Advanced Review
Guarding the ‘translation
apparatus’: defective ribosome
biogenesis and the p53 signaling
pathway
Anirban Chakraborty, Tamayo Uechi and Naoya Kenmochi∗
Ribosomes, the molecular factories that carry out protein synthesis, are essential
for every living cell. Ribosome biogenesis, the process of ribosome synthesis,
is highly complex and energy consuming. Over the last decade, many exciting
and novel findings have linked various aspects of ribosome biogenesis to cell
growth and cell cycle control. Defects in ribosome biogenesis have also been
linked to human diseases. It is now clear that disruption of ribosome biogenesis
causes nucleolar stress that triggers a p53 signaling pathway, thus providing
cells with a surveillance mechanism for monitoring ribosomal integrity. Although
the exact mechanisms of p53 induction in response to nucleolar stress are still
unknown, several ribosomal proteins have been identified as key players in this
ribosome–p53 signaling pathway. Recent studies of human ribosomal pathologies
in a variety of animal models have also highlighted the role of this pathway in the
pathophysiology of these diseases. However, it remains to be understood why the
effect of ribosomal malfunction is not a universal response in all cell types but is
restricted to particular tissues, causing the specific phenotypes seen in ribosomal
diseases. A challenge for future studies will be to identify additional players in
this signaling pathway and to elucidate the underlying molecular mechanisms that
link defective ribosome synthesis to p53.  2011 John Wiley & Sons, Ltd. WIREs RNA 2011
DOI: 10.1002/wrna.73
INTRODUCTION
T
he translation of messenger RNAs (mRNAs) into
proteins is catalyzed by ribosomes, the most
complex macromolecules of the cell. In eukaryotes,
a mature ribosome (80S) has two subunits, large (60S)
and small (40S), that together contain four ribosomal
RNA (rRNA) species and 79 different ribosomal
proteins (RPs).1,2 Although eukaryotic ribosomes
possess more rRNAs and RPs than those in eubacteria,
ribosomal components have been conserved to a
substantial degree throughout evolution.3,4 Ribosome
biogenesis is a multistep process that begins with the
synthesis of preribosomal particles in the nucleolus
and ends with the assembly of two mature subunits
∗ Correspondence
to: [email protected]
Frontier Science Research Center, University of Miyazaki, Miyazaki,
Japan
DOI: 10.1002/wrna.73
in the cytoplasm. The synthesis of the ribosome is
tightly regulated and uses a substantial amount of
cellular energy.5 All three types of RNA polymerases
and several hundred accessory factors (ribosomeassociated proteins and noncoding RNAs), in addition
to the RPs and the rRNAs themselves, participate in
this massive process that occurs throughout the cell.6
rRNA genes are transcribed by RNA polymerase I
(Pol I) into a single rRNA precursor within the
nucleolus, which is subsequently cleaved and modified
by several accessory factors to yield 18S, 5.8S, and 28S
rRNA.7,8 The 5S rRNA gene is transcribed separately
in the nucleoplasm by RNA polymerase III (Pol III).9
The RP genes are transcribed in the nucleoplasm by
RNA polymerase II (Pol II) and these transcripts are
exported to the cytoplasm for translation.10 RPs and
5S RNA are imported to the nucleolus, where they
assemble with rRNAs to form the small (40S) and
the large (60S) subunits. These preassembled subunits
are then exported to the cytoplasm, where they
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Advanced Review
undergo additional maturation to form the mature
(80S) ribosome.11
Cell growth and cell proliferation, two intricately connected events, are associated with changes in
ribosome production.12 Upon the detection of favorable stimuli (growth factors or nutrients), cells induce
ribosome production and protein synthesis to ensure
accurate growth and proliferation. In contrast, in
stress situations, cells must downregulate ribosome
activity to reduce protein synthesis and halt proliferation. A landmark study by Volarević et al.13 identified
a direct link between ribosome biogenesis and the cell
cycle. This study showed that the conditional deletion
of RPS6 in mouse liver cells results in the complete
loss of regenerative capacity of liver cells following
partial hepatectomy due to interruption of the cell
cycle at the G1 phase. Thus, the control of ribosome
biogenesis is critical for cell cycle progression, and
the loss of this control may result in an altered cell
cycle and deregulated cell growth, such as that seen in
cancer.14,15 Indeed, many human diseases have been
linked to defects in ribosome biogenesis, and, interestingly, the majority of these diseases appear to be
associated with increased cancer susceptibility.16–18
How do cells control the fidelity of ribosome
biogenesis? Do the cells possess a surveillance mechanism for monitoring ribosomal integrity? What are
the pathways that link ribosome biogenesis to the cell
cycle? Although our knowledge about the exact mechanisms is still in its infancy, we do know that several
RPs, presumably through extraribosomal functions,19
participate in a surveillance mechanism that senses
defects in ribosome biogenesis. Not surprisingly, this
involves the p53 tumor suppressor protein, the master
guardian of the cell.20 The ability of some RPs to interact with murine double minute 2 (MDM2) (HDM2
in humans), the negative regulator of p53, has been
shown to be critical for p53 activation (discussed later
in this review).
Recent evidence seems to suggest that the pathways linking defective ribosome biogenesis and p53
signaling are very complex, and several additional
factors and regulatory loops, which remain to be
identified, may be involved in this network in addition to the MDM2-binding RPs. For instance, human
ribosomal disorders or RP mutations in mice produce
distinct tissue-specific phenotypes; the p53 pathway
appears to be critical for the clinical manifestations,
but it is not clear why the effects of ribosomal dysfunction are not universal but rather are restricted to
particular cell types, such as red blood cells, neural
cells, or skin cells. Here, we focus on recent advances
toward understanding this ribosomal stress–p53 signaling pathway, with an emphasis on in vivo studies
of ribosomal anomalies in various mammalian and
nonmammalian model organisms.
HELPING THE MASTER GUARDIAN:
RPs IN p53 ACTIVITY AND
REGULATION
The p53 protein orchestrates a myriad of signaling
pathways that prevent a damaged or abnormal cell
from undergoing malignant transformation (Figure 1).
A variety of cellular stresses (DNA damage, oncogenic
activation, and hypoxia) activate p53,21 which then
undergoes many posttranslational modifications22,23
and transactivates several genes critical for cell growth
inhibition. The four major outcomes of an activated
p53 response are cell cycle arrest, apoptosis, DNA
repair, and senescence. These ultimately contribute to
tumor suppression. The importance of p53 in tumor
prevention can be gauged by the fact that almost
half of human tumors carry mutations in this gene24 ;
in the remaining tumors, the p53 network is functionally inoperative.25 Although cancer prevention
remains the most important function of p53, it is
becoming increasingly clear that p53 also functions in
diverse cellular processes such as metabolism, reproduction, stem cell renewal, microRNA processing, and
development.26–28 Interestingly, these functions do not
require stress-induced activation, but rather depend on
basal levels of p53. Thus, the control and maintenance
of p53 levels (both transcriptional and translational)
are critical for normal homeostasis. Usually, MDM2,
an E3 ubiquitin ligase, controls the p53 protein level
through ubiquitin-mediated proteolysis,29 whereas
MDMX (an MDM2 homolog, also known as MDM4)
controls the transcriptional activity of p53.30 MDM2
expression is stimulated by increased levels of p53
because MDM2 is a transcriptional target of p53.31
MDM2 mediates the attachment of ubiquitin to p53;
the ubiquitin is recognized by proteasomes, resulting
in p53 degradation. Decreased levels of p53, in turn,
reduce the transcription of MDM2, thereby providing an autoregulatory feedback loop.32 Therefore, the
disruption of this MDM2–p53 regulatory loop is critical for activation and stabilization of p53. Depending
on the type of stress signal, several distinct pathways
modify p53 or MDM2 to block their interaction and
stabilize p53.33 Recently, it was shown that ribosomal
stress can also suppress MDM2 activity through the
extraribosomal functions of RPs.19
At present, four RPs, RPL11,34,35 RPL23,36,37
RPL5,38,39 and RPS7,40 have been confirmed as
MDM2 regulators. These RPs bind in similar yet
unique patterns to the zinc finger domain within the
central acidic region of MDM2.40–42 By doing so,
 2011 Jo h n Wiley & So n s, L td.
WIREs RNA
Defective ribosome and p53
Ionizing radiation
UV irradiation, hypoxia
Ribosomal malfunction
Oncogene overexpression
RPL11, RPL5,
RPL23, RPS7
ATM, ATR
ARF
Modifications
MDM2
p53
MicroRNA processing
Stem cell renewal
Development
Metabolism
Reproduction
MDMX
Ub
Ub
Target gene transcription
Ub
Ub
p53
Proteasomal
degradation
Cell cycle arrest
DNA repair
Apoptosis
Senescence
FIGURE 1 | The p53 signaling pathway. The tumor suppressor p53 protein plays the central role in coordinating a complex network of signaling
pathways that prevent aberrant cell growth and proliferation. In normal conditions, p53 is maintained at low steady-state levels. Crucial for this
regulation are two proteins, murine double minute 2 (MDM2) and MDMX. MDM2, through its E3 ligase function, mediates the attachment of
ubiquitin (Ub) molecules to p53 and targets it for proteasomal degradation. MDM2 also binds p53 and influences its transcriptional activity. MDMX
lacks the E3 ligase function and suppresses the transcriptional activity of p53, which is independent of MDM2. However, it also forms a heterodimeric
complex with MDM2 and stimulates MDM2-mediated p53 degradation. The expression of MDM2 is controlled by p53 itself through a negative
feedback loop (see text for details). MDMX levels are controlled by MDM2 through the Ub-mediated degradation. Deregulated functions of these p53
inhibitory proteins are critical for an activated p53 response in stress situations. For example, exposures to ionizing radiation, ultraviolet (UV) light,
and many other DNA-damaging stressors activate several kinases [ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related
(ATR), and other checkpoint kinases], which modify p53, MDMX, and MDM2. The modifications cause conformational changes in these proteins and
block their interactions, resulting in p53 stabilization. Overexpression of oncogenes stimulates the production of alternative reading frame (ARF;
p14ARF in human, p19ARF in mouse) that binds to MDM2 and stabilizes p53. An impaired ribosome biogenesis causes the release of several RPs,
which bind to and suppress the E3 ligase activity of MDM2, resulting in p53 accumulation. An activated p53 protein subsequently transactivates
several target gene expressions. Depending on the cell type and the stressors, the consequence could either be cell cycle arrest, DNA repair,
apoptosis, or senescence. Basal levels of p53 (inactivated state) also contribute to many cellular processes in normal cells, which are independent of
its gene transcription functions.
they inhibit the E3 ligase activity of MDM2 and prevent MDM2-mediated p53 degradation, resulting in
activation and stabilization of p53. Numerous studies have demonstrated that perturbation of ribosome
biogenesis either by drugs that inhibit RNA Pol I
activity or by growth inhibition enhances the interaction of these RPs with MDM2, whereas depletion
of these RPs attenuates the stress-induced p53 stabilization (for detail, see review in Ref 43). Moreover,
the interaction of these RPs with MDM2 appears to
increase only in conditions of ribosomal stress, but
not of DNA damage or oncogene overexpression.35,36
These RPs can also inhibit MDM2 more efficiently in
combination, as seen for RPL5 and RPL11.44 These
observations led to the widely accepted notion that
inhibition of ribosome biogenesis causes nucleolar
stress. As a result of this stress, several RPs enter the
nucleoplasm, where they interact with and suppress
the E3 ligase activity of the MDM2s to promote p53
stabilization.43 Indeed, disruption of the nucleolus is
required for p53 activation and stabilization.45
However, recent evidence suggests that RPs
functionally interact with MDM2 during other genotoxic stresses as well, such as those induced by DNAdamaging agents. The induction of p53 in response
to various types of stress caused by different kinds
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Advanced Review
of drugs is attenuated in a similar manner when
either RPS7 or RPL11 is downregulated.46 Hence, it
appears that general nucleolar disruption, rather than
a specific ribosome biogenesis defect, can cause the
interaction of these RPs with MDM2. Another issue
is the role of the MDMX protein in the RP–MDM2
interaction. Activation of p53 by ribosomal stress
requires degradation of MDMX, and RPL11, but not
RPL5 or RPL23, stimulates MDMX polyubiquitination by MDM2.41 In contrast, RPS7 requires MDMX
to inhibit the E3 ligase activity of MDM2.46 These
results imply that each RP may have a unique way
of inhibiting MDM2 function. Interestingly, MDM2
itself can target its RP-binding partners, suggesting
an alternative means of p53 regulation. For instance,
RPL26, which binds to p53 mRNA and promotes its
translation,47 is ubiquitinated by MDM2, resulting
in proteosomal degradation of RPL26 and decreased
binding with p53 mRNA.48 RPS7 is also a substrate
for MDM2, but it is not known if MDM2 targets it
only for proteosomal degradation or also for other
functions.46
Recently, another RP, RPS3, was identified that
physically interacts with both p53 and MDM2.49
Whereas the KH domain of RPS3 appears to be critical for this interaction, the central acidic domain
of MDM2 is dispensable. Full-length MDM2 with a
mutation in the acidic domain can still bind to RPS3.
Furthermore, a reduction in RPS3 levels attenuates
the oxidative stress-induced MDM2 inhibition and
p53 activation.49 However, RPS3 depletion does not
induce ribosomal stress because a 50% reduction in
RPS3 levels has no effect on ribosomal stability and
protein synthesis; only cytosolic, ribosome-free RPS3
is reduced, whereas ribosome-bound RPS3 remains
unaffected.50
Thus, it is clear that several RPs interact with
MDM2 and suppress its function in response to a variety of nucleolar stresses, including genotoxic stresses
other than ribosomal stress. It is also clear that these
MDM2-binding RPs do not compensate for each other
in reducing MDM2 function. For example, the induction of p53 in response to various stress conditions
is attenuated when RPL11 or RPS7 is depleted,46,51
although one would expect other RPs, such as RPL5
or RPL23, to bind to MDM2 and stabilize p53. In
contrast, knockdown of RPL23 increases p53 levels36
even in unstressed conditions, but downregulation of
RPL11 decreases p53 levels.46 Moreover, the response
of a cell to reduced levels of an RP, e.g., RPS7, is not
consistent in all cell types. In some cells, the ability to inhibit MDM2 and stabilize p53 is decreased
due to RPS7 depletion, but in other cells, ablation
of RPS7 leads to p53-dependent and -independent
cell cycle arrest, suggesting that other mechanisms
are responsible for p53 induction independently of
MDM2.46 Despite differences in cellular responses to
the depletion of a single RP, it is conceivable that
ribosomal biogenesis defects can lead to the accumulation of several RPs within the nucleus, resulting in
p53 induction by RPs, either through inhibition of
MDM2 function or through increased p53 translation (e.g., RPL2647 ). However, knockdown of RPs
decreases the abundance of other RPs belonging to
the same subunit,52 probably due to the decreased
stability of individual RPs because RPs are usually
produced in excess and ribosome-free RPs are quickly
degraded in the nucleoplasm.53 The mechanism by
which these RPs are stabilized in the nucleoplasm so
that they can interact with MDM2 in response to
nucleolar stress is still unknown. Nevertheless, given
that MDM2-binding RPs continue to be identified,
it is likely that many RPs (if not all) have extraribosomal MDM2 modulatory functions and that the
interacting RP varies depending on the type, duration,
and intensity of the stress signal. The growth rate of
the cells might also be important for relocalization or
accumulation of specific RPs in the nucleoplasm. In
an MDM2 peptide pull-down assay, RPS20, in addition to RPS3, coprecipitated as an MDM2-interacting
protein,49 and unpublished data in a recent review43
indicate that RPS27L (RPS27-like protein) could be
yet another MDM2-binding RP.
RIBOSOMAL STRESS AND p53:
THE ABERRANCY OF RIBOSOME
BIOGENESIS FACTORS
As mentioned earlier, the synthesis of the ribosome
requires active participation of several hundred accessory factors, commonly known as Ribi (ribosome
biogenesis) factors.12 These include many nucleolar
proteins and small nucleolar RNAs (snoRNAs) that
play critical roles in pre-RNA processing and preribosomal assembly within the nucleolus, the organelle
where the majority of ribosome biogenesis takes place.
Over the last 10 years, several interesting findings have demonstrated that the control of ribosome
biogenesis within the nucleolus is rate limiting for
cell proliferation. Many oncoproteins and tumor
suppressors regulate ribosome biogenesis within the
nucleolus, and this regulation can be lost in cancer
cells, which require increased protein synthesis and
increased ribosome production. Recently, the oncoprotein c-Myc was identified as a direct regulator of
ribosome biogenesis and protein synthesis54 due to
its ability to enhance Pol I-mediated transcription of
rRNA genes,55,56 the Pol II-mediated transcription
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Defective ribosome and p53
of RPs and other ribosome-associated genes,57 and
the Pol III-mediated transcription of transfer RNA,
5S rRNA, and other small RNA genes.58 Deregulated
c-Myc activity leads to tumorigenesis59 and overexpression of c-Myc has been observed in many human
cancers.60 Tumor suppressors such as retinoblastoma
protein (RB) and p53 inhibit rRNA synthesis by
repressing Pol I and Pol III transcription activity in
the nucleolus.61–64 Indeed, mutations in p5362 and
RB65 cause an increase in rRNA synthesis that results
in upregulation of ribosome biogenesis, and p53 and
RB are frequently mutated in human tumors.24,66 The
most compelling evidence that demonstrates a direct
link between nucleolar ribosome biogenesis and the
control of cell proliferation comes from the study of
Pestov et al.67 In this pioneering study, it was demonstrated that expression of an aberrant dominantnegative form of a nucleolar protein involved in rRNA
processing and ribosome assembly, Bop1, causes
nucleolar stress that leads to cell cycle arrest in a
p53-dependent manner. Subsequently, several studies in cell lines and animal models have shown that
alterations in many other ribosome-associated nucleolar proteins elicit a similar response. For instance,
overexpression of nucleophosmin68 and nucleolin69
activates p53 through direct binding of these proteins
to MDM2. On the other hand, the deficiency of nucleolar proteins such as WDR12,70 Bap28,71 WDR36,72
WDR55,73 hUTP18,74 and WDR375 also leads to p53
induction, which in some cases (hUTP18 and WDR3
deficiency) depends on RPL11. Intriguingly, both
overexpression and reduction of nucleostemin activate
p53.76,77 Overexpressed nucleostemin stabilizes p53
and induces p53-dependent cell cycle arrest by directly
binding to MDM2, whereas knockdown of nucleostemin enhances the interaction of RPL5 and RPL11
with MDM2, resulting in an activated p53 response.77
Collectively, these findings indicate that the aberrant expression of nucleolar proteins affects ribosome
biogenesis, and the resultant nucleolar stress activates
p53. Given that many of these nucleolar proteins can
bind to MDM2, the activated p53 response could
also be due to interaction of these proteins with
MDM2, rather than with the RPs alone. In fact,
we have observed an upregulation of several nucleolar proteins, including those that bind MDM2, in
RPL11-deficient zebrafish (unpublished data). Interestingly, besides regulating the MDM2–p53 feedback
loop, RPL11 also acts as a feedback regulator of cMyc transcriptional activity and a reduction of RPL11
enhances c-Myc-mediated transcription of ribosomeassociated genes.78 Thus, it is likely that RPL11
regulates ribosome biogenesis by controlling c-Myc
function and the loss of RPL11 activates a checkpoint
response to prevent aberrant ribosome biogenesis due
to deregulated c-Myc activity. Although RPL11 is an
MDM2-binding RP, our results showed that a deficiency of this protein activates the p53 pathway in
zebrafish,79 supporting the above hypothesis.
RIBOSOMAL STRESS AND P 53: THE
DEFICIENCY OF RIBOSOMAL
PROTEINS
Insufficient RP production can also trigger a ribosomal stress response leading to p53 accumulation and
stabilization. To date, several reports of RP deficiency
in various in vivo and in vitro models have been
described (Table 1). The results of these studies have
brought up several interesting issues. First, the activation of p53 seems to be a general response of the cell
to RP insufficiency. As mentioned earlier, several RPs
(RPL5, RPL11, RPL23, and RPS7) have been identified as positive regulators of p53.43 However, we
have shown that in vivo knockdown of RPL11 activates p53 in zebrafish,79 a response similar to in vitro
knockdown of RPL23 in human cell lines.36 Thus,
the deficiency of any RP, regardless of its role in p53
regulation, may activate p53.
Second, the phenotypes associated with an RP
deficiency in vertebrates are quite heterogeneous.
In the invertebrate Drosophila, haploinsufficiency of
many RPs results in similar-looking mutants, known
as Minutes, which show complex phenotypes such
as slow development, short bristles, and impaired
fertility.88 These phenotypes are usually thought to
arise from insufficient ribosome production because
RPs are considered to be ‘housekeeping’ genes, essential for all cell types. However, unlike Drosophila, RP
depletion in mammalian and nonmammalian vertebrates causes variable phenotypes. Depending on the
type of RP, the effect can either be lethal or pleiotropic,
with a specific defect in a particular tissue and additional phenotypes, or it may not have any effect at
all. It is not clear whether Dmp53 (the Drosophila
p53 homolog) contributes to Minute phenotype in
Drosophila as there is no known Drosophila homolog
of MDM2 and developmental defects due to impaired
ribosome synthesis [loss of transcription initiation
factor IA (Tif-IA)] are not rescued in a Dmp53 null
background.89 However, the abnormalities due to RP
deficiency in vertebrates mostly involve the p53 pathway. Heterozygous mutations in RPS6 in mice result
in a severe phenotype leading to embryonic lethality,81
whereas a conditional deletion in the liver results in
the complete loss of hepatocyte proliferative capacity
following partial hepatectomy due to cell cycle arrest
at G1 phase.13 Mutations in many RP genes result in
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TABLE 1 Ribosomal Protein (RP) Deficiency and the p53 Pathway
RP
Coinhibition
of p53
Experimental Model
Method of Inactivation
Role of RPL11 in p53 Response
References
RPS6
In vivo, mouse
Conditional deletion (liver) Not done
RPS6
In vitro , human A549 cells Knockdown
Rescue
RPS6
In vivo , mouse
Deletion
Partial rescue Independent, no change in RPL11
protein levels
81
RPS6
In vivo , mouse
Conditional deletion
(T lymphocytes)
Rescue
Not analyzed
82
RPS9
In vitro , human U2OS cells Knockdown
Rescue
Dependent, co-knockdown of RPL11
attenuates induction of p53
83
Not analyzed
13
Dependent, increase in RPL11
protein levels
80
RPS8, RPS11, In vivo , zebrafish
RPS18
Insertion
Not done
Not analyzed
84
RPS19
In vivo , zebrafish
Knockdown
Rescue
Not analyzed
84
RPS19
In vivo , mouse
Missense mutation
Rescue
Not analyzed
85
RPS20
In vivo , mouse
Missense mutation
Rescue
Not analyzed
85
RPS23
In vitro , human A549 cells Knockdown
Not done
Dependent, co-knockdown of RPL11
attenuates induction of p53
80
RPL7a
In vitro , human A549 cells Knockdown
Not done
Dependent, co-knockdown of RPL11
attenuates induction of p53
80
RPL11
In vivo , zebrafish
Rescue
—
79
RPL22
In vivo , mouse
Deletion
Rescue
Not analyzed
RPL24
In vivo , mouse
Deletion
Lethality
Knockdown
In vitro , human A549 cells Knockdown
similar phenotypes in zebrafish: homozygous mutants
show deformities in the head and gut,90 similar to
what we have seen for RPL11 and other RP-deficient
zebrafish,79,91 whereas heterozygous mutants show
developmental delay and growth impairment.92 Interestingly, 17 of these heterozygous mutants develop a
rare kind of malignant tumor.93 Mutations in RPS19
and RPS20 result in dark-skinned mice with a reduced
body size and mild anemia.85 Our morpholinoinduced knockdown of RPS19 in zebrafish, however, shows a more drastic erythropoiesis defect with
severe anemia, in addition to other developmental
defects.94 Surprisingly, RPL22-deficient mice show
specific defects only in T-cell development,86 whereas
haploinsufficiency of RPL24 in mice results in a
kinked tail, white hind feet, and a ventral midline
spot [belly spot and tail (Bst) mutants].95 Intriguingly,
the loss of RPL29 does not cause any phenotypic
effects except for general growth impairment.96
Third, disruption of the nucleolus and defects
in rRNA processing are not a prerequisite for p53
induction in response to an RP deficiency. For
example, the loss of RPS6 and RPL24 in human
A549 cells leads to an activated p53 response without
86
87
Dependent, increase in RPL11
protein levels
any effect on the integrity of the nucleolus. Although
RPS6-deficient cells show impaired rRNA processing,
RPL24-silenced cells show no defects.80,87 Similarly,
silencing of RPS9 in U2OS cells affects 18S rRNA
production and causes an upregulation of the p53
pathway, but the nucleoli remain relatively intact.83
Fourth, the deficiency of RPs and the resultant
p53 induction are not dependent on ribosomal stress
alone. For instance, the depletion of RPS9 not only
reduces the synthesis of 18S rRNA (ribosome stress)
but it also causes DNA replication stress.83 Similarly,
downregulation of RPS7 (cell-specific) and RPL11
attenuates stress-induced MDM2 inhibition and p53
stabilization not only in ribosomally stressed cells
(ActD-treated cells) but also in cells treated with
various kinds of DNA-damaging agents.46
Finally, p53 seems to have contrasting roles in
determining survival versus death in response to RP
deficiency. The p53 pathway is responsible for the
embryonic lethality of many RP-deficient embryos
(RPS6, RPS19, RPL11; see Table 1), and coinhibition of p53 rescues the phenotypes. However, the
activation of p53 during embryonic stages promotes
the survival of Bst mutants (RPL24-deficient mice).
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Defective ribosome and p53
In these mice, induction of p53 delays the cell cycle
during embryonic development (a p21-dependent process), and the p21-independent apoptotic consequence
of p53 induction causes the Bst phenotypes in the
adults.87
RIBOSOMES, HUMAN DISEASES,
AND p53
As discussed above, ribosomes are ubiquitous
organelles essential for all types of cells. Any perturbation in ribosomal components would therefore
be expected to have serious consequences for cell
survival. However, this is not the case. It is now universally accepted that ribosomal dysfunction due to
haploinsufficiency of RP genes or mutations in genes
essential for ribosome biogenesis can lead to specific
disease conditions in humans called ribosomopathies,
a collection of rare genetic disorders associated with
an increased risk of developing cancer.16,17 However,
it should be noted that the type and occurrence rate
of cancers vary considerably in these diseases. Intriguingly, increased ribosome activity is also a common
feature in many malignancies; in fact, overexpression
of several RPs is seen in cancer cell lines and primary
tumors,15,97 although an elevated ribosomal function
in cancers could simply be a result of increased cellular proliferation. It is also not known whether any
extraribosomal function of RPs is responsible for cellular transformation. Hence, our discussion in this
section is restricted to diseases caused by decreased
ribosome activity, particularly those involving the p53
pathway (Table 2).
X-Linked Dyskeratosis Congenita (OMIM
305000)
X-linked dyskeratosis congenita (X-DC) is a rare
genetic disorder characterized by multiple pathological features, including bone marrow failure, skin
abnormalities, and high risk of cancer.113 X-DC is
caused by a mutation in the DKC1 gene, which
encodes dyskerin.114 Dyskerin is a nucleolar protein
that associates with boxH/ACA (Box H: AnAnnA/Box
ACA: ACA) snoRNPs to catalyze a posttranscriptional modification (pseudouridylation) of rRNA.115
Dyskerin is also a component of the telomerase complex that maintains telomere length.116 Hypomorphic
Dkc1 mutant mice (Dkc1m ) recapitulate many clinical features of X-DC and display impaired rRNA
modification.113 Mouse cells harboring a knock-in of a
DKC1 human deletion, Dkc115 , show increased p53
levels, independent of telomere length.98 Surprisingly,
both Dkc1m cells99 and DKC1-depleted human breast
cancer cells117 show a significant reduction in p53
mRNA translation mediated by an internal ribosome
entry site (IRES). This impaired p53 expression allows
these cells to bypass p53-mediated responses, such as
oncogenic or genotoxic stress responses, leading to
increased cell proliferation.99,117 X-DC patients also
show similar defects in p53 IRES-dependent translation and display reduced p53 protein expression99 ,
suggesting a basis for the increased cancer susceptibility in X-DC patients.99,117
Treacher Collins Syndrome (OMIM
154500)
Autosomal dominant mutations in TCOF1 cause
Treacher Collins syndrome (TCS), a disease characterized by numerous anomalies in the face, head, and
neck.101 Tumors or other forms of malignancy have
not been reported in TCS. TCOF1 encodes Treacle,
a nucleolar phosphoprotein involved in transcription
of ribosomal DNA into rRNA118 and methylation of
18S rRNA.119 In a mouse model of TCS, haploinsufficiency of Tcof1 results in diminished production of
ribosomes, which correlates with decreased proliferation of neural ectoderm and neural crest cells.120 An
activated p53 pathway is responsible for the clinical
manifestation of this disease, and inhibition of p53
(either genetically or pharmacologically) rescues the
craniofacial defects in Tcof1 haploinsufficient mice.102
Diamond-Blackfan Anemia (OMIM
105650)
Diamond-Blackfan anemia (DBA) is an inherited
genetic disease of infants characterized by bone marrow failure, congenital anomalies, and a severe erythroid defect.121 The patients are also predisposed
to an increased risk of cancer, although, according
to the latest statistics from the DBA registry, malignancy has been observed only in a small percentage
of patients.16 A subset of patients (∼30–50%) also
show other physical anomalies, such as short stature,
craniofacial abnormalities, upper limb malformations, and kidney dysfunction.122 The most commonly
affected gene in DBA is RPS19 (∼25%).103 However,
some patients show mutations in other RPs, including RPL5 (∼6.6%),104 RPS10 (∼6.4%),105 RPL11
(∼4.8%),104 RPL35A (∼3%),106 RPS26 (∼2.6%),105
RPS24 (2%),107 RPS7 (∼1%),104 and RPS17 (1%).108
Together, these nine genes account for approximately
53% of DBA cases.105 In addition, possible mutations in RPL9, RPL36, RPS15, and RPS27A have
been reported.104,105 Physical abnormalities are more
predominant in patients with RPL5 and RPL11
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TABLE 2 Ribosomal Dysfunction, Human Diseases, and the p53 Pathway
Disease
Mutated Gene Clinical Features
Cancer Propensity
Role of p53
References
X-linked
dyskeratosis
congenita
(X-DC)
DKC1
Bone marrow failure
Skin hyperpigmentation
Nail dystrophy
Oral leukoplakia
High risk of leukemia,
solid tumors, and
pulmonary fibrosis
Controversial; both
upregulated and
downregulated p53
activity observed in
mouse models and
patients
98–100
TCOF1
Treacher Collins
syndrome (TCS)
Craniofacial abnormalities
Not known
Upregulated p53 activity;
coinhibition leads to
phenotypic rescue in a
mouse model
101,102
Diamond-Blackfan RPS19, RPL5,
anemia (DBA) RPS10, RPL11,
RPL35A,
RPS26, RPS24,
RPS17, RPS7,
RPL9,
RPL36, RPS15,
RPS27A
Anemia
Bone marrow failure
Retarded growth
Thumb abnormalities
Craniofacial anomalies
Kidney dysfunction
Debatable; can progress
to acute myeloid
leukemia (AML),
osteosarcoma
Upregulated p53 activity;
proapoptotic erythroid
precursors
Suppression of p53
leads to phenotypic
rescue in mouse and
zebrafish models
84,85,103–108
5q− Syndrome
Macrocytic anemia
Normal or high platelet
count
Hypolobulated
megakaryocytes
Low risk of AML in
Upregulated p53 activity;
drug-responsive
coinhibition leads to
patients
phenotypic rescue in a
High risk of AML in
mouse model
nonresponsive patients
RPS14
mutations; the cleft lip and/or palate phenotype is
associated only with RPL5 mutations, except for
one patient with a RPS26 mutation,104,105 whereas
isolated thumb abnormalities are predominant in
patients with mutations in RPL11.104 Despite considerable research on DBA, the exact molecular
mechanism underlying this disease is not fully understood. Although several interesting hypotheses have
been proposed for the DBA pathophysiology (see
recent reviews in Refs 16, 121, 123), we are still
far from unraveling this disease completely. Although
the ‘ribosomal stress and p53’ hypothesis appears
to be the most widely accepted, the presence of
RPL5 and RPL11 mutations in DBA patients challenges this hypothesis, as both of these RPs are
clearly essential (in mammalian cells) for p53 activation under conditions of ribosomal stress (discussed
above). Cells with siRNA-mediated downregulation
of DBA-associated RPs such as RPS19,124 RPS24,125
RPL5 and RPL11,104 or RPS10 and RPS26105 exhibit
defects in the rRNA maturation pathway. Similarly,
CD34+ cells from DBA patients and RPS19-deficient
erythroid cells show defects in rRNA processing.126
These cells also undergo cell cycle arrest127 and
increased apoptosis,128 suggesting the involvement
of the p53 pathway in DBA. RPS19 deficiency in
zebrafish faithfully recapitulates the hematopoietic
109–112
and developmental phenotype of DBA.94 Using a
similar strategy, Danilova et al.84 demonstrated that
an activated p53 pathway causes the erythroid defects,
and mutations in p53 or drug-induced inhibition of
p53 function can improve the DBA phenotype of
zebrafish. An initial attempt to model DBA in mice was
unsuccessful because Rps19 heterozygous mice displayed no abnormalities in the hematopoietic system,
whereas Rps19 null mice were embryonic lethal.129
Subsequently, another model of DBA has been developed in mice that harbor a heterozygous missense
mutation in Rps19 [Dark skin 3 (Dsk3) mutant].85
However, unlike DBA patients, the Dsk3 mutants
show only mild anemia and a more prominent pigmented phenotype (dark skin) without any physical
deformities.85 The role of p53 in mediating DBA phenotype was further confirmed in this mouse model,
which showed the complete rescue of all the phenotypes, including erythrocytic hypoplasia, when crossed
with p53 knockout mice.85
The 5q− Syndrome (OMIM 153550)
The 5q− syndrome is a type of myelodysplastic syndrome associated with hematological abnormalities
and is caused by a deletion of the long arm of
chromosome 5.109 The patients typically have macrocytic anemia, normal/elevated platelets counts, and
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WIREs RNA
Defective ribosome and p53
nonlobulated megakaryocytes in the bone marrow.
Patients who respond well to lenalidomide (an
immunomodulatory drug) treatment have a low risk
for acute myeloid leukemia (AML) but in nonresponders the risk is significantly higher.110 The 5q− common deleted region contains 40 genes.130 Deficiency
of RPS14 probably accounts for the erythroid defects,
whereas its contribution to the other phenotypes
remains unclear.111 Knockdown of RPS14 in normal
hematopoietic progenitor cells impairs erythroid differentiation, blocks the processing of 18S rRNA, and
results in 40S subunit deficiency. Cells from patients
with 5q− syndrome also show a pre-rRNA processing defect, and overexpression of RPS14 rescues the
erythroid defects in these patients.111 Recently, it was
shown that deletion of miR-145 and miR-146a, which
are transcribed from the common deleted region, is
responsible for other hematological phenotypes seen
in 5q− syndrome, such as elevated platelet counts
and megakaryocytic dysplasia.131 An activated p53
pathway has been implicated in the pathophysiology
of 5q− syndrome.112,132 Elevated levels of p53 and
increased bone marrow cell apoptosis were observed
in a mouse model of 5q− syndrome that displays
macrocytic anemia and erythroid dysplasia. Notably,
when the 5q− deletion is introduced in a p53-null
background, these mice show a complete rescue of the
hematopoietic phenotypes.112
CONCLUSION AND FUTURE
PERSPECTIVES
Over the last decade, our understanding of the ribosome has changed considerably. In the past, ribosomes
were considered to be critical for cellular survival, but
it is now clear that impaired ribosome synthesis does
not necessarily make a cell inviable. Rather, it causes
variable effects that may result in specific disease conditions in humans. RPs, which were earlier thought to
play only a housekeeping role, are now known to have
many extraribosomal functions, including the surveillance of ribosome production.19 Given the complexity
associated with the process of ribosome synthesis, it
is logical that ribosome biogenesis is under constant
surveillance at multiple levels, and we now know
that p53 is the central player in this monitoring process. Disruption of ribosome biogenesis, either due to
an RP haploinsufficiency or mutations in nucleolar
proteins involved in rRNA processing and ribosome
assembly, causes ‘nucleolar stress’ that triggers a p53
signaling pathway, resulting in cell cycle arrest and
apoptosis (Figure 2). As expected, the p53 pathway is
responsible for the clinical manifestation of many ribosomal diseases of humans, which often present with a
prominent tissue-specific phenotype, such as the anemia in DBA and the 5q− syndrome. Interestingly, associated anomalies such as short stature, craniofacial
abnormalities, and physical deformities are also common in ribosomal diseases. Thus, it appears that the
activation of the p53 pathway is a common response
in all cells, but the consequences of this response vary
among different cell types, which may explain why
we have such heterogeneous pathological outcomes
in these diseases. Indeed, coinhibition of p53 in animal models of ribosomal pathologies completely rescues not only the tissue-specific erythroid defects but
also the associated pleiotropic phenotypes of growth
retardation, craniofacial abnormalities, and hyperpigmented skin.84,85,102 The factors that make p53 target
only the erythroid cells in diseases like DBA and
the 5q− syndrome, while allowing other cells to grow,
remain to be defined. It has been suggested that rapidly
developing tissues, such as the bone marrow, would
require increased ribosome activity, and hence would
be more susceptible to a ribosomal deficiency.133
However, in a developing embryo, bone marrow is not
the only rapidly dividing tissue and, most importantly,
myeloid differentiation is almost normal in these diseases, with only the erythroid precursors affected.
A deregulated translational readout due to ribosomal or RP insufficiency may lead to an increase
or a decrease in the translation of specific mRNAs,
which interacts with the p53 regulatory system, causing the upregulation and stabilization of p53. Indeed,
disruption of the 40S ribosomal subunit due to
RPS6 deficiency leads to the upregulated translation
of 5 -terminal oligopyrimidine tract (TOP) mRNAs,
including that of RPL11.80 This increases the levels of
ribosome-free RPL11 protein, making it available for
interactions with MDM2 and subsequent p53 induction. Consistent with this finding, an activated p53
response due to RPS9 deficiency involves the upregulation of RPL11.83 These observations raise the possibility that in diseases like DBA and the 5q− syndrome
that show predominant mutations in 40S subunit proteins, targeting the signaling pathways contributing
to RPL11 upregulation, rather than suppressing p53,
could be a potential therapeutic strategy that would
not increase the risk of cancer development. However, to make matters more complex, RPL11 is also
mutated in DBA, along with other 60S subunit RPs
(RPL5, RPL35A, RPL36).104,105 Depletion of an RP
causes a decrease in the levels of the other RPs belonging to the same subunit52 but, surprisingly, the loss of
RPL24 (one of the 60S proteins) results in the accumulation of ribosome-free RPL11 without any effect
on ribosome biogenesis or pre-rRNA processing.87
How do the cells maintain this increased level of
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Advanced Review
Pre-rRNA
5S
p53
2
MDM
RPs
18S
5.8S
Accessory
factors
28S
40S
60S
Nucleoplasm
Nucleolus
Cytoplasm
S7
Processing
defect
L5
L23
Nucleolar
stress
5′TOP mRNA
(L11, others?)
Free RPs
2
MDM
L11
p53
Cell cycle arrest
apoptosis
Accessory factor
deregulation
FIGURE 2 | p53-Dependent surveillance system for monitoring ribosome biogenesis. The synthesis of ribosomes is a complex and
energy-demanding process that involves the coordinated participation of several hundred factors. In normal cells (upper panel), the biogenesis of the
ribosome begins with the transcription of ribosomal DNA into pre-ribosomal RNA (rRNA) precursors by RNA polymerase I in the nucleolus (gray). This
pre-RNA cluster then undergoes a series of modifications and cleavage by several hundred small nucleolar RNAs (snoRNAs) and ribosome-associated
nucleolar proteins [accessory factors, shown as filled green rhombi; synthesized in the cytoplasm (white)] to form rRNA intermediates and finally the
mature rRNAs (18S, 5.8S, and 28S). Seventy-nine ribosomal proteins (RPs, shown as purple circles; produced in the cytoplasm) and 5S rRNA
[synthesized in the nucleoplasm (sky blue)] are imported into the nucleolus, where they associate with other rRNAs to form the small (40S) and large
(60S) subunits, which are then assembled and exported to the cytoplasm to form the mature ribosome for the initiation of protein synthesis. Under
these conditions, p53 is maintained at low levels in the nucleoplasm by murine double minute 2 (MDM2). In ribosomally stressed cells (lower panel),
deficiencies of RPs (shown as dotted purple circles) or accessory factors (shown as partially filled green rhombi) cause defects at various stages of
rRNA processing, leading to defective 60S and 40S biogenesis, evoking a nucleolar stress response. This results in the translocation of ribosome-free
RPs or accumulated (unutilized) accessory factors to the nucleoplasm, where they bind and inhibit MDM2, leading to the activation and stabilization
of p53. Impaired 40S biogenesis can also lead to translational upregulation of 5 -terminal oligopyrimidine tract (5 TOP) messenger RNAs (mRNAs),
such as RPL11 and possibly other MDM2-binding RPs, which can enter the nucleoplasm and intercept the MDM2-mediated p53 degradation.
Depending on the cell type, the consequence of the activated p53 response could either be cell cycle arrest or apoptosis.
RPL11, when excess RPs are quickly degraded in the
nucleus?53 Perhaps some nonribosomal components
that remain to be identified are important for synthesis and stabilization of RPL11 and possibly other
MDM2-binding RPs.
There may be another twist to this story: a
p53-independent pathway might be responsible for
the erythropoietic failure in DBA. We have seen that
simultaneous knockdown of p53 in RPS19-depleted
zebrafish rescues the morphological phenotypes, but
not the erythroid defects (unpublished data). Indeed,
two reports presented in a recent scientific conference
(51st ASH Annual Meeting) showed that both RPS19depleted zebrafish134 and RPL35A-deficient human
bone marrow progenitors135 exhibit erythroid defects
even on a p53 mutant background, further supporting
our data. More recently, Iadevaia et al.136 showed
 2011 Jo h n Wiley & So n s, L td.
WIREs RNA
Defective ribosome and p53
that alterations in ribosome synthesis within erythroid
cell lines, either by knocking down RPs (RPS19, RPS6,
and RPL7a) or by inhibiting RNA Pol I activity, cause
a drastic reduction in pim-1 oncogene (PIM1), a serine/threonine kinase involved in cell cycle regulation.
A decrease in PIM1 level induces an increase in p27kip1
(a CDK inhibitor and PIM1 target), which causes cell
cycle arrest and blocks cell proliferation even in the
absence of p53. This suggests that ribosomal stress
can also trigger a p53-independent response.136
Finally, the ribosomal stress–p53 pathway has
been suggested as a cellular surveillance mechanism
for cancer prevention,43 and we know that this
pathway is functional in many ribosome-associated
diseases of humans (discussed above). Yet, many
ribosomal diseases confer a high propensity to the
development of cancers, including leukemia, sarcomas, and other solid organ tumors. Given the variable
outcome of ribosomal defects in different tissues, several studies have tried to answer the fundamental
question of how different cells can respond differently
to the same stress. The exciting findings made it clear
that the pathways linking defective ribosomes and p53
signaling are more complex than previously imagined,
and it is most likely that several players in addition to
these MDM2-binding RPs are involved. A challenge
for future studies will be to identify the additional
players in this signaling network and to elucidate the
underlying molecular mechanisms that link defective
ribosome synthesis to the p53 signaling pathway.
ACKNOWLEDGEMENTS
We thank Dr. Jonathan Warner for useful comments on the manuscript. This work was supported in part by
Grants-in-Aid (21790288 to AC, 22790989 to TU, and 22370065 to NK) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) and Japan Society for the Promotion of Science (JSPS).
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