Download Ribosome Biogenesis and Control of Cell

Published OnlineFirst January 26, 2012; DOI: 10.1158/0008-5472.CAN-11-3992
Cancer
Research
Perspective
Ribosome Biogenesis and Control of Cell Proliferation:
p53 Is Not Alone
Giulio Donati1, Lorenzo Montanaro1, and Massimo Derenzini2
Abstract
Cell growth is a prerequisite for cell proliferation, and ribosome biogenesis is a limiting factor for cell growth. In
mammalian cells, the tumor suppressor p53 has been shown to induce cell-cycle arrest in response to impaired
ribosome biogenesis. Recently, p53-independent mechanisms of cell-cycle arrest in response to alterations of
ribosome biogenesis have been described. These findings provide a rational basis for the use of drugs that
specifically impact ribosome biogenesis for the treatment of cancers lacking active p53 and extend the scenario of
mechanisms involved in the relationship between cell growth and cell proliferation. Cancer Res; 72(7); 1–6. Ó2012
AACR.
Introduction
Cell growth (increase in cell mass) and cell proliferation
(increase in cell number) are two tightly linked phenomena.
In cells stimulated to proliferate, a progressive increase in
cell constituents occurs before division ensuring appropriately sized daughter cells (1). Cell growth is the consequence
of an enhanced stimulation of protein synthesis that characterizes proliferating cells. The increased demand for protein synthesis is accomplished by changes in the rate of
ribosome biogenesis, and ribosome biogenesis is the major
metabolic effort in a proliferating cell (2). Ribosome biogenesis is the result of a series of coordinated steps occurring in the nucleolus. These include the transcription of
ribosomal genes by RNA polymerase I (Pol I) to produce the
47S rRNA precursor, the modification and processing of this
transcript to generate the mature 18S, 5.8S, and 28S rRNA,
the import to the nucleolus of 5S rRNA and ribosomal
proteins, the assembly of the rRNAs with the ribosomal
proteins to form the large 60S and the small 40S subunits
of the mature ribosome, and the export of ribosomal subunits to the cytoplasm (3). Transcription of ribosomal genes
requires the assembly of a specific multiprotein complex at
the rDNA promoter containing Pol I and, in mammals, at
least 3 other basal factors: the transcription initiation factor
I (TIF-I) A, the selectivity factor 1 (SL1), and the upstream
binding factor (UBF; reviewed in ref. 4; see Fig. 1).
Authors' Affiliations: 1Department of Experimental Pathology, and 2Clinical Department of Radiological and Histocytopathological Sciences, Alma
di Bologna, Bologna, Italy
Mater Studiorum - Universita
Current address for G. Donati: Bellvitge Biomedical Research Institute
(IDIBELL)-Hospital Duran i Reynals, Barcelona, Spain.
Corresponding Author: Massimo Derenzini, Clinical Department of Radiological and Histocytopathological Sciences, Alma Mater Studiorum - Uni di Bologna, Via Massarenti 9, Bologna 40138, Italy. Phone: 39-051versita
302874; Fax: 39-051-306861; E-mail: [email protected]
doi: 10.1158/0008-5472.CAN-11-3992
Ó2012 American Association for Cancer Research.
It is well established that at the end of G1 phase, the so-called
restriction point defines a limit beyond which the cell is
committed to divide, independent of growth (5). Therefore, it
is within the G1 phase that a proliferating cell has to carry out
its effort of supplying the components necessary for the transit
from G1 to S-phase, and it is at the end of G1 phase that the cell
must determine whether this effort has been successfully
accomplished. Data indicate that it is the amount of ribosomes
produced that controls the G1–S-phase transition, thus regulating the cell-cycle progression. In partially hepatectomized
mice with induced conditional deletion of 40S ribosomal
protein S6, hepatocytes with hindered ribosome production
but not hindered protein synthesis failed to enter the S-phase
(6). Drug-induced stimulation or inhibition of rRNA synthesis
caused an accelerated or delayed G1–S-phase progression,
respectively, in rat hepatoma cells, due to an accelerated or
delayed achievement of the appropriate amount of ribosomes
during the G1 phase (7). Regarding the mechanism that regulates the cross-talk between ribosome biogenesis and cellcycle progression, there is a general consensus on the key role
played by the tumor suppressor p53. In fact, as described more
extensively later, it has been clearly shown that altered ribosome biogenesis is responsible for p53 stabilization and,
therefore, for the arrest of cell-cycle progression (reviewed in
refs. 8–10). On the other hand, very recent data indicate that
p53-independent mechanisms are also activated that hinder
proliferation as a consequence of altered ribosome biogenesis
(11–15).
Ribosome Biogenesis and the Control of
Cell-Cycle Progression: the p53 Paradigm
Defects in ribosome production cause p53 stabilization and
induce a marked p53-dependent inhibition of cell proliferation
(10). It is worth recalling that in proliferating mammalian cells,
the G1–S-phase restriction point can be overwhelmed by the
activation of the E2F transcription factor family (16), which
regulates the expression of genes whose products are necessary
for the synthesis of DNA, and therefore for the progression
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Donati et al.
Promoter
Pol I
TIF-IA
SL1
UBF
Nucleolus
18S
28S
5.8S
Transcription
47S precursor RNA
18S
5.8S
28S
Modification and processing
18S
5.8S
28S
Assembly
Nucleus
5S
Export
5S
Ribosomal
proteins
Cytoplasm
40S
Figure 1. Schematic representation
of the main processes involved in
ribosome biogenesis. One
ribosomal gene unit is repeated
hundreds of times in the genome
and includes the promoter and the
transcribed region. The major basal
factors binding to the promoter
region and required for ribosomal
gene transcription are shown in the
inset. After transcription, the 47S
pre-rRNA is processed. The
mature rRNAs are assembled with
ribosomal proteins (RP) to generate
mature ribosomal subunits. In
particular, 18S is assembled with
small subunit RPs to generate the
40S small ribosomal subunit,
whereas 5.8S and 28S rRNA are
assembled with 5S rRNA (which is
transcribed by Pol III in the
nucleus), and with large subunit
RPs to form the 60S large
ribosomal subunit. Mature 40S and
60S subunits are then exported to
the cytoplasm to constitute the
ribosomes.
60S
from G1 to S-phase. The retinoblastoma protein (pRB), the
product of the tumor suppressor RB1 gene, in its active
hypophosphorylated form, is bound to E2Fs and prevents
them from inducing E2F target genes. In the hyperphosphorylated form, pRB no longer binds to E2Fs, which can then
activate their target genes. Phosphorylation of pRB is triggered
in the early G1 phase by cyclin D–cyclin-dependent kinase
(CDK)-4 and -6 complexes and is completed at the end of the G1
phase by cyclin E–CDK-2 complexes. pRB phosphorylation is
hindered by CDK inhibitors: CDK-4 and CDK-6 are inhibited
mainly by p16Ink4a, whereas CDK-2 is negatively regulated by
p21(Cip1) and p27(Kip1), as shown in Fig. 2A. p53 stabilization,
occurring in response to a variety of cellular stresses, leads
to induction of the CDK-2 inhibitor p21, inhibition of cyclin
E–CDK-2 complexes, and pRB-dependent cell-cycle arrest at
the G1–S-phase checkpoint (16).
The mechanism of p53 stabilization after perturbation of
ribosome biogenesis is apparently the consequence of changes
in functional and physical interactions of the tumor suppressor
with MDM2. MDM2 negatively controls p53 activity in 2 ways:
by binding to the protein and interfering with its transactivation activity and by facilitating p53 proteasomal degradation
thereby acting as an E3 ubiquitin ligase (17). As a consequence
of altered ribosome biogenesis, several ribosomal proteins no
longer used for ribosome construction bind to MDM2 and
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relieve its inhibitory activity toward p53. In fact, it was shown
that the ribosomal proteins RPL5 (18), RPL11 (19–21), RPL23
(22, 23), and RPS7 (24) bind MDM2, thus inducing p53 stabilization by inhibiting MDM2's E3 ubiquitin ligase function (also
reviewed in ref. 10). The inhibition of rRNA transcription,
induced either by drugs such as actinomycin D, 5-fluorouracil,
or mycophenolic acid, or by depletion of essential Pol I
complex components (10, 15, 25), stabilizes p53 by causing
ribosomal protein–induced inactivation of MDM2. These data
are consistent with a mechanism by which altered ribosome
biogenesis inhibits cell proliferation in a strictly p53-dependent manner through the activation of the ribosomal protein–
MDM2–p53 pathway.
p53-Independent Mechanisms
The regulation of the cell cycle in response to defects in
ribosome biogenesis, far from being exclusive to mammalian
cells, also occurs in organisms where p53 does not regulate the
cell cycle or is not even present. In the metazoan Drosophila
melanogaster, p53 does not regulate p21 transcription, nor does
it regulate the cell cycle (26). In this organism, haploinsufficiency of several ribosomal protein genes gives rise to the
minute phenotype. Cells from minute mutants are the same
size as wild type, but their proliferation rate is reduced (27),
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p53-Independent Control of Cell Proliferation
Figure 2. A, schematic and
simplified representation of the
mechanisms leading to the cell-cycle
progression from G1 to S-phase.
After cell-cycle entry, cyclin D–CDK4 and -6 and cyclin E–CDK-2
complexes phosphorylate pRB
during G1 phase. Phosphorylation of
pRB leaves E2F1 free to activate the
E2F1 target genes whose products
are necessary for entry and
progression through S-phase. B,
p53-dependent cell-cycle arrest
after ribosomal stress. Regardless of
the nature of ribosomal stress, an
increased availability of RPs
inactivates MDM2 for p53 digestion.
Accumulated p53 induces
transcription of p21 that, in turn,
hinders pRB phosphorylation by
cyclin-dependent kinases, thus
blocking E2F-1 activity. C, p53independent cell-cycle arrest after
ribosomal stress. Alterations in
ribosomal assembly and ribosomal
processing increase the level of the
cyclin-dependent kinase inhibitor
p27, thus reducing pRB
phosphorylation. This should lead to
a decreased activation of E2F-1.
Changes of ribosomal biogenesis
caused by inhibition of factors
constituting the complex of rDNA
gene promoter increases RP
availability. RP binding to MDM2
lowers its protective effect on E2F-1.
The amount of E2F-1 is therefore
reduced by proteasome-mediated
digestion with a consequent reduced
activation of the E2F-1 target genes.
implying the existence of a mechanism controlling cell-cycle
progression in response to hampered ribosome biogenesis.
Depletion of the RNA polymerase I cofactor TIF-IA induces a
p53-independent proliferation arrest in Drosophila cells (28).
Furthermore, in the yeast Saccharomyces cerevisiae, where no
p53 homolog has been found, defective ribosome biogenesis
delays the cell-cycle progression to S-phase before any variation in protein synthesis capacity ensues (29).
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The presence of a p53-independent pathway regulating
the relationship between ribosome biogenesis and cell proliferation in mammalian cells was first suggested by the
observation that selective inhibition of rRNA synthesis by
actinomycin D was able to induce a perturbation of cellcycle progression also in cells silenced for p53 expression,
although milder than that occurring in the presence of p53
(30). In the past 2 years, some light has been shed on how
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altered ribosome biogenesis can hinder cell proliferation in a
p53-independent way. A good example is constituted by
pescadillo depletion. The pescadillo nucleolar protein plays
a role in the processing of pre-rRNA molecules during
assembly of 60S ribosomal subunits, through formation of
the PeBoW complex with Bop1 and WDR12 proteins (11).
Depletion of pescadillo inhibits ribosome biogenesis, and,
similar to other mechanisms that hinder ribosome production, stabilizes p53, leading to cell-cycle arrest (11). However,
pescadillo gene knockdown impaired cell proliferation in
cells harboring mutated p53, indicating that in these cells,
the observed cell-cycle control mediated by pescadillo protein was p53 independent (13). In fact, pescadillo depletion
resulted in decreased expression of cell-cycle protein cyclin
D1 and upregulation of the CDK inhibitor p27, with the
consequent marked reduction of pRB phosphorylation (13).
Another p53-independent mechanism of cell proliferation
arrest induced by impaired ribosome biogenesis was shown by
the downregulation of PIM1 expression caused by ribosomal
protein deficiency and various other ribosomal stressors (14).
PIM1 is a constitutively active serine–threonine kinase regulated by cytokines, growth factors, and hormones that has been
shown to reduce the activity of p27Kip1 and increase its
degradation (31). Furthermore, PIM1 kinase has been shown
to interact with the ribosomal protein RPS19, and it has been
shown that depletion of RPS19 or other ribosomal proteins
caused increased PIM1 kinase proteasome degradation (14).
The downregulation of PIM1 kinase stabilized and activated
p27Kip1, thus causing a block in cell-cycle progression regardless of p53 status (14).
The data reported above indicate that changes in the
biogenesis of single ribosome subunit hinder cell proliferation in cells with activated or inactivated p53. Moreover,
data have recently been reported showing that specific
inhibition of rRNA transcription by depletion of POLR1A
hindered cell-cycle progression in cancer cell lines with
inactivated p53 (15). This was due to the fact that the
inhibition of rRNA synthesis decreased the expression of
E2F-1. Normally, E2F-1 is protected from proteasome-mediated degradation by the interaction with MDM2, which
prevents the binding of other E3 ligases responsible for
E2F-1 ubiquitination (32). The inhibition of rRNA synthesis
releases the ribosomal protein L11, which, by binding to
MDM2, prevents its stabilizing function on the E2F-1 protein
(15). The downregulation of the E2F-1 protein caused a
reduction in the expression of the E2Fs target genes that
are necessary for the entry and progression through the Sphase. RB1 silencing rescued the expression of these genes
completely and prevented the effect of the rRNA synthesis
inhibition on cell proliferation. The inhibition of rRNA
synthesis is not always associated with a downregulation
of E2F-1. In fact, actinomycin D, cisplatin, and etoposide—
drugs that inhibit rRNA transcription—caused an accumulation of E2F-1 protein (33). However, these drugs are also
DNA-damaging agents, and it has been shown that these
agents increase E2F-1 half-life and its transcriptional activity
(33). Importantly, reducing the synthesis of rRNA by TIF-IA
silencing, that is, a non–DNA-damaging procedure to inhibit
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Cancer Res; 72(7) April 1, 2012
rRNA transcription, reduced the expression of the E2F-1
protein (15).
Finally, another mechanism defining the relationship
between ribosome biogenesis and cell proliferation in cells
with inactive p53 is the downregulation of c-Myc in response to
ribosome stress. c-Myc, in addition to stimulating cell proliferation, controls all the steps of ribosome biogenesis: It
increases Pol I activity by facilitating the recruitment of SL1
to promoters, stimulates ribosomal protein synthesis by
increasing Pol II transcription, and enhances Pol III transcription by activating TFIIIB (34). It was found that, in response to
ribosome biogenesis inhibition, RPL11 binds to c-Myc, reducing its transcriptional activity and to c-Myc mRNA, promoting
its degradation (12). The RPL11-mediated downregulation
of c-Myc reduced cell proliferation, and this effect was also
observed in p53-null cells, thus showing another p53-independent mechanism of proliferation control (12).
In conclusion, there is now evidence that ribosomal stress
hinders cell proliferation in mammalian cells with and without
p53. The p53-dependent and -independent mechanisms by
which ribosome biogenesis controls cell-cycle progression are
schematically summarized in Fig. 2.
Ribosome Biogenesis Inhibition and
Chemotherapy of p53-Deficient Cancer
The disruption of p53 function occurs in more than 50% of
human tumors, thus representing the most frequent gene
alteration in cancers (35). Commonly used chemotherapeutic
agents in human cancer induce some cell stress, which activates
the p53-mediated cell-cycle blockage and/or apoptosis. Therefore, tumors without functioning p53 are less sensitive to
cytostatic and cytotoxic drug treatment than those harboring
wild-type p53 (36). The p53-independent control of ribosome
biogenesis on cell proliferation may explain some recent data
showing an antiproliferative effect of Pol I complex inhibitors
on cancer lacking functional p53. Indeed, a study conducted by
Drygin and colleagues (37) showed that targeting factors of the
rDNA transcription complex represents a promising strategy
for chemotherapeutic treatment of cancers, both p53 proficient
and deficient. During a screening assay for agents that selectively inhibit Pol I transcription relative to Pol II transcription,
CX-5461 (Cylene Pharmaceuticals Inc.), a potent small molecule
that selectively inhibits Pol I–driven transcription, was identified (37). It was shown that CX-5461 disrupts the binding of
the SL1 transcription factor to the rDNA promoter, thus preventing the initiation of rRNA synthesis by the Pol I multiprotein complex. In fact, SL1 mediates specific interactions
between the rDNA promoter region and the Pol I enzyme
complex by recruiting Pol I, together with a series of Pol I–
associated factors, to rDNA. CX-5461 exhibited antiproliferative
activity in numerous cancer cells in vitro, and, importantly, this
occurred in wild-type and mutant p53 cell lines. In this study,
the authors found that the mechanisms leading to cell death
after inhibition of rRNA synthesis involved autophagy and
senescence. Unfortunately, potential mechanisms affecting
the control of cell-cycle progression were not investigated.
However, according to the results obtained by Pol I and TIF-IA
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p53-Independent Control of Cell Proliferation
depletion, it is likely that the inhibitory effect on proliferation
of cells lacking active p53 observed after CX-5461 treatment
might be mediated by a downregulation of E2F-1.
Perspectives
Studies on p53-independent mechanisms regulating the
relationship between cell growth and cell-cycle progression
are expected not only to increase our knowledge of the
homeostatic control of cell proliferation but also to reveal
new aspects of the process of tumorigenesis and potential
chemotherapeutic therapies for p53-negative cancers.
The stabilization of p53 following ribosomal stress plays an
important role against neoplastic transformation (38). An
altered ribosome biogenesis may be responsible for a failure
in the p53 activation pathway, and this may facilitate tumor
onset (39). Similarly, functional inhibition of p53-independent
mechanisms for opposing cell-cycle progression after ribosomal stress could downregulate the tumor suppressor potential of the cell. Experimental studies of the effect of alterations
of factors involved in these mechanisms (such as Pim1, pescadillo, Bop1) on tumorigenesis, together with the analysis of
the integrity of their function in human tumors could possibly
point out their involvement in the process of neoplastic
transformation and identify new targets for therapeutic
applications.
The results reported in this review strongly encourage
studies to develop inhibitors of ribosome biogenesis that
downregulate E2F-1 expression. Furthermore, considering the
role of pRB in controlling E2F-1 function, it might be of interest
to combine the ribosome biogenesis inhibitors with drugs
that hinder the activity of the CDKs. The resulting reduction
of E2F-1 expression, together with the increased E2F-1 binding
to hypophosphorylated pRB can be reasonably expected to
have a very strong impact on cell proliferation in cancers
lacking active p53. A similar chemotherapeutic approach
should be highly effective on those cancers in which this
transcription factor is known to exert a major role in the
biology of the transformed cells. For example, aberrant E2F-1
activity is indeed a critical factor for the initiation and progression of B-cell Burkitt lymphoma (40) and for the emergence of castration-resistant prostate cancer (41).
The use of drugs targeting the CDKs in combination with
ribosome biogenesis inhibitors that downregulate E2F-1
expression may also be very useful for treatment of cancers
characterized by Myc overexpression, which is frequently
observed in human tumors of different origin. In fact, these
drugs may exert a p53-independent antiproliferative activity by
both downregulating c-Myc mRNA expression as a consequence of an increased availability of RPL11 after the inhibition
of rRNA synthesis and by reducing E2F-1 expression and
activity.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: L. Montanaro, M. Derenzini
Writing, review, and/or revision of the manuscript: G. Donati, L. Montanaro, M. Derenzini
Acknowledgments
The authors thank Dr. Angela Drew for critically editing the manuscript.
Grant Support
This work was funded by the Pallotti legacy for cancer research and RFO
funds from Bologna University to L. Montanaro and M. Derenzini. G. Donati
was supported by a grant fellowship by the Vanini Cavagnino Legacy
(Centro Interdipartimentale per le Ricerche sul Cancro "G.Prodi," Bologna
University).
Received December 7, 2011; revised January 18, 2012; accepted January 18,
2012; published OnlineFirst January 26, 2012.
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Cancer Research
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Published OnlineFirst January 26, 2012; DOI: 10.1158/0008-5472.CAN-11-3992
Ribosome Biogenesis and Control of Cell Proliferation: p53
Is Not Alone
Giulio Donati, Lorenzo Montanaro and Massimo Derenzini
Cancer Res Published OnlineFirst January 26, 2012.
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