T, Bard F, Basi GS, Sham H, Chilcote TJ, McConlogue
L, Griswold-Prenner I, Anderson JP. Polo-like kinase 2 (PLK2) phosphorylates alphasynuclein at serine 129 in central nervous system. J Biol Chem 284:2598 –2602, 2009.
149. Jablonska B, Aguirre A, Vandenbosch R, Belachew S, Berthet C, Kaldis P, Gallo V.
Cdk2 is critical for proliferation and self-renewal of neural progenitor cells in the adult
subventricular zone. J Cell Biol 179:1231–1245, 2007.
150. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA. Effects of an
Rb mutation in the mouse. Nature 359:295–300, 1992.
154. Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM. Bub1 mediates
cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J Cell Biol 179:255–267, 2007.
155. Jeon YJ, Lee KY, Cho YY, Pugliese A, Kim HG, Jeong CH, Bode AM, Dong Z. The role
of NEK6 in tumor promoter-induced transformation in JB6 C141 mouse skin epidermal cells. J Biol Chem 285:28126 –28133, 2010.
156. Jessberger S, Gage FH, Eisch AJ, Lagace DC. Making a neuron: Cdk5 in embryonic and
adult neurogenesis. Trends Neurosci 32:575–582, 2009.
157. Johnson HJ, Gandhi MJ, Shafizadeh E, Langer NB, Pierce EL, Paw BH, Gilligan DM,
Drachman JG. In vivo inactivation of MASTL kinase results in thrombocytopenia. Exp
Hematol 37:901–908, 2009.
158. Johnston CA, Hirono K, Prehoda KE, Doe CQ. Identification of an Aurora-A/PinsLINKER/Dlg spindle orientation pathway using induced cell polarity in S2 cells. Cell
138:1150 –1163, 2009.
159. Jopling C, Sleep E, Raya M, Marti M, Raya A, Belmonte JC. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464:606 –
609, 2010.
160. Ju H, Cho H, Kim YS, Kim WH, Ihm C, Noh SM, Kim JB, Hahn DS, Choi BY, Kang C.
Functional polymorphism 57Val⬎Ile of aurora kinase A associated with increased risk
of gastric cancer progression. Cancer Lett 242:273–279, 2006.
161. Kadri Z, Shimizu R, Ohneda O, Maouche-Chretien L, Gisselbrecht S, Yamamoto M,
Romeo PH, Leboulch P, Chretien S. Direct binding of pRb/E2F-2 to GATA-1 regulates
maturation and terminal cell division during erythropoiesis. PLoS Biol 7:e1000123,
2009.
162. Katis VL, Lipp JJ, Imre R, Bogdanova A, Okaz E, Habermann B, Mechtler K, Nasmyth
K, Zachariae W. Rec8 phosphorylation by casein kinase 1 and Cdc7-Dbf4 kinase
regulates cohesin cleavage by separase during meiosis. Dev Cell 18:397– 409, 2010.
163. Kauselmann G, Weiler M, Wulff P, Jessberger S, Konietzko U, Scafidi J, Staubli U,
Bereiter-Hahn J, Strebhardt K, Kuhl D. The polo-like protein kinases Fnk and Snk
associate with a Ca2⫹- and integrin-binding protein and are regulated dynamically
with synaptic plasticity. EMBO J 18:5528 –5539, 1999.
164. Kawabe T. G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther 3:513–519,
2004.
165. Kawasaki A, Matsumura I, Miyagawa J, Ezoe S, Tanaka H, Terada Y, Tatsuka M, Machii
T, Miyazaki H, Furukawa Y, Kanakura Y. Downregulation of an AIM-1 kinase couples
with megakaryocytic polyploidization of human hematopoietic cells. J Cell Biol 152:
275–287, 2001.
166. Kawashima SA, Yamagishi Y, Honda T, Ishiguro K, Watanabe Y. Phosphorylation of
H2A by Bub1 prevents chromosomal instability through localizing shugoshin. Science
327:172–177, 2010.
167. Kellogg DR. Wee1-dependent mechanisms required for coordination of cell growth
and cell division. J Cell Sci 116:4883– 4890, 2003.
168. Kelly AE, Funabiki H. Correcting aberrant kinetochore microtubule attachments: an
Aurora B-centric view. Curr Opin Cell Biol 21:51–58, 2009.
169. Khazaei MR, Puschel AW. Phosphorylation of the par polarity complex protein Par3 at
serine 962 is mediated by aurora a and regulates its function in neuronal polarity. J Biol
Chem 284:33571–33579, 2009.
170. Kim JM, Kakusho N, Yamada M, Kanoh Y, Takemoto N, Masai H. Cdc7 kinase
mediates Claspin phosphorylation in DNA replication checkpoint. Oncogene 27:
3475–3482, 2008.
151. Jackson SP, Bartek J. The DNA-damage response in human biology and disease.
Nature 461:1071–1078, 2009.
171. Kim JM, Nakao K, Nakamura K, Saito I, Katsuki M, Arai K, Masai H. Inactivation of
Cdc7 kinase in mouse ES cells results in S-phase arrest and p53-dependent cell death.
EMBO J 21:2168 –2179, 2002.
152. Janssen A, Kops GJ, Medema RH. Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells. Proc Natl Acad Sci USA 106:19108 –19113,
2009.
172. Kimmins S, Crosio C, Kotaja N, Hirayama J, Monaco L, Hoog C, van Duin M, Gossen
JA, Sassone-Corsi P. Differential functions of the Aurora-B and Aurora-C kinases in
mammalian spermatogenesis. Mol Endocrinol 21:726 –739, 2007.
1002
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
139. Huang YF, Chang MD, Shieh SY. TTK/hMps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at Thr18. Mol Cell Biol 29:2935–2944, 2009.
153. Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T,
DePinho RA, Sharpless NE, Scadden DT. Stem-cell ageing modified by the cyclindependent kinase inhibitor p16INK4a. Nature 443:421– 426, 2006.
CELL CYCLE KINASES
173. Kimura MT, Mori T, Conroy J, Nowak NJ, Satomi S, Tamai K, Nagase H. Two
functional coding single nucleotide polymorphisms in STK15 (Aurora-A) coordinately
increase esophageal cancer risk. Cancer Res 65:3548 –3554, 2005.
192. Liao HS, Kang PM, Nagashima H, Yamasaki N, Usheva A, Ding B, Lorell BH, Izumo S.
Cardiac-specific overexpression of cyclin-dependent kinase 2 increases smaller
mononuclear cardiomyocytes. Circ Res 88:443– 450, 2001.
174. Kippin TE, Martens DJ, van der Kooy D. p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation
capacity. Genes Dev 19:756 –767, 2005.
193. Liem DA, Zhao P, Angelis E, Chan SS, Zhang J, Wang G, Berthet C, Kaldis P, Ping P,
MacLellan WR. Cyclin-dependent kinase 2 signaling regulates myocardial ischemia/
reperfusion injury. J Mol Cell Cardiol 45:610 – 616, 2008.
175. Ko HW, Norman RX, Tran J, Fuller KP, Fukuda M, Eggenschwiler JT. Broad-minded
links cell cycle-related kinase to cilia assembly and hedgehog signal transduction. Dev
Cell 18:237–247, 2010.
194. Liu C, Yang Z, Yang J, Xia Z, Ao S. Regulation of the yeast transcriptional factor PHO2
activity by phosphorylation. J Biol Chem 275:31972–31978, 2000.
176. Ko MA, Rosario CO, Hudson JW, Kulkarni S, Pollett A, Dennis JW, Swallow CJ. Plk4
haploinsufficiency causes mitotic infidelity and carcinogenesis. Nat Genet 37:883– 888,
2005.
177. Kokuryo T, Senga T, Yokoyama Y, Nagino M, Nimura Y, Hamaguchi M. Nek2 as an
effective target for inhibition of tumorigenic growth and peritoneal dissemination of
cholangiocarcinoma. Cancer Res 67:9637–9642, 2007.
195. Liu D, Vader G, Vromans MJ, Lampson MA, Lens SM. Sensing chromosome biorientation by spatial separation of aurora B kinase from kinetochore substrates.
Science 323:1350 –1353, 2009.
196. Liu Q, Hirohashi Y, Du X, Greene MI, Wang Q. Nek2 targets the mitotic checkpoint
proteins Mad2 and Cdc20: a mechanism for aneuploidy in cancer. Exp Mol Pathol
88:225–233, 2010.
197. Liu S, Lu W, Obara T, Kuida S, Lehoczky J, Dewar K, Drummond IA, Beier DR. A
defect in a novel Nek-family kinase causes cystic kidney disease in the mouse and in
zebrafish. Development 129:5839 –5846, 2002.
179. Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless
NE. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453– 457, 2006.
198. Liu ST, Chan GK, Hittle JC, Fujii G, Lees E, Yen TJ. Human MPS1 kinase is required for
mitotic arrest induced by the loss of CENP-E from kinetochores. Mol Biol Cell 14:
1638 –1651, 2003.
180. Kulkarni AA, Kingsbury SR, Tudzarova S, Hong HK, Loddo M, Rashid M, RodriguezAcebes S, Prevost AT, Ledermann JA, Stoeber K, Williams GH. Cdc7 kinase is a
predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma. Clin
Cancer Res 15:2417–2425, 2009.
199. Lo YL, Yu JC, Chen ST, Yang HC, Fann CS, Mau YC, Shen CY. Breast cancer risk
associated with genotypic polymorphism of the mitosis-regulating gene Aurora-A/
STK15/BTAK. Int J Cancer 115:276 –283, 2005.
181. Kurat CF, Wolinski H, Petschnigg J, Kaluarachchi S, Andrews B, Natter K, Kohlwein
SD. Cdk1/Cdc28-dependent activation of the major triacylglycerol lipase Tgl4 in yeast
links lipolysis to cell-cycle progression. Mol Cell 33:53– 63, 2009.
182. Kushner JA, Ciemerych MA, Sicinska E, Wartschow LM, Teta M, Long SY, Sicinski P,
White MF. Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth.
Mol Cell Biol 25:3752–3762, 2005.
183. Kwiatkowski N, Jelluma N, Filippakopoulos P, Soundararajan M, Manak MS, Kwon M,
Choi HG, Sim T, Deveraux QL, Rottmann S, Pellman D, Shah JV, Kops GJ, Knapp S,
Gray NS. Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function. Nat Chem Biol 6:359 –368, 2010.
184. Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW. Cyclin D1-dependent kinase
activity in murine development and mammary tumorigenesis. Cancer Cell 9:13–22,
2006.
185. Lange C, Huttner WB, Calegari F. Cdk4/cyclinD1 overexpression in neural stem cells
shortens G1, delays neurogenesis, promotes the generation and expansion of basal
progenitors. Cell Stem Cell 5:320 –331, 2009.
186. Lechler T, Fuchs E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437:275–280, 2005.
187. Lee CY, Andersen RO, Cabernard C, Manning L, Tran KD, Lanskey MJ, Bashirullah A,
Doe CQ. Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating
aPKC/Numb cortical polarity and spindle orientation. Genes Dev 20:3464 –3474,
2006.
188. Lee JH, Jo J, Hardikar AA, Periwal V, Rane SG. Cdk4 regulates recruitment of quiescent beta-cells and ductal epithelial progenitors to reconstitute beta-cell mass. PLoS
One 5:e8653, 2010.
189. Leland S, Nagarajan P, Polyzos A, Thomas S, Samaan G, Donnell R, Marchetti F,
Venkatachalam S. Heterozygosity for a Bub1 mutation causes female-specific germ
cell aneuploidy in mice. Proc Natl Acad Sci USA 106:12776 –12781, 2009.
190. Li T, Inoue A, Lahti JM, Kidd VJ. Failure to proliferate and mitotic arrest of
CDK11(p110/p58)-null mutant mice at the blastocyst stage of embryonic cell development. Mol Cell Biol 24:3188 –3197, 2004.
191. Li X, Sakashita G, Matsuzaki H, Sugimoto K, Kimura K, Hanaoka F, Taniguchi H,
Furukawa K, Urano T. Direct association with inner centromere protein (INCENP)
activates the novel chromosomal passenger protein, Aurora-C. J Biol Chem 279:
47201– 47211, 2004.
200. Lordier L, Chang Y, Jalil A, Aurade F, Garcon L, Lecluse Y, Larbret F, Kawashima T,
Kitamura T, Larghero J, Debili N, Vainchenker W. Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process. Blood 116:
2345–2355, 2010.
201. Loyer P, Trembley JH, Grenet JA, Busson A, Corlu A, Zhao W, Kocak M, Kidd VJ, Lahti
JM. Characterization of cyclin L1 and L2 interactions with CDK11 and splicing factors:
influence of cyclin L isoforms on splice site selection. J Biol Chem 283:7721–7732,
2008.
202. Loyer P, Trembley JH, Katona R, Kidd VJ, Lahti JM. Role of CDK/cyclin complexes in
transcription and RNA splicing. Cell Signal 17:1033–1051, 2005.
203. Lu LY, Wood JL, Minter-Dykhouse K, Ye L, Saunders TL, Yu X, Chen J. Polo-like
kinase 1 is essential for early embryonic development and tumor suppression. Mol Cell
Biol 28:6870 – 6876, 2008.
204. Llamazares S, Moreira A, Tavares A, Girdham C, Spruce BA, Gonzalez C, Karess RE,
Glover DM, Sunkel CE. polo encodes a protein kinase homolog required for mitosis
in Drosophila. Genes Dev 5:2153–2165, 1991.
205. Ma S, Charron J, Erikson RL. Role of Plk2 (Snk) in mouse development and cell
proliferation. Mol Cell Biol 23:6936 – 6943, 2003.
206. Macaluso M, Montanari M, Giordano A. Rb family proteins as modulators of gene
expression and new aspects regarding the interaction with chromatin remodeling
enzymes. Oncogene 25:5263–5267, 2006.
207. Maciejowski J, George KA, Terret ME, Zhang C, Shokat KM, Jallepalli PV. Mps1
directs the assembly of Cdc20 inhibitory complexes during interphase and mitosis to
control M phase timing and spindle checkpoint signaling. J Cell Biol 190:89 –100, 2010.
208. Malumbres M, Barbacid M. Cell cycle kinases in cancer. Curr Opin Genet Dev 17:60 –
65, 2007.
209. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev
Cancer 9:153–166, 2009.
210. Malumbres M, Barbacid M. Is Cyclin D1-CDK4 kinase a bona fide cancer target?
Cancer Cell 9:2– 4, 2006.
211. Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci
30:630 – 641, 2005.
212. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat
Rev Cancer 1:222–231, 2001.
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
1003
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
178. Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: aneuploidy and the
mitotic checkpoint. Nat Rev Cancer 5:773–785, 2005.
MARCOS MALUMBRES
213. Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, Morgan DO, Tsai
LH, Wolgemuth DJ. Cyclin-dependent kinases: a family portrait. Nat Cell Biol 11:
1275–1276, 2009.
214. Malumbres M, Pevarello P, Barbacid M, Bischoff JR. CDK inhibitors in cancer therapy:
what is next? Trends Pharmacol Sci 29:16 –21, 2008.
215. Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A, Ortega S, Dubus P, Barbacid M. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and
Cdk6. Cell 118:493–504, 2004.
216. Manchado E, Eguren M, Malumbres M. The anaphase-promoting complex/cyclosome
(APC/C): cell-cycle-dependent and -independent functions. Biochem Soc Trans 38:65–
71, 2010.
217. Manchado E, Guillamot M, de Cárcer G, Eguren M, Trickey M, García-Higuera I,
Moreno S, Yamano H, Cañamero M, Malumbres M. Targeting mitotic exit leads to
tumor regression in vivo: modulation by Cdk1, Mastl and the PP2A/B55alpha,delta
phosphatase. Cancer Cell 18:641– 654, 2010.
219. Mao D, Hinds PW. p35 is required for CDK5 activation in cellular senescence. J Biol
Chem 285:14671–14680, 2010.
220. Marchetti F, Venkatachalam S. The multiple roles of Bub1 in chromosome segregation
during mitosis and meiosis. Cell Cycle 9:58 – 63, 2010.
221. Martin-Lluesma S, Stucke VM, Nigg EA. Role of Hec1 in spindle checkpoint signaling
and kinetochore recruitment of Mad1/Mad2. Science 297:2267–2270, 2002.
235. Mori D, Yamada M, Mimori-Kiyosue Y, Shirai Y, Suzuki A, Ohno S, Saya H, WynshawBoris A, Hirotsune S. An essential role of the aPKC-Aurora A-NDEL1 pathway in
neurite elongation by modulation of microtubule dynamics. Nat Cell Biol 11:1057–
1068, 2009.
236. Mori D, Yano Y, Toyo-oka K, Yoshida N, Yamada M, Muramatsu M, Zhang D, Saya H,
Toyoshima YY, Kinoshita K, Wynshaw-Boris A, Hirotsune S. NDEL1 phosphorylation
by Aurora-A kinase is essential for centrosomal maturation, separation, and TACC3
recruitment. Mol Cell Biol 27:352–367, 2007.
237. Morris EJ, Ji JY, Yang F, Di Stefano L, Herr A, Moon NS, Kwon EJ, Haigis KM, Naar AM,
Dyson NJ. E2F1 represses beta-catenin transcription and is antagonized by both pRB
and CDK8. Nature 455:552–556, 2008.
238. Mross K, Frost A, Steinbild S, Hedbom S, Rentschler J, Kaiser R, Rouyrre N, Trommeshauser D, Hoesl CE, Munzert G. Phase I dose escalation and pharmacokinetic
study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid
tumors. J Clin Oncol 26:5511–5517, 2008.
239. Mukhopadhyay A, Kramer JM, Merkx G, Lugtenberg D, Smeets DF, Oortveld MA,
Blokland EA, Agrawal J, Schenck A, van Bokhoven H, Huys E, Schoenmakers EF, van
Kessel AG, van Nouhuys CE, Cremers FP. CDK19 is disrupted in a female patient with
bilateral congenital retinal folds, microcephaly and mild mental retardation. Hum
Genet 128:281–291, 2010.
222. Martin J, Hunt SL, Dubus P, Sotillo R, Nehme-Pelluard F, Magnuson MA, Parlow AF,
Malumbres M, Ortega S, Barbacid M. Genetic rescue of Cdk4 null mice restores
pancreatic beta-cell proliferation but not homeostatic cell number. Oncogene 22:
5261–5269, 2003.
240. Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nat Rev
Mol Cell Biol 8:379 –393, 2007.
223. Massague J. G1 cell-cycle control and cancer. Nature 432:298 –306, 2004.
241. Myers JS, Zhao R, Xu X, Ham AJ, Cortez D. Cyclin-dependent kinase 2 dependent
phosphorylation of ATRIP regulates the G2-M checkpoint response to DNA damage.
Cancer Res 67:6685– 6690, 2007.
224. Matarasso N, Bar-Shira A, Rozovski U, Rosner S, Orr-Urtreger A. Functional analysis
of the Aurora Kinase A Ile31 allelic variant in human prostate. Neoplasia 9:707–715,
2007.
225. Matos J, Lipp JJ, Bogdanova A, Guillot S, Okaz E, Junqueira M, Shevchenko A, Zachariae W. Dbf4-dependent CDC7 kinase links DNA replication to the segregation of
homologous chromosomes in meiosis I. Cell 135:662– 678, 2008.
226. Matsuura S, Matsumoto Y, Morishima K, Izumi H, Matsumoto H, Ito E, Tsutsui K,
Kobayashi J, Tauchi H, Kajiwara Y, Hama S, Kurisu K, Tahara H, Oshimura M, Komatsu K, Ikeuchi T, Kajii T. Monoallelic BUB1B mutations and defective mitotic-spindle
checkpoint in seven families with premature chromatid separation (PCS) syndrome.
Am J Med Genet A 140:358 –367, 2006.
227. Matthew EM, Yen TJ, Dicker DT, Dorsey JF, Yang W, Navaraj A, El-Deiry WS.
Replication stress, defective S-phase checkpoint and increased death in Plk2-deficient
human cancer cells. Cell Cycle 6:2571–2578, 2007.
228. Mbefo MK, Paleologou KE, Boucharaba A, Oueslati A, Schell H, Fournier M,
Olschewski D, Yin G, Zweckstetter M, Masliah E, Kahle PJ, Hirling H, Lashuel HA.
Phosphorylation of synucleins by members of the Polo-like kinase family. J Biol Chem
285:2807–2822, 2010.
229. McGuinness BE, Anger M, Kouznetsova A, Gil-Bernabe AM, Helmhart W, Kudo NR,
Wuensche A, Taylor S, Hoog C, Novak B, Nasmyth K. Regulation of APC/C activity in
oocytes by a Bub1-dependent spindle assembly checkpoint. Curr Biol 19:369 –380,
2009.
242. Nassirpour R, Shao L, Flanagan P, Abrams T, Jallal B, Smeal T, Yin MJ. Nek6 mediates
human cancer cell transformation and is a potential cancer therapeutic target. Mol
Cancer Res 8:717–728, 2010.
243. Neumann B, Walter T, Heriche JK, Bulkescher J, Erfle H, Conrad C, Rogers P, Poser
I, Held M, Liebel U, Cetin C, Sieckmann F, Pau G, Kabbe R, Wunsche A, Satagopam V,
Schmitz MH, Chapuis C, Gerlich DW, Schneider R, Eils R, Huber W, Peters JM,
Hyman AA, Durbin R, Pepperkok R, Ellenberg J. Phenotypic profiling of the human
genome by time-lapse microscopy reveals cell division genes. Nature 464:721–727,
2010.
244. Ng SS, Cheung YT, An XM, Chen YC, Li M, Li GH, Cheung W, Sze J, Lai L, Peng Y, Xia
HH, Wong BC, Leung SY, Xie D, He ML, Kung HF, Lin MC. Cell cycle-related kinase:
a novel candidate oncogene in human glioblastoma. J Natl Cancer Inst 99:936 –948,
2007.
245. Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol
Cell Biol 2:21–32, 2001.
246. Nihira K, Taira N, Miki Y, Yoshida K. TTK/Mps1 controls nuclear targeting of c-Abl by
14 –3-3-coupled phosphorylation in response to oxidative stress. Oncogene 27:7285–
7295, 2008.
247. Nurse P. Genetic control of cell size at cell division in yeast. Nature 256:547–551,
1975.
248. Nurse P. A long twentieth century of the cell cycle and beyond. Cell 100:71–78, 2000.
230. Miao X, Sun T, Wang Y, Zhang X, Tan W, Lin D. Functional STK15 Phe31Ile polymorphism is associated with the occurrence and advanced disease status of esophageal squamous cell carcinoma. Cancer Res 64:2680 –2683, 2004.
249. O’Regan L, Blot J, Fry AM. Mitotic regulation by NIMA-related kinases. Cell Div 2:25,
2007.
231. Miller CT, Gabrielse C, Chen YC, Weinreich M. Cdc7p-Dbf4p regulates mitotic exit
by inhibiting Polo kinase. PLoS Genet 5:e1000498, 2009.
250. Orford KW, Scadden DT. Deconstructing stem cell self-renewal: genetic insights into
cell-cycle regulation. Nat Rev Genet 9:115–128, 2008.
232. Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE,
Morrison SJ. Increasing p16INK4a expression decreases forebrain progenitors and
neurogenesis during ageing. Nature 443:448 – 452, 2006.
251. Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, Barbero JL, Malumbres M,
Barbacid M. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell
division in mice. Nat Genet 35:25–31, 2003.
233. Montagnoli A, Moll J, Colotta F. Targeting Cdc7 kinase: a new approach for cancer
therapy. Clin Cancer Res 16:24503– 4508, 2010.
252. Pak DT, Sheng M. Targeted protein degradation and synapse remodeling by an inducible protein kinase. Science 302:1368 –1373, 2003.
1004
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
218. Manning G, Plowman GD, Hunter T, Sudarsanam S. Evolution of protein kinase
signaling from yeast to man. Trends Biochem Sci 27:514 –520, 2002.
234. Montagnoli A, Valsasina B, Croci V, Menichincheri M, Rainoldi S, Marchesi V, Tibolla
M, Tenca P, Brotherton D, Albanese C, Patton V, Alzani R, Ciavolella A, Sola F,
Molinari A, Volpi D, Avanzi N, Fiorentini F, Cattoni M, Healy S, Ballinari D, Pesenti E,
Isacchi A, Moll J, Bensimon A, Vanotti E, Santocanale C. A Cdc7 kinase inhibitor
restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol 4:357–
365, 2008.
CELL CYCLE KINASES
253. Parker JD, Bradley BA, Mooers AO, Quarmby LM. Phylogenetic analysis of the Neks
reveals early diversification of ciliary-cell cycle kinases. PLoS One 2:e1076, 2007.
254. Pasumarthi KB, Nakajima H, Nakajima HO, Soonpaa MH, Field LJ. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in
transgenic mice. Circ Res 96:110 –118, 2005.
255. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, Fend
F, Graw J, Atkinson MJ. Germ-line mutations in p27Kip1 cause a multiple endocrine
neoplasia syndrome in rats and humans. Proc Natl Acad Sci USA 103:15558 –15563,
2006.
256. Pellegrino R, Calvisi DF, Ladu S, Ehemann V, Staniscia T, Evert M, Dombrowski F,
Schirmacher P, Longerich T. Oncogenic and tumor suppressive roles of polo-like
kinases in human hepatocellular carcinoma. Hepatology 51:857– 868, 2010.
257. Perera D, Tilston V, Hopwood JA, Barchi M, Boot-Handford RP, Taylor SS. Bub1
maintains centromeric cohesion by activation of the spindle checkpoint. Dev Cell
13:566 –579, 2007.
259. Perez de Castro I, de Carcer G, Montoya G, Malumbres M. Emerging cancer therapeutic opportunities by inhibiting mitotic kinases. Curr Opin Pharmacol 8:375–383,
2008.
260. Petretti C, Savoian M, Montembault E, Glover DM, Prigent C, Giet R. The PITSLRE/
CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation. EMBO Rep 7:418 – 424, 2006.
261. Petronczki M, Lenart P, Peters JM. Polo on the rise: from mitotic entry to cytokinesis
with Plk1. Dev Cell 14:646 – 659, 2008.
262. Poss KD, Nechiporuk A, Hillam AM, Johnson SL, Keating MT. Mps1 defines a proximal
blastemal proliferative compartment essential for zebrafish fin regeneration. Development 129:5141–5149, 2002.
263. Poss KD, Nechiporuk A, Stringer KF, Lee C, Keating MT. Germ cell aneuploidy in
zebrafish with mutations in the mitotic checkpoint gene mps1. Genes Dev 18:1527–
1532, 2004.
264. Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science 298:2188 –
2190, 2002.
275. Richie CT, Golden A. Chromosome segregation: Aurora B gets Tousled. Curr Biol
15:R379 –382, 2005.
276. Risebro CA, Smart N, Dupays L, Breckenridge R, Mohun TJ, Riley PR. Hand1 regulates cardiomyocyte proliferation versus differentiation in the developing heart. Development 133:4595– 4606, 2006.
277. Rosales JL, Rattner JB, Lee KY. The primary microcephaly 3 (MCPH3) interacting
protein, p35 and its catalytic subunit, Cdk5, are centrosomal proteins. Cell Cycle
9:618 – 620, 2010.
278. Rosario CO, Ko MA, Haffani YZ, Gladdy RA, Paderova J, Pollett A, Squire JA, Dennis
JW, Swallow CJ. Plk4 is required for cytokinesis and maintenance of chromosomal
stability. Proc Natl Acad Sci USA 107:6888 – 6893, 2010.
279. Ruchaud S, Carmena M, Earnshaw WC. Chromosomal passengers: conducting cell
division. Nat Rev Mol Cell Biol 8:798 – 812, 2007.
280. Russell KJ, Wiens LW, Demers GW, Galloway DA, Plon SE, Groudine M. Abrogation
of the G2 checkpoint results in differential radiosensitization of G1 checkpoint-deficient and G1 checkpoint-competent cells. Cancer Res 55:1639 –1642, 1995.
281. Sabbattini P, Canzonetta C, Sjoberg M, Nikic S, Georgiou A, Kemball-Cook G, Auner
HW, Dillon N. A novel role for the Aurora B kinase in epigenetic marking of silent
chromatin in differentiated postmitotic cells. EMBO J 26:4657– 4669, 2007.
282. Salem H, Rachmin I, Yissachar N, Cohen S, Amiel A, Haffner R, Lavi L, Motro B. Nek7
kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy. Oncogene 29:4046 – 4057, 2010.
283. Salomoni P, Calegari F. Cell cycle control of mammalian neural stem cells: putting a
speed limit on G1. Trends Cell Biol 20:233–243, 2010.
284. Sankaran VG, Orkin SH, Walkley CR. Rb intrinsically promotes erythropoiesis by
coupling cell cycle exit with mitochondrial biogenesis. Genes Dev 22:463– 475, 2008.
285. Sano M, Abdellatif M, Oh H, Xie M, Bagella L, Giordano A, Michael LH, DeMayo FJ,
Schneider MD. Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. Nat Med 8:1310 –1317, 2002.
265. Prokopenko SN, Chia W. When timing is everything: role of cell cycle regulation in
asymmetric division. Semin Cell Dev Biol 16:423– 437, 2005.
286. Sano M, Wang SC, Shirai M, Scaglia F, Xie M, Sakai S, Tanaka T, Kulkarni PA, Barger
PM, Youker KA, Taffet GE, Hamamori Y, Michael LH, Craigen WJ, Schneider MD.
Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart
failure. EMBO J 23:3559 –3569, 2004.
266. Puyol M, Martin A, Dubus P, Mulero F, Pizcueta P, Khan G, Guerra C, Santamaria
D, Barbacid M. A synthetic lethal interaction between K-Ras oncogenes and Cdk4
unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18:
63–73, 2010.
287. Santaguida S, Tighe A, D’Alise AM, Taylor SS, Musacchio A. Dissecting the role of
MPS1 in chromosome biorientation and the spindle checkpoint through the small
molecule inhibitor reversine. J Cell Biol 190:73– 87, 2010.
267. Qiu H, Dai H, Jain K, Shah R, Hong C, Pain J, Tian B, Vatner DE, Vatner SF, Depre C.
Characterization of a novel cardiac isoform of the cell cycle-related kinase that is
regulated during heart failure. J Biol Chem 283:22157–22165, 2008.
288. Santamaria D, Barriere C, Cerqueira A, Hunt S, Tardy C, Newton K, Caceres JF,
Dubus P, Malumbres M, Barbacid M. Cdk1 is sufficient to drive the mammalian cell
cycle. Nature 448:811– 815, 2007.
268. Quarmby LM, Mahjoub MR. Caught Nek-ing: cilia and centrioles. J Cell Sci 118:5161–
5169, 2005.
289. Santos-Rosa H, Leung J, Grimsey N, Peak-Chew S, Siniossoglou S. The yeast lipin
Smp2 couples phospholipid biosynthesis to nuclear membrane growth. EMBO J 24:
1931–1941, 2005.
269. Quereda V, Malumbres M. Cell cycle control of pituitary development and disease. J
Mol Endocrinol 42:75– 86, 2009.
270. Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M. Loss of
Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in betaislet cell hyperplasia. Nat Genet 22:44 –52, 1999.
271. Rao CV, Yang YM, Swamy MV, Liu T, Fang Y, Mahmood R, Jhanwar-Uniyal M, Dai W.
Colonic tumorigenesis in BubR1⫹/-ApcMin/⫹ compound mutant mice is linked to
premature separation of sister chromatids and enhanced genomic instability. Proc Natl
Acad Sci USA 102:4365– 4370, 2005.
290. Sarruf DA, Iankova I, Abella A, Assou S, Miard S, Fajas L. Cyclin D3 promotes adipogenesis through activation of peroxisome proliferator-activated receptor gamma. Mol
Cell Biol 25:9985–9995, 2005.
291. Sasai K, Katayama H, Stenoien DL, Fujii S, Honda R, Kimura M, Okano Y, Tatsuka M,
Suzuki F, Nigg EA, Earnshaw WC, Brinkley WR, Sen S. Aurora-C kinase is a novel
chromosomal passenger protein that can complement Aurora-B kinase function in
mitotic cells. Cell Motil Cytoskeleton 59:249 –263, 2004.
272. Reinhardt HC, Yaffe MB. Kinases that control the cell cycle in response to DNA
damage: Chk1, Chk2, and MK2. Curr Opin Cell Biol 21:245–255, 2009.
292. Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CA,
Jin J, Cai Y, Washburn MP, Conaway JW, Conaway RC. A set of consensus mammalian
mediator subunits identified by multidimensional protein identification technology.
Mol Cell 14:685– 691, 2004.
273. Rekhtman N, Choe KS, Matushansky I, Murray S, Stopka T, Skoultchi AI. PU1 and pRB
interact and cooperate to repress GATA-1 and block erythroid differentiation. Mol
Cell Biol 23:7460 –7474, 2003.
293. Satyanarayana A, Berthet C, Lopez-Molina J, Coppola V, Tessarollo L, Kaldis P. Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic
function of Cdk2. Development 135:3389 –3400, 2008.
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
1005
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
258. Perez de Castro I, de Carcer G, Malumbres M. A census of mitotic cancer genes: new
insights into tumor cell biology and cancer therapy. Carcinogenesis 28:899 –912, 2007.
274. Richards MW, O’Regan L, Mas-Droux C, Blot JM, Cheung J, Hoelder S, Fry AM,
Bayliss R. An autoinhibitory tyrosine motif in the cell-cycle-regulated Nek7 kinase is
released through binding of Nek9. Mol Cell 36:560 –570, 2009.
MARCOS MALUMBRES
294. Sawa H. Specification of neurons through asymmetric cell divisions. Curr Opin Neurobiol 20:44 – 49, 2010.
316. Sun T, Miao X, Wang J, Tan W, Zhou Y, Yu C, Lin D. Functional Phe31Ile polymorphism in Aurora A and risk of breast carcinoma. Carcinogenesis 25:2225–2230, 2004.
295. Schmidt M, Budirahardja Y, Klompmaker R, Medema RH. Ablation of the spindle
assembly checkpoint by a compound targeting Mps1. EMBO Rep 6:866 – 872, 2005.
317. Sunkel CE, Glover DM. polo, a mitotic mutant of Drosophila displaying abnormal
spindle poles. J Cell Sci 89:25–38, 1988.
296. Schoffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist 14:559 –570, 2009.
318. Swords R, Mahalingam D, O’Dwyer M, Santocanale C, Kelly K, Carew J, Giles F. Cdc7
kinase: a new target for drug development. Eur J Cancer 46:33– 40, 2010.
297. Schoffski P, Blay JY, De Greve J, Brain E, Machiels JP, Soria JC, Sleijfer S, Wolter P,
Ray-Coquard I, Fontaine C, Munzert G, Fritsch H, Hanft G, Aerts C, Rapion J, Allgeier
A, Bogaerts J, Lacombe D. Multicentric parallel phase II trial of the polo-like kinase 1
inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer,
ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European
Organization for Research and Treatment of Cancer (EORTC) Network Of Core
Institutes (NOCI). Eur J Cancer 46:2206 –2215, 2010.
319. Syed N, Smith P, Sullivan A, Spender LC, Dyer M, Karran L, O’Nions J, Allday M,
Hoffmann I, Crawford D, Griffin B, Farrell PJ, Crook T. Transcriptional silencing of
Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies. Blood 107:
250 –256, 2006.
298. Seeburg DP, Feliu-Mojer M, Gaiottino J, Pak DT, Sheng M. Critical role of CDK5 and
Polo-like kinase 2 in homeostatic synaptic plasticity during elevated activity. Neuron
58:571–583, 2008.
300. Seeburg DP, Sheng M. Activity-induced Polo-like kinase 2 is required for homeostatic
plasticity of hippocampal neurons during epileptiform activity. J Neurosci 28:6583–
6591, 2008.
301. Sheu YJ, Stillman B. Cdc7-Dbf4 phosphorylates MCM proteins via a docking sitemediated mechanism to promote S phase progression. Mol Cell 24:101–113, 2006.
302. Sheu YJ, Stillman B. The Dbf4-Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4. Nature 463:113–117, 2010.
303. Shichiri M, Yoshinaga K, Hisatomi H, Sugihara K, Hirata Y. Genetic and epigenetic
inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to
survival. Cancer Res 62:13–17, 2002.
304. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev
Cancer 3:155–168, 2003.
305. Simanis V, Nurse P. The cell cycle control gene cdc2⫹ of fission yeast encodes a
protein kinase potentially regulated by phosphorylation. Cell 45:261–268, 1986.
306. Simiz US, Osada H. Mutations in the Plk gene lead to instability of Plk protein in human
tumour cell lines. Nat Cell Biol 2:852– 854, 2000.
307. Slattery SD, Moore RV, Brinkley BR, Hall RM. Aurora-C and Aurora-B share phosphorylation and regulation of CENP-A and Borealin during mitosis. Cell Cycle 7:787–
795, 2008.
308. Soonpaa MH, Koh GY, Pajak L, Jing S, Wang H, Franklin MT, Kim KK, Field LJ. Cyclin
D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in
transgenic mice. J Clin Invest 99:2644 –2654, 1997.
309. Sotillo R, Dubus P, Martin J, de la Cueva E, Ortega S, Malumbres M, Barbacid M. Wide
spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4
inhibitors. EMBO J 20:6637– 6647, 2001.
310. Stead E, White J, Faast R, Conn S, Goldstone S, Rathjen J, Dhingra U, Rathjen P,
Walker D, Dalton S. Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin
A/E and E2F activities. Oncogene 21:8320 – 8333, 2002.
311. Steigemann P, Wurzenberger C, Schmitz MH, Held M, Guizetti J, Maar S, Gerlich
DW. Aurora B-mediated abscission checkpoint protects against tetraploidization. Cell
136:473– 484, 2009.
312. Steinman RA. Cell cycle regulators and hematopoiesis. Oncogene 21:3403–3413,
2002.
321. Tang CJ, Lin CY, Tang TK. Dynamic localization and functional implications of Aurora-C kinase during male mouse meiosis. Dev Biol 290:398 – 410, 2006.
322. Tchatchou S, Wirtenberger M, Hemminki K, Sutter C, Meindl A, Wappenschmidt B,
Kiechle M, Bugert P, Schmutzler RK, Bartram CR, Burwinkel B. Aurora kinases A and
B and familial breast cancer risk. Cancer Lett 247:266 –272, 2007.
323. Thornton GK, Woods CG. Primary microcephaly: do all roads lead to Rome? Trends
Genet 25:501–510, 2009.
324. Tighe A, Staples O, Taylor S. Mps1 kinase activity restrains anaphase during an unperturbed mitosis and targets Mad2 to kinetochores. J Cell Biol 181:893–901, 2008.
325. Tilston V, Taylor SS, Perera D. Inactivating the spindle checkpoint kinase Bub1 during
embryonic development results in a global shutdown of proliferation. BMC Res Notes
2:190, 2009.
326. Tio M, Udolph G, Yang X, Chia W. cdc2 links the Drosophila cell cycle and asymmetric
division machineries. Nature 409:1063–1067, 2001.
327. Tripathi BK, Zelenka PS. Cdk5: a regulator of epithelial cell adhesion and migration.
Cell Adh Migr 4:333–336, 2010.
328. Tsai LH, Lee MS, Cruz J. Cdk5, a therapeutic target for Alzheimer’s disease? Biochim
Biophys Acta 1697:137–142, 2004.
329. Tseng TC, Chen SH, Hsu YP, Tang TK. Protein kinase profile of sperm and eggs:
cloning and characterization of two novel testis-specific protein kinases (AIE1, AIE2)
related to yeast and fly chromosome segregation regulators. DNA Cell Biol 17:823–
833, 1998.
330. Tsuji T, Lau E, Chiang GG, Jiang W. The role of Dbf4/Drf1-dependent kinase Cdc7 in
DNA-damage checkpoint control. Mol Cell 32:862– 869, 2008.
331. Tsunoda N, Kokuryo T, Oda K, Senga T, Yokoyama Y, Nagino M, Nimura Y, Hamaguchi M. Nek2 as a novel molecular target for the treatment of breast carcinoma.
Cancer Sci 100:111–116, 2009.
332. Tsutsui T, Hesabi B, Moons DS, Pandolfi PP, Hansel KS, Koff A, Kiyokawa H. Targeted
disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity. Mol Cell
Biol 19:7011–7019, 1999.
333. Turenchalk GS, ,St John MA, Tao W, Xu T. The role of lats in cell cycle regulation and
tumorigenesis. Biochim Biophys Acta 1424:M9 –M16, 1999.
334. Ubersax JA, Woodbury EL, Quang PN, Paraz M, Blethrow JD, Shah K, Shokat KM,
Morgan DO. Targets of the cyclin-dependent kinase Cdk1. Nature 425:859 – 864,
2003.
313. Strebhardt K, Ullrich A. Targeting polo-like kinase 1 for cancer therapy. Nat Rev
Cancer 6:321–330, 2006.
335. Ullah Z, Kohn MJ, Yagi R, Vassilev LT, DePamphilis ML. Differentiation of trophoblast
stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity. Genes
Dev 22:3024 –3036, 2008.
314. Stucke VM, Sillje HH, Arnaud L, Nigg EA. Human Mps1 kinase is required for the
spindle assembly checkpoint but not for centrosome duplication. EMBO J 21:1723–
1732, 2002.
336. Upadhya P, Birkenmeier EH, Birkenmeier CS, Barker JE. Mutations in a NIMA-related
kinase gene, Nek1, cause pleiotropic effects including a progressive polycystic kidney
disease in mice. Proc Natl Acad Sci USA 97:217–221, 2000.
315. Suijkerbuijk SJ, van Osch MH, Bos FL, Hanks S, Rahman N, Kops GJ. Molecular causes
for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy. Cancer Res 70:4891– 4900, 2010.
337. Uren AG, Wong L, Pakusch M, Fowler KJ, Burrows FJ, Vaux DL, Choo KH. Survivin
and the inner centromere protein INCENP show similar cell-cycle localization and
gene knockout phenotype. Curr Biol 10:1319 –1328, 2000.
1006
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
299. Seeburg DP, Pak D, Sheng M. Polo-like kinases in the nervous system. Oncogene
24:292–298, 2005.
320. Takaki T, Trenz K, Costanzo V, Petronczki M. Polo-like kinase 1 reaches beyond
mitosis– cytokinesis, DNA damage response, and development. Curr Opin Cell Biol
20:650 – 660, 2008.
CELL CYCLE KINASES
338. Van de Weerdt BC, Littler DR, Klompmaker R, Huseinovic A, Fish A, Perrakis A,
Medema RH. Polo-box domains confer target specificity to the Polo-like kinase family.
Biochim Biophys Acta 1783:1015–1022, 2008.
339. Van de Weerdt BC, Medema RH. Polo-like kinases: a team in control of the division.
Cell Cycle 5:853– 864, 2006.
340. Van Vugt MA, Bras A, Medema RH. Restarting the cell cycle when the checkpoint
comes to a halt. Cancer Res 65:7037–7040, 2005.
341. Vigneron S, Brioudes E, Burgess A, Labbe JC, Lorca T, Castro A. Greatwall maintains
mitosis through regulation of PP2A. EMBO J 28:2786 –2793, 2009.
342. Walsh K, Perlman H. Cell cycle exit upon myogenic differentiation. Curr Opin Genet
Dev 7:597– 602, 1997.
343. Wang H, Ouyang Y, Somers WG, Chia W, Lu B. Polo inhibits progenitor self-renewal
and regulates Numb asymmetry by phosphorylating Pon. Nature 449:96 –100, 2007.
345. Wang L, Gao J, Dai W, Lu L. Activation of Polo-like kinase 3 by hypoxic stresses. J Biol
Chem 283:25928 –25935, 2008.
346. Wang Q, Liu T, Fang Y, Xie S, Huang X, Mahmood R, Ramaswamy G, Sakamoto KM,
Darzynkiewicz Z, Xu M, Dai W. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood 103:1278 –1285, 2004.
347. Wang S, Fischer PM. Cyclin-dependent kinase 9: a key transcriptional regulator and
potential drug target in oncology, virology and cardiology. Trends Pharmacol Sci 29:
302–313, 2008.
348. Wasch R, Hasskarl J, Schnerch D, Lubbert M. BI_2536 –targeting the mitotic kinase
Polo-like kinase 1 (Plk1). Recent Results Cancer Res 184:215–218, 2010.
349. White J, Dalton S. Cell cycle control of embryonic stem cells. Stem Cell Rev 1:131–138,
2005.
350. Wilker EW, van Vugt MA, Artim SA, Huang PH, Petersen CP, Reinhardt HC, Feng Y,
Sharp PA, Sonenberg N, White FM, Yaffe MB. 14 –3-3sigma controls mitotic translation to facilitate cytokinesis. Nature 446:329 –332, 2007.
351. Winey M, Goetsch L, Baum P, Byers B. MPS1 and MPS2: novel yeast genes defining
distinct steps of spindle pole body duplication. J Cell Biol 114:745–754, 1991.
352. Winkles JA, Alberts GF. Differential regulation of polo-like kinase 1, 2, 3, and 4 gene
expression in mammalian cells and tissues. Oncogene 24:260 –266, 2005.
353. Wirtz-Peitz F, Nishimura T, Knoblich JA. Linking cell cycle to asymmetric division:
Aurora-A phosphorylates the Par complex to regulate Numb localization. Cell 135:
161–173, 2008.
354. Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, De Plaen E, Hankeln
T, Meyer zum Buschenfelde KH, Beach D. A p16INK4a-insensitive CDK4 mutant targeted
by cytolytic T lymphocytes in a human melanoma. Science 269:1281–1284, 1995.
355. Wu GQ, Xie D, Yang GF, Liao YJ, Mai SJ, Deng HX, Sze J, Guan XY, Zeng YX, Lin MC,
Kung HF. Cell cycle-related kinase supports ovarian carcinoma cell proliferation via
regulation of cyclin D1 and is a predictor of outcome in patients with ovarian carcinoma. Int J Cancer 125:2631–2642, 2009.
356. Xie S, Wang Q, Wu H, Cogswell J, Lu L, Jhanwar-Uniyal M, Dai W. Reactive oxygen
species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like
kinase-3. J Biol Chem 276:36194 –36199, 2001.
357. Xie S, Wu H, Wang Q, Cogswell JP, Husain I, Conn C, Stambrook P, Jhanwar-Uniyal
M, Dai W. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at
least in part via the p53 pathway. J Biol Chem 276:43305– 43312, 2001.
359. Yan X, Cao L, Li Q, Wu Y, Zhang H, Saiyin H, Liu X, Zhang X, Shi Q, Yu L. Aurora C
is directly associated with Survivin and required for cytokinesis. Genes Cells 10:617–
626, 2005.
360. Yang KT, Li SK, Chang CC, Tang CJ, Lin YN, Lee SC, Tang TK. Aurora-C kinase
deficiency causes cytokinesis failure in meiosis I and production of large polyploid
oocytes in mice. Mol Biol Cell 21:2371–2383, 2010.
361. Yang Y, Bai J, Shen R, Brown SA, Komissarova E, Huang Y, Jiang N, Alberts GF, Costa
M, Lu L, Winkles JA, Dai W. Polo-like kinase 3 functions as a tumor suppressor and is
a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditions.
Cancer Res 68:4077– 4085, 2008.
362. Ye X, Zhu C, Harper JW. A premature-termination mutation in the Mus musculus
cyclin-dependent kinase 3 gene. Proc Natl Acad Sci USA 98:1682–1686, 2001.
363. Yokoyama H, Gruss OJ, Rybina S, Caudron M, Schelder M, Wilm M, Mattaj IW,
Karsenti E. Cdk11 is a RanGTP-dependent microtubule stabilization factor that regulates spindle assembly rate. J Cell Biol 180:867– 875, 2008.
364. Yu H, Yuan Y, Shen H, Cheng T. Hematopoietic stem cell exhaustion impacted by
p18 INK4C and p21 Cip1/Waf1 in opposite manners. Blood 107:1200 –1206, 2006.
365. Yu J, Fleming SL, Williams B, Williams EV, Li Z, Somma P, Rieder CL, Goldberg ML.
Greatwall kinase: a nuclear protein required for proper chromosome condensation
and mitotic progression in Drosophila. J Cell Biol 164:487– 492, 2004.
366. Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1
ablation. Nature 411:1017–1021, 2001.
367. Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa
H, Harris LN, Stal O, Sicinski P. Requirement for CDK4 kinase function in breast
cancer. Cancer Cell 9:23–32, 2006.
368. Yuan Y, Shen H, Franklin DS, Scadden DT, Cheng T. In vivo self-renewing divisions of
haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nat Cell Biol 6:436 – 442, 2004.
369. Zeng X, Shaikh FY, Harrison MK, Adon AM, Trimboli AJ, Carroll KA, Sharma N,
Timmers C, Chodosh LA, Leone G, Saavedra HI. The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2.
Oncogene 29:5103–5112, 2010.
370. Zhang J, Li H, Yabut O, Fitzpatrick H, D’Arcangelo G, Herrup K. Cdk5 suppresses the
neuronal cell cycle by disrupting the E2F1-DP1 complex. J Neurosci 30:5219 –5228,
2010.
371. Zhang Y, Nagata Y, Yu G, Nguyen HG, Jones MR, Toselli P, Jackson CW, Tatsuka M,
Todokoro K, Ravid K. Aberrant quantity and localization of Aurora-B/AIM-1 and
survivin during megakaryocyte polyploidization and the consequences of Aurora-B/
AIM-1-deregulated expression. Blood 103:3717–3726, 2004.
372. Zhong W, Chia W. Neurogenesis and asymmetric cell division. Curr Opin Neurobiol
18:4 –11, 2008.
373. Zhong W, Mao S, Tobis S, Angelis E, Jordan MC, Roos KP, Fishbein MC, de Alboran
IM, MacLellan WR. Hypertrophic growth in cardiac myocytes is mediated by Myc
through a Cyclin D2-dependent pathway. EMBO J 25:3869 –3879, 2006.
374. Zimmerman WC, Erikson RL. Polo-like kinase 3 is required for entry into S phase. Proc
Natl Acad Sci USA 104:1847–1852, 2007.
Physiol Rev • VOL 91 • JULY 2011 • www.prv.org
1007
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
344. Wang H, Somers GW, Bashirullah A, Heberlein U, Yu F, Chia W. Aurora-A acts as a
tumor suppressor and regulates self-renewal of Drosophila neuroblasts. Genes Dev
20:3453–3463, 2006.
358. Yamanaka Y, Heike T, Kumada T, Shibata M, Takaoka Y, Kitano A, Shiraishi K,
Kato T, Nagato M, Okawa K, Furushima K, Nakao K, Nakamura Y, Taketo MM,
Aizawa S, Nakahata T. Loss of Borealin/DasraB leads to defective cell proliferation, p53 accumulation and early embryonic lethality. Mech Dev 125:441– 450,
2008.