Leukemia (2001) 15, 1011–1021
 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00
www.nature.com/leu
REVIEW
Suppression of apoptosis: role in cell growth and neoplasia
MK White1 and JA McCubrey2
1
Department of Pathology, Anatomy and Cell Biology, The Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA; and
Department of Microbiology and Immunology, East Carolina University School of Medicine, Greenville, NC, USA
2
A cell is a potentially dangerous thing. In unicellular organisms,
cells divide and multiply in a manner that is chiefly determined
by the availability of nutritional substrates. In a multicellular
organism, each cell has a distinct growth potential that is
designed to subsume a role in the function of the whole body.
Departure from this path to one of uncontrolled cellular proliferation leads to cancer. For this reason, evolution has endowed
cells with an elaborate set of systems that cause errant cells
to self-destruct. This process of cell suicide is known as
apoptosis or programmed cell death and it plays a crucial role
in the growth of both normal and malignant cells. In this review,
we describe the mechanisms whereby programmed cell death
is induced and executed. In particular, we concentrate on how
anti-apoptotic signals generated by cytokines promote cell survival and how these signal transduction pathways may be
involved in the pathogenesis of neoplasia. Understanding how
these processes contribute to tumorigenesis may suggest new
therapeutic options. Leukemia (2001) 15, 1011–1021.
Keywords: suppression of apoptosis; phosphatidylinositol 3-kinase; NF-␬B; bcl-2; IAPs; PTEN
Introduction
Metazoan cells are able to initiate a series of events that
causes the activation of intracellular proteases and ultimately
results in the destruction of the cell. This is known as
apoptosis or programmed cell death and is evolutionary
ancient.1 Apoptosis refers to both the initiation and execution
of the events whereby a cell commits suicide and it is distinct
from other forms of cell death.2,3 Two examples of non-apoptotic cell death are: (1) necrosis – cells die from external
insults such as oxygen deprivation or exposure to cytotoxic
chemical agents;4,5 (2) senescence – cells expire when they
reach the end of their replicative lifetime.6 Apoptosis is
marked by an orderly series of hallmark biochemical and morphological events including cell shrinkage, mitochondrial
breakdown and nuclear DNA fragmentation.7 Eventually the
dying cell degrades into apoptotic bodies that are subcellular
membrane-bound vesicles that are ultimately removed by
phagocytosis.
There are two reasons for a cell to undergo apoptosis.
Firstly, the death of the cell may be required for normal
development of a tissue or organ. The classic example is the
resorption of the tail when a tadpole undergoes metamorphosis into a frog.8 Apoptosis provides a means of cell elimination during development, tissue homeostasis and the removal
of self-reactive immune cells.4,5,9 In the lung, for example,
Correspondence: M White, Department of Pathology, Anatomy and
Cell Biology, Jefferson Medical College, Jefferson Alumni Hall, Room
251, 1020 Locust Street, Philadelphia, PA 19107, USA; Fax: (215)
955–8703
Received 19 January 2001; accepted 23 February 2001
apoptosis is involved in normal structural maturation during
both fetal and postnatal development.10,11
Secondly, apoptosis is needed to destroy errant cells that
pose a threat to the organism. For example, virus-infected cells
are eliminated by the interaction with cytotoxic T lymphocytes that kill the virus-infected cells by inducing them to
undergo apoptosis.12,13 Similarly, cells that have DNA damage
undergo apoptosis.14–17 This eliminates cells that have
accrued genetic mutations and may thereby become
cancerous.
An important paradigm of the ontogeny of cancer came
from the discovery of the roles of dormant proto-oncogenes
that mutate into growth promoting oncogenes typified by such
genes as src, ras and raf.18–21 However, on the other hand,
there is another class of genes, known as tumor suppressors
or anti-oncogenes, that suppress oncogenesis.22,23 For
example, cell fusion experiments demonstrated that the malignant potential of cells can be abrogated by fusing them with
normal cells.24,25 Some tumor suppressors are able to counteract the proliferative consequences of oncogenes through their
ability to induce apoptosis. Our present understanding of cancer pivots on the understanding of these opposing influences
and how this knowledge may be used for therapeutic intervention. Indeed, induction of apoptosis is the mode of action
of many anti-tumor chemotherapeutic agents that are
currently in use.14–17
How apoptosis transpires: caspase activation
Activation of the family of proteins known as caspases
(cysteinyl, aspartate-specific proteases) constitutes the means
of execution of apoptosis.26–28 There are at least 14 caspases,
the prototypical member (caspase 1 or ICE) being first recognized because of the sequence similarity between the nematode Caenorhabditis elegans developmental cell death gene
CED-3 and mammalian interleukin-1␤-converting enzyme
(ICE).29 Caspases are synthesized as proenzymes that are activated by proteolysis at two or three sites to remove an Nterminal peptide and divide the proenzyme into a large and
small subunit, which in some cases are separated by a linker
domain. The mature caspase is a heterotetramer of two large
and two small subunits. For example, procaspase 1 is a 45
kDa protein that is cleaved to give 20 kDa and 10 kDa
subunits (p20 and p10) following removal of an 11 kDa Nterminal prodomain and a 2 kDa linker region of unknown
function.30,31
All caspases are activated by cleavage at a specific aspartate
residue. A model has been proposed in which caspases
sequentially activate others, ie there is a cascade that begins
with the activation of an ‘initiator’ caspase, eg caspase 8 (see
below), which activates an ‘amplifier’ caspase, eg caspase 1,
which in turn activates an ‘effector’ caspase, eg caspases 3
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MK White and JA McCubrey
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and 7, that are responsible for the destruction by proteolysis
of the cellular substrates responsible for apoptosis.32
What are the protein substrates that are cleaved by caspases
during the execution phase of apoptosis?
Poly(ADP-ribose) polymerase (PARP)
PARP is the best characterized substrate of caspases. Intact
PARP (116 kDa) is cleaved into two fragments (89 kDa and
24 kDa) during apoptosis in many cell systems.33,34 Cleavage
of PARP is a valuable indicator of apoptosis but its biological
relevance is not known. Caspases 3 and 7 are primarily
responsible for PARP cleavage.26
Caspase-activated deoxyribonuclease (CAD)
CAD is a cytoplasmic endonuclease whose activation is
thought to be responsible for generating the oligonucleosomal
DNA fragments that are the hallmark of apoptosis.35 In nonapoptotic cells, CAD is inactive because of its association with
an inhibitory protein (ICAD) which masks the nuclear localization sequence of CAD. Induction of apoptosis results in
cleavage and inactivation of ICAD allowing CAD to translocate to the nucleus where it fragments the DNA.36
DNA-dependent protein kinase (DNA-PK)
DNA-PK is a DNA repair enzyme that is degraded during
apoptosis by caspase 3.36,37 Degradation of DNA-PK will
result in a decrease in the capacity of the cell to repair damage
to nuclear DNA, thus facilitating the breakdown of DNA that
is associated with apoptosis.
Lamins
Lamins are the major structural component proteins of the
nuclear envelope. During apoptosis, lamins undergo proteolysis38,39 and this may be responsible for the observed morphological changes in the nucleus that are observed during
the course of apoptosis. It is thought that caspase 6 is the
major caspase responsible for lamin degradation.40,41
Fodrin, Gas2, actin
Cleavage of the cytoskeletal proteins fodrin,42 Gas243 and
actin44,45 during apoptosis may induce cell shrinkage, membrane blebbing and alter cell signaling pathways. Consequent
changes in the plasma membrane of the apoptotic cell are
important for its recognition by phagocytic cells.
U1-70 kDa
U1 is a small ribonucleosomal particle that functions in the
splicing of mRNA transcripts. One of its protein components
U1-70 kDa is essential for its function and is cleaved during
apoptosis.37,46 In this way, any cellular process that is dependent on new mRNA synthesis is blocked.
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Translation initiation factors
When apoptosis is induced, the rate of cellular protein synthesis is rapidly diminished and this occurs at the level of
translation initiation. Caspases cleave the initiation factors
eIF4G, eIF4B, eIF2␣ and p35-eIF3.47 Proteolytic cleavage of
these factors may cause the inhibition of translation during
apoptosis.
Cell signaling proteins
Certain cell signaling proteins are cleaved by caspases and
this may contribute to apoptosis. For example, certain protein
kinases are cleaved and rendered constitutively active and
pro-apoptotic. These include protein kinase C-␦,48,49 protein
kinase C-␪,50 MEKK-151 and hPAK65.52 Conversely, protein
kinases involved in anti-apoptotic pathways (eg Raf-1 and protein kinase B, also known as Akt) may be cleaved and inactivated by caspases.53 Cleavage of APC and the tumor suppressor retinoblastoma protein, Rb, have been reported during
apoptosis.54,55 Also the anti-apoptotic proteins Bcl-2 and BclXL (see below) may be degraded during apoptosis.56,57
How apoptosis is initiated; mechanisms of induction of
apoptosis
What makes a cell decide to kill itself? The survival of the cell
hinges on the balance between positive and negative signals.
Many cells require positive signals provided by external
growth factors to survive (Figure 1). For example, nerve
growth factor activates pro-survival signals in neuronal cells58
and cytokines (interleukins) inhibit apoptosis of hematopoietic
cells.27,59,60 Negative signals include stress, oxidants,
irradiation, and toxic chemicals, eg chemotherapeutic agents.
Also discussed below are death activators, eg FasL and TNF.
There are two ways by which a cell is induced to undergo
apoptosis: internal signals arising within the cell or external
signals triggered by death activators that bind to receptors
located at the cell surface. The pathways involved in both
mechanisms are complex, redundant, interdependent and
incompletely understood.
Apoptosis triggered from within: the apoptosome
The key to the initiation of apoptosis by internal signals is the
mitochondrion.61–63 The multi-protein complex that leads to
the autoproteolytic activation of the upstream caspases is
termed the apoptosome (Figure 1). Apoptosome formation is
triggered by the release of cytochrome c from the mitochondrion.64,65 The released cytochrome c binds to Apaf-1, a cytoplasmic protein, which is induced to oligomerize and recruit
and activate procaspase-9.66 Active caspase-9 in turn activates
the executioner caspase-3.
This mitochondrial pathway is controlled by the Bcl-2
family of proteins.
The Bcl-2 family of proteins: the finger on the button
The Bcl-2 family of cytoplasmic proteins are key regulators of
the internal pathway of apoptosis induction.67–69 The prototype of this family, Bcl-2, is a proto-oncogene that is activated
Suppression of apoptosis
MK White and JA McCubrey
1013
Figure 1
Effects of cytokines on the prevention of apoptosis. This figure illustrates the effects of cytokines on the activation of the PI3K/Akt,
Ras/Raf/MEK/ERK and Jak/STAT pathways. Kinases and transcription factors are indicated in green as is the cytokine receptor. Pro-apoptotic
molecules such as activation of the caspase cascade, decrease in the mitochondrial membrane potential and the FKHR transcription factor are
indicated in black.
by translocation in human follicular lymphoma.70 Rather than
exerting an effect on cellular proliferation, activated Bcl-2 was
found to exert its effect by promoting cell survival. Thus Bcl2 permits cytokine-dependent hematopoietic cells to survive
in a quiescent state in the absence of cytokine71 and co-operates with the Raf-MAPK pathway in transforming hematopoietic cells.72–75 An anti-apoptotic cell death gene in C. elegans,
CED-9, proved to be a structural and functional homologue
of Bcl-2 demonstrating the remarkable evolutionary conservation of the apoptotic machinery.76,77
There are at least 15 members of the Bcl-2 protein family
that share homology in at least one of three conserved
domains (BH1-BH4) and these may either promote survival,
eg Bcl-2, Bcl-XL or promote apoptosis, eg Bax, Bak.67–69 A
second type of pro-apoptotic subfamily known as the BH3only proteins possess only the central short BH3 domain eg
Bid, Bad, Blk, Noxa. The Bcl-2 family of proteins are able
to register a variety of stimuli both positive and negative and
integrate them to determine whether the mitochondrial apoptotic pathway is turned on or off. Pro-and anti-apoptotic family
members are able to form heterodimers with each other and
this has led to the idea that their relative abundance may
act as a rheostat controlling the mitochondrial initiation
pathway.78
Interaction of Bax with Bid causes Bax to oligomerize and
insert into the outer membrane of the mitochondrion79 triggering the sudden and complete release into the cytoplasm
of cytochrome c and other proteins from the intermembrane
compartment of all of the cellular mitochondria.28,80 As discussed above, this causes procaspases’ activation. Bcl-2 protects against cell death by blocking the release of proteins
from the intermembrane space of the mitochondrion. However, once this release has occurred, the mitochondrial apoptotic initiation process is beyond the point of no return and
can no longer be prevented by Bcl-2 family members.81
The importance of the Bcl-2 family of proteins is underscored by reports of their dysregulation in many hematological malignancies that can contribute to the resistance of such
malignancies to pro-apoptotic chemotherapeutic drugs.82–90
Apoptosis due to the cell receiving an abnormal
proliferative signal
Oncogenes encode mutated versions of the signaling proteins
that control normal cell proliferation. The effects of oncogenes
such as Ras on proliferation and tumorigenesis have been
well-documented in immortal cell lines.91–93 However, there
is evidence that mechanisms exist in many other types of cells
whereby abnormal Ras signaling actually induces apoptosis.
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MK White and JA McCubrey
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This may reflect a defense mechanism against pathological
changes in this crucial signaling nexus that eliminates potential neoplastic cells. Antiproliferative responses of oncogenic
Ras were observed in non-transformed fibroblasts, primary rat
Schwann cells, rat pheochromocytoma PC12 cells, NIH-3T3L1 fibroblast cells, and primary fibroblasts of human and
murine origins.94–99 It is believed that the cell proliferation
arrest induced by oncogenic Ras was not an immediate outcome of Ras signaling, but a late cellular response due to
abnormal Ras activity. In the fibroblasts that were transfected
with oncogenic Ras, induction of cell cycle inhibitors,
p16Ink4a, p21Cip1 and p53 as well as decreases in the levels of
cyclin A and Cdk2 kinase activity and hyperphosphorylated
pRb, were observed. In p53−/− and p16−/− mutant fibroblasts,
proliferation was observed in the presence of oncogenic Ras.
Thus, p53 and p16Ink4a tumor suppressor genes are essential
for the cell cycle arrest mediated by Ras.
Similarly, overexpression of an activated form of the Raf
oncoprotein has also been associated with cell cycle arrest in
some cell lines, including rat Schwann cells, mouse PC12
cells, human promyelocytic leukemia HL-60 cells, and small
cell lung cancer (SCLC) cell lines.100–103 In contrast, T cell differentiation is accelerated in transgenic mice expressing activated Raf in the thymus.104 It is not clear why over-expression
of the Raf gene can lead to such conflicting results, but recent
reports have suggested that it is the amount or activity of the
Raf oncoprotein that leads to the opposite outcomes.73,74
Depletion of Raf-1 was shown to abrogate p21Cip1 induction
after taxol treatment in a human prostate cancer cell line.100
Furthermore, recent studies involving conditionally active
⌬Raf:ER proteins have implicated the Raf family of kinases in
cell cycle control.105,106 Raf-1 was determined to be sufficient
for p21Cip1 induction as long as the MEK/ERK pathway was
left intact.101 Further study of Raf-mediated p21Cip1 induction
has led to a model that integrates proliferative signals with cell
cycle arrest. The effect of Raf activation seems to be determined either by the level or duration of Raf activity in the cell.
Upon stimulation, Raf delivers a proliferative signal that
results in immediate–early gene activation and induction of
the cyclins. However, prolonged signaling through the
MEK/ERK proteins results in induction of p21Cip1 and cell
cycle arrest. This dual activity of Raf might serve as a means
of feedback inhibition and could maintain checks and balances on the generation of proliferative signals. The three different Raf proteins have varying levels of kinase activity.73,74
Thus, one would expect differences in the biological effects
of A-Raf, B-Raf and Raf-1. This is supported by the fact that
A-Raf, a weaker kinase than either B-Raf or Raf-1, is a poor
inducer of p21Cip1 expression while B-Raf and Raf-1 can
readily induce p21Cip1 and cell cycle arrest in NIH-3T3
fibroblasts.74
In NIH-3T3 cells transfected with different Raf genes, Raf
molecules are able to upregulate the expression of cyclin D1,
cyclin E, Cdk2 and Cdk4 and downregulate the expression of
Cdk inhibitor p27Kip1.106 These changes induce cells to pass
through G1 phase and enter S phase. However, in B-Raf and
Raf-1 transfected cells, there was also a significant induction
of p21Cip1. Study of Raf-mediated cell cycle arrest should
provide multiple targets for therapeutic intervention in
malignancies involving a deregulated cell cycle.
Apoptosis triggered from without: death activators and
their receptors
The second way in which the apoptotic program can be
initiated is by way of the action of extracellular messengers,
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termed death ligands. These bind to cell surface receptors,
termed death receptors, that activate intracellular signaling
events that begin an apoptotic cascade.107–109 That certain
cells can be ‘instructed’ to undergo apoptosis is important
especially in the immune system.110 Death receptors belong
to the tumor necrosis factor (TNF) receptor superfamily that is
characterized by a cysteine-rich extracellular ligand-binding
domain.111 Death receptors contain a consensus module
known as the death domain that is found in the intracellular
portion of the molecule and is involved in transducing the
apoptotic signal.112,113
Fas113 and the TNF receptor111 are the two best characterized death receptors and the cognate ligands for them are
FasL and TNF, respectively. Activation of Fas by FasL is
involved in the mechanism of action of cytotoxic T cells and
NK cells against virus-infected and cancerous cells. It is also
important in modulating the immune response by peripheral
deletion of activated T cells and mutations in Fas can lead to
autoimmune disorders.113 FasL is a trimer and binds three Fas
molecules resulting in Fas clustering that is aided by the tendency of death domains to associate with each other. The clustered death domains of Fas associate with an adapter protein
called FADD (Fas-associated death domain) that binds
through its own death domain.114,115 FADD contains a second
type of domain called DED (death effector domain) responsible for the recruitment of procaspase 8 through DED
domains present in this proenzyme.116,117 Procaspase 8
undergoes self-cleavage and activation following its oligomerization at the Fas-associated protein complex. This in turn
activates effector caspases committing the cell to apoptosis as
described above.
The TNF receptor also signals to activate caspase 8 through
death adapter proteins, but TNF alone rarely induces
apoptosis perhaps due to the intervention of anti-apoptotic
pathways such as NF-␬B, JNK and phosphatidylinositol 3-kinase (PI3K)107,117,118 and these are discussed later.
Other members of the TNF/FasL family of death ligands
have been identified by screening DNA sequence databases.
TRAIL (TNF-related apoptosis inducing ligand, also known as
Apollo) is closely related to FasL119,120 and, like FasL, potently
induces apoptosis in tumor cells78 as does another family
member, TWEAK.107 Other members of the superfamily of
receptors for these ligands (death receptors) have been found
that are pro-apoptotic eg DR3, DR4, DR5 and DR6. Interestingly, there are death receptors homologs that do not contain
effective cytoplasmic signaling domains, and thus complete
for death ligand, and are known as decoy receptors, eg DcR1,
DcR2, DcR3 and osteoprotegrin.108,109
Protection from apoptosis: the other side of the coin
The life or death decision-making process responsible for
apoptosis hangs in the balance of positive and negative influences. We have described the molecular events whereby
apoptosis is initiated and executed. Throughout this process,
from receipt of the initial apoptotic stimulus until activation
of the terminal executioner caspase, anti-apoptotic counterbalances exist that may intervene and save the life of the cell.
An inappropriate equilibrium at some point during the program of cell death, resulting from either abrogation of a proapoptotic process or improper induction of an anti-apoptotic
occurrence, can be a major factor in the etiology of neoplasia.
Suppression of apoptosis
MK White and JA McCubrey
The ‘inhibitors of apoptosis’ (IAPs): the brakes on the
machine
IAPs are a group of cellular proteins that act to directly inhibit
specific caspases and thereby inhibit apoptosis.121,122 IAPs
were first discovered as viral proteins encoded by insect baculoviruses that enhance virus replication.123,124 Apoptosis of
cells in response to viruses is a host defense mechanism
against viral infections and many viruses have evolved strategies to circumvent this.125 Thus the genomes of many viruses
encode proteins that block apoptosis and baculovirus IAP is
such a protein. Within this protein is a conserved functional
domain known as the baculovirus IAP repeat (BIR) found in
all IAPs that has conserved cysteine and histidine residues that
facilitate co-ordination of a zinc ion in a fashion similar to the
classical zinc finger motif of DNA-binding proteins.126
At the present time, six mammalian IAPs have been identified. These are: inhibitor of apoptosis-1 (c-IAP1), inhibitor of
apoptosis-2 (c-IAP2), neuronal apoptosis inhibitory protein
(NAIP), survivin, X-linked inhibitor of apoptosis (XIAP), and
BIR repeat-containing ubiquitin-conjugating enzyme (BRUCE).
These endogenous inhibitors of apoptosis form an essential
part of the apoptotic machinery and serve to protect cells from
indiscriminate induction of death. However, they are also
implicated in the progression of malignancies.127 Overexpression of exogenous IAPs in cells protects them from the
induction of apoptosis.128,129
Survivin is expressed in many cancers and transformed cell
lines127 and may contribute to their resistance to apoptosis.129
In normal cells, survivin is expressed in the G2/M phase of the
cell cycle and associates with the microtubules of the mitotic
spindle in a specific and saturable manner.130 If this interaction is disrupted, survivin loses its anti-apoptotic activity indicating that survivin may counteract default induction of
apoptosis at a G2/M phase mitotic signal checkpoint. Overexpression of survivin in malignant cells may thus allow them
to progress aberrantly through mitosis.130
Induction of c-IAP1 and c-IAP2 expression has found to be
a consequence of the NF-␬B anti-apoptotic pathway (see
below). For example, TNF activates NF-␬B which induces the
transcription of c-IAP1 and c-IAP2 and thereby suppresses
caspase-8 activation.131
Besides the defining BIR domain that is found in all IAPs
and is essential for their function, some IAPs (XIAP, c-IAP1
and c-IAP2) also have a domain known as a RING finger.
Recently this domain has been implicated in the process of
ubiquitin conjugation.132 Ubiquitin conjugation to a protein
is part of the process whereby it is targeted for proteolysis by
the proteasome. This process is important in cell cycle regulation and signal transduction and involves distinct classes of
enzymes denoted as E1, E2 and E3. The RING finger domain
is thought to be involved in E3 ubiquitin ligase activity.132 cIAP1 and XIAP are selectively lost when thymocytes are
induced to undergo apoptosis by etoposide or glucocorticoids
and this loss is proteasome-dependent.133 IAPs are able to
auto-ubiquitinate and this activity requires the RING domain.
Overexpressed IAPs are spontaneously ubiquitinated and
degraded but not a RING domain mutant. Thus lack of the
RING domain makes IAPs more effective at preventing
apoptosis.133 Auto-ubiquitination of IAPs may be an important
part of the apoptotic process.
Finally, a further level of complexity has recently been
revealed by the discovery of proteins that bind to and inhibit
IAPs. Du et al134 reported a novel protein, Smac, that is
released from mitochondria when cells undergo apoptosis.
Verhagen et al135 identified a protein, DIABLO (direct IAP
binding protein with low pI) that coimmunoprecipitates with
XIAP and is released into the cytosol during apoptosis counteracting the effect of XIAP.
1015
Help from the outside: how extracellular cytokines
protect cells from apoptosis
As discussed above, the survival of a cell depends on a balance between positive and negative signals. Positive signals
provided by external growth factors (Figure 1) promote cell
survival, eg nerve growth factor activates survival signaling in
neuronal cells58 and cytokines inhibit apoptosis of hematopoietic cells.27,59,60
The phosphatidylinositol 3-kinase pathway
The anti-apoptotic signal from receptors for extracellular
growth factors and cytokines is delivered through the enzyme
phosphatidylinositol 3-kinase (PI3K).58,136–138 PI3K is the
prototypical member of a family of enzymes that phosphorylate phosphatidylinositol on the 3⬘ position of the inositol ring
(reviewed in Ref. 139). In addition to its protective role against
apoptosis, this enzyme plays a central role in a diverse range
of cellular responses including cell growth and differentiation,
metabolic regulation, membrane trafficking and control of the
cytoskeleton.139 The first evidence for PI3K involvement in signaling from cell surface tyrosine kinase receptors was the
observation that PI3K activity and an 85 kDa phosphoprotein
were recruited into anti-phosphotyrosine immunoprecipitates
after stimulation of cells with platelet-derived growth factor
PDGF.140,141
Signaling pathways initiated by receptor tyrosine kinases
depend on the recruitment of signaling proteins that bind to
phosphotyrosine residues resulting from activation of the
receptor tyrosine kinase activity (Figure 1). These phosphotyrosines may either be present on the receptor protein itself
(ie autophosphorylation sites) or on a transphosphorylated
receptor-associated substrate protein (eg IRS-1).142 Protein
modules known as Src homology-2 (SH2) domains143 mediate
binding of signaling proteins to phosphotyrosine residues.
PI3K was one of the first signaling proteins found to operate
in this way. It has two subunits p85 and p110 that serve regulatory and catalytic functions, respectively. The regulatory
subunit has an SH2 domain and binds to the phosphorylated
tyrosine residues. Examples include the PDGF receptor that
has undergone tyrosine autophosphorylation as a result of
ligand binding132 and IRS-1 that has been phosphorylated by
the insulin receptor.142
The binding of p85 to such upstream phosphoproteins activates the p110 catalytic subunit that transfers phosphate from
ATP to phosphatidylinositides (Figure 2). Phosphatidylinositides that are phosphorylated on the 3⬘ position are second
messengers that activate downstream signaling molecules
such as the serine/threonine protein kinase B (PKB, also
known as Akt).144,145 Like other molecules that bind 3⬘-phosphorylated phosphoinositides, PKB/Akt contains a pleckstrin
homology (PH) domain that serves to target it to the membrane. Once targeted to the membrane (Figure 2), PKB/Akt is
phosphorylated by two enzymes, phosphatidylinositol 3,4,5triphosphate-dependent kinase-1 (PDK1, which is itself has a
PH domain and is activated by 3⬘-phosphorylated
phosphoinositides) and PDK2 leading to full PDK actiLeukemia
Suppression of apoptosis
MK White and JA McCubrey
1016
Figure 2
Activation of AKT by IL-3. (A) In cytokine-deprived cells,
Akt is not localized to plasma membrane. Also, the phosphatase encoded by the PTEN tumor suppressor can result in the inactivation of
PI3K. The LY294002 drug inhibits the catalytic activity of the p110
kinase. (B) When IL-3 binds the receptor, phosphorylation of a tyrosine residue on the IL-3␤ chain occurs creating a binding site for the
PI3K p85 regulatory subunit. This results in the recruitment of p85 via
an Sh2 domain. P85 in turn activates the PI3K p110 catalytic site.
P110 PI3K then phosphorylates certain membrane lipids which result
in the activation of PDK-1 and PDK-2 which occurs via their plextrin
homology domains. (C) PDK-1 and PDK-2 phosphorylate Akt on two
different serine/threonine residues which results in activation of Akt.
(D) Akt can phosphorylate many downstream targets which result in
their activation/inactivation and the prevention of apoptosis.
vation.146 Activation of PKB/Akt is prevented by pharmacological inhibitors of PI3K, by dominant negative mutants of
PI3K or by deletion of the tyrosine residues from tyrosine kinase receptors that mediate binding of the PI3K p85 subunit.
On the other hand, introduction of constitutively activated
mutants of the p110 catalytic subunit into cells activates
PKB/Akt. Thus PKB/Akt is clearly downstream from PI3K.144,145
There are three known mammalian isoforms of PKB/Akt – ␣,
␤ and ␥. Identification of targets that are phosphorylated by
PKB/Akt is an area of intensive research. Biological conseLeukemia
quences of PKB/Akt action include alteration of cellular carbohydrate metabolism, stimulation of protein synthesis, and
suppression of apoptosis.
What targets of PKB/Akt are important in delivering the
apoptotic signal? PKB/Akt phosphorylates the pro-apoptotic
protein Bad (discussed above).147,148 Phosphorylation of the
pro-apoptotic protein Bad by PKB/Akt results in its inactivation
and hence should favor cell survival (Figure 2). However, it
is unlikely that Bad phosphorylation represents the major
mechanism by which PKB/Akt acts as an inhibitor apoptosis
in most cell types because Bad is not ubiquitously
expressed.149 Other protein targets of PKB/Akt may be responsible for surfactant-associated protein-A (SP-A) protection from
apoptosis, eg caspase-9.150 The PKB/Akt phosphorylation site
in caspase-9 is present in the human but is not conserved in
rodents.151 Thus, caspase-9 phosphorylation by PKB/Akt may
be involved in the protection from apoptosis of human cells
but not in mouse or rat cells. However, there is evidence for
the existence of an additional, evolutionarily conserved mechanism by which PKB/Akt can suppress activation of caspases
(discussed in Ref. 152). A third type of protein that are targets
for PKB/Akt are the forkhead transcription factors such as
FKHRL1 that are potent at inducing apoptosis, an event that
can be inhibited by phosphorylation by PKB/Akt.153,154
PKB/Akt phosphorylates and inactivates glycogen synthase
kinase-3 (GSK-3) and thereby mediates the activation of glycogen synthesis by insulin.144,145 There is also evidence that
GSK-3 delivers an anti-apoptotic signal. Thus transfection of
a catalytically active GSK-3 into fibroblasts induced apoptosis
while a dominant negative form of GSK-3 prevented
apoptosis.155
Although the details of the downstream signaling pathways
remain to be elaborated, clearly the PI3K-PKB/Akt pathway is
a powerful protector of cells against apoptosis. Dysregulation
of this pathway can contribute to oncogenesis. For example,
the PKB/Akt is the cellular homologue of the v-akt oncogene
of the AKT8 transforming retrovirus.144,145 In addition,
mutation in a lipid phosphatase, PTEN (also known as
MMAC1 and TEP1), that removes the phosphate from the 3⬘
position of the inositol ring of 3⬘-phosphoinositides can pathologically boost the cellular levels of 3⬘-phosphoinositide
second messengers activating PKB/Akt and promoting oncogenesis.156,157 PTEN is a dual specific lipid and protein phosphatase with homology to the cytoskeletal protein tensin that
acts to restrain the PI3K-PKB/Akt pathway and is an important
tumor suppressor gene product that is mutated in a variety of
tumors.156,157 PTEN is also mutated in the germline of a variety
of human autosomal cancer predisposition syndromes including Cowden disease, Bannayan-Zonana syndrome and Lhermitte-Duclos disease that are characterized by developmental
defects and tumor susceptibility.158 Mutations in PTEN have
been found in a significant percentage of several types of leukemia including acute myeloid leukemia,159 lymphoblastic
leukemia/lymphoma, large B cell lymphoma, Burkitt’s lymphoma,160,161 B cell non-Hodgkin’s lymphoma,161,162 and primary cutaneous T cell lymphoma.163 These observations indicate that restoration of PTEN function is an attractive target
for gene therapy of certain subclasses of neoplasm.
Role of the Rel/NF-␬B transcription factors in the
control of apoptosis
The Rel/NF-␬B family of transcription factors are comprised
of several related proteins including c-rel, RelA, RelB,
Suppression of apoptosis
MK White and JA McCubrey
p50/p105, and p52/p100 that are induced in response to
many signals and are involved in cell growth, differentiation,
neoplasia, inflammation and the control of apoptosis.164,165
Rel/NF-␬B proteins form homo- or hetero-dimers and control
the expression of many genes by binding to DNA regulatory
elements known as ␬B sites. The most common heterodimer
found in most cell types is p50-RelA (NF-␬B) which is retained
in an inactive form in the cytoplasm through association with
an inhibitor protein, I␬B. Several forms of I␬B exist – I␬B␣,
-␤, -⑀, -␥, p105, p100 and Bcl-3.166 In response to a variety
of stimuli, I␬B becomes phosphorylated leading to its polyubiquitination and consequent degradation by the proteosome
allowing the release of NF-␬B that is then translocated to the
nucleus where it modulates gene expression. The kinase that
phosphorylates I␬B is a high molecular weight protein complex, IkappaB-kinase (IKK), containing two subunits IKK␣ and
IKK␤ together with a modulator known as NF-␬B essential
modulator (NEMO).167
In certain cell types, eg B cells, there may be a high level
of basal or constitutive NF-␬B activation.165 Constitutive NF␬B activation and nuclear ␬B site binding and transactivation
activity may also be found in many tumor cells.168 A role for
NF-␬B transcription factors in suppressing apoptosis was first
indicated by study of the oncogene v-rel from the avian retrovirus reticuloendotheliosis virus stain T169 which causes leukemia in chickens and whose cellular homologue is c-rel.170 Vrel renders chicken B cells resistant to radiation-induced
apoptosis171 and chicken spleen cells transformed by temperature-sensitive v-rel proteins undergo apoptosis when cells are
shifted to the non-permissive temperature.172
NF-␬B was first described as a nuclear protein promoting
immunoglobulin light chain transcription in B cells173 and has
subsequently been shown to mediate survival signals that protect against apoptosis in most cells (although it may be proapoptotic under some circumstances).174–176 As discussed
above, the pro-inflammatory tumor necrosis factor (TNF) binds
to a death receptor leading to the activation of caspase 8.
However, TNF alone rarely induces apoptosis perhaps due to
the intervention of anti-apoptotic pathways.107,111,118 The proapoptotic signal from the TNF receptor (that leads to caspase
activation) is transduced through FADD as described above,
while the anti-apoptotic signal (that leads to the activation of
NF-␬B) is transduced through an adapter molecule named
TNF-receptor-associated factor 2 (TRAF2).177 Activation of NF␬B by TNF requires the successive action of NF-␬B-inducing
kinase (NIK) and IKK.164 Furthermore, the PI3K-PKB/Akt pathway described above also appears to be involved in the activation of IKK as well as NIK.178 Thus wortmannin (a PI3K
inhibitor), a dominant negative PI3K or a kinase-dead PKB/Akt
inhibit TNF-mediated NF-␬B activation while constitutively
active PKB/Akt activates NF-␬B, an effect that is blocked by
dominant negative NIK.178 Thus PKB/Akt appears to function
in parallel with NIK to activate IKK. Similarly, the PI3KPKB/Akt pathway (Figure 2) is involved in the activation of NF␬B by PDGF,179 insulin,180 IGF-1181 and NGF.182 Activation of
NF-␬B has a role in the anti- apoptotic signaling of these
cytokines.
The mechanism whereby NF-␬B promotes cell survival is
due, at least in part, to the induction of the transcription of a
number of anti-apoptotic genes and these have recently been
reviewed.165 Experimentally, the role of a gene in suppressing
apoptosis can be demonstrated by showing that: (1) it is upregulated by activation of NF-␬B; (2) inhibiting the gene product
abrogates apoptotic protection; (3) ectopic expression of the
gene is anti-apoptotic. Such genes include members of the
Bcl-2 family (Al/Bfl1, Bcl-XL and Nrl3), death receptor signal
transduction proteins (TRAF1 and TRAF2), inhibitors of
apoptosis (c-IAP1, c-IAP2 and X-IAP), transcription factors
(c-myc and p53).165
Inhibition of NF-␬B nuclear translocation enhances apoptotic cell killing by TNF, ionizing radiation, overexpression of
oncoproteins or the cancer chemotherapeutic agent daunorubicin. Thus, activation of NF-␬B is a mechanism of cellular
resistance to killing and this may offer insights for potential
improvement of the efficacy of cancer therapies.166,183,184
1017
Conclusions
Apoptosis is a very tightly regulated cellular program with
many levels of checks and balances. The multitude of players
involved in this process is indicated by the profusion of proteins described in this review. In fact, we have only scratched
the surface. Apoptosis is intimately connected to the machinery of the eukaryotic cell cycle with its DNA-damage-induced
checkpoints and connection to DNA repair. Several tumor
suppressor genes, eg ATM, NBS1, BRCA1, BRCA2, Rb and the
p53 gene family, are involved in these processes and cancer
is often associated with the mutation and compromise of the
function of one or more of these genes.185–190 Addressing this
big picture is beyond the scope of this review. Rather, we have
concentrated on the mechanisms of execution of programmed
cell death and how their suppression is involved in the etiology of malignancy. Understanding the complexities of the
interplay of the opposing signaling events that promote and
suppress apoptosis in normal and neoplastic cells will be an
important guide in providing a framework for the design of
new therapeutic interventions.
Acknowledgements
This work was supported by Public Health Services Grants
DK45718 (MKW) and CA51025 (JAM).
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