S6-Haploinsufficiency Activates the p53 Tumor Suppressor

Panić, Linda; Montagne, Jacques; Cokarić, Maja; Volarević, Siniša

doi:10.4161/cc.6.1.3666

Cited by 37 publications

(38 citation statements)

References 53 publications

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“…It is now well documented that ribosomal stress, defined as an alteration of ribosome synthesis, can induce the activation of the tumor suppressor p53 blocking cell proliferation and activating apoptosis (Pestov et al, 2001;Sulic et al, 2005;Anderson et al, 2007;Panic et al, 2007;Danilova et al, 2008;McGowan et al, 2008;Fumagalli et al, 2009). Here, we report the analysis of the effect of RPS19 deficiency on the metabolism of two erythroid cell lines.…”

Section: Discussionmentioning

confidence: 92%

“…It involves four ribosomal RNA molecules, about 80 RPs and nearly 200 non-ribosomal factors that are required for the synthesis, maturation and export of the two ribosomal subunits (Fatica and Tollervey, 2002). A number of reports suggest that perturbations of ribosome biogenesis, owing to a variety of causes (ribosomal stress), can activate a specific checkpoint and block cell proliferation mostly through a p53-dependent mechanism (Pestov et al, 2001;Rubbi and Milner, 2003;Anderson et al, 2007;Panic et al, 2007;Danilova et al, 2008;McGowan et al, 2008;Fumagalli et al, 2009). This occurs, for example, in the case of conditional deletion of RPS6 (Volarevic et al, 2000;Sulic et al, 2005) or in response to drugs that disrupt nucleolar structures (Rubbi and Milner, 2003).…”

Section: Introductionmentioning

confidence: 99%

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PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression

et al. 2010

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PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors and hormones. It has been implicated in the control of cell cycle progression and apoptosis and its overexpression has been associated with various kinds of lymphoid and hematopoietic malignancies. The activity of PIM1 is dependent on the phosphorylation of several targets involved in transcription, cell cycle and apoptosis. We have recently observed that PIM1 interacts with ribosomal protein (RP)S19 and cosediments with ribosomes. Defects in ribosome synthesis (ribosomal stress) have been shown to activate a p53-dependent growth arrest response. To investigate if PIM1 could have a role in the response to ribosomal stress, we induced ribosome synthesis alterations in TF-1 and K562 erythroid cell lines. We found that RP deficiency, induced by RNA interference or treatment with inhibitor of nucleolar functions, causes a drastic destabilization of PIM1. The lower level of PIM1 induces an increase in the cell cycle inhibitor p27 Kip1 and blocks cell proliferation even in the absence of p53. Notably, restoring PIM1 level by transfection causes a recovery of cell growth. Our data indicate that PIM1 may act as a sensor for ribosomal stress independently of or in concert with the known p53-dependent mechanisms.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression

et al. 2010

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“…Previous studies were conducted using models based on: (1) induction of a defective nucleolar protein necessary for both rRNA processing and the 60S ribosome subunit production (Pestov et al, 2001;Hölzel et al, 2005); (2) conditional deletion of the gene encoding the 40S ribosome protein S6 (Sulić et al, 2005); and (3) genetic inactivation of TIF-IA (Yuan et al, 2005), which is an essential RNA polymerase I transcription factor that also regulates the levels of both 5S rRNA and mRNAs encoding ribosomal proteins in Drosophila (Grewal et al, 2007). In these cases, the effect on cell proliferation could be ascribed not only to the inhibition of rRNA transcription, but also to ribosome biogenesis errors, decreased number of ribosomes, changes in the ratio of the 40S and 60S ribosome subunits, and defective ribosome translation (Panic et al, 2007). In agreement with what has been demonstrated to occur with the use of these models of deranged ribosome biogenesis, we found that POLR1A silencing hindered cell proliferation in p53-and pRb-proficient human cancer cell lines by activating the p53-p21-pRb pathway (Mayer and Grummt, 2005;Opferman and Zambetti, 2006;Panic et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…The derangement of cell growth caused by a defective ribosome biogenesis induces a checkpoint control that prevents the G1-S phase transition. Similarly to the mechanism by which an aberrant ribosome biogenesis activates the checkpoint, several studies pointed to the tumour suppressor p53 as the key factor in the response to ribosome biogenesis perturbations in mammalian cells (Mayer and Grummt, 2005;Opferman and Zambetti, 2006;Panic et al, 2007). Stabilised p53 activates the transcription of p21 WAF1 , an inhibitor of the cyclindependent kinases, which, by hindering pRb phosphorylation, prevents the cell from overcoming the G1-S phase restriction point (Sherr and Roberts, 1999).…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of rRNA transcription downregulates E2F-1: a new p53-independent mechanism linking cell growth to cell proliferation

Donati

Brighenti

Vici

et al. 2011

Journal of Cell Science

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SummaryThe tumour suppressor p53 negatively controls cell cycle progression in response to perturbed ribosome biogenesis in mammalian cells, thus coordinating growth with proliferation. Unlike mammalian cells, p53 is not involved in the growth control of proliferation in yeasts and flies. We investigated whether a p53-independent mechanism of response to inadequate ribosome biogenesis rate is also present in mammalian cells. We studied the effect of specific inhibition of rRNA synthesis on cell cycle progression in human cancer cell lines using the small-interfering RNA procedure to silence the POLR1A gene, which encodes the catalytic subunit of RNA polymerase I. We found that interference of POLR1A inhibited the synthesis of rRNA and hindered cell cycle progression in cells with inactivated p53, as a consequence of downregulation of the transcription factor E2F-1. Downregulation of E2F-1 was due to release of the ribosomal protein L11, which inactivated the E2F-1-stabilising function of the E3 ubiquitin protein ligase MDM2. These results demonstrated the existence of a p53-independent mechanism that links cell growth to cell proliferation in mammalian cells, and suggested that selective targeting of the RNA polymerase I transcription machinery might be advisable to hinder proliferation of p53-deficient cancer cells.

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“…The most characterized response to ribosomal stress involves the activation of tumor suppressor p53, with a consequent cell cycle arrest, senescence or apoptosis. 141,[157][158][159][160][161][162][163] However, in addition to the p53-dependent mechanisms, other possible signaling molecules are thought to mediate growth inhibitory effects of ribosomal stress independently of p53. 156,164,165 The best evidence of p53 involvement in the response to ribosomal stress is that p53 suppression by genetical or biochemical means in experimental model systems can rescue at least part of the defects caused by ribosome alteration.…”

Section: Ribosomes and Cancermentioning

confidence: 99%

Translation factors and ribosomal proteins control tumor onset and progression: how?

2013

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Gene expression is shaped by translational control. The modalities and the extent by which translation factors modify gene expression have revealed therapeutic scenarios. For instance, eukaryotic initiation factor (eIF)4E activity is controlled by the signaling cascade of growth factors, and drives tumorigenesis by favoring the translation of specific mRNAs. Highly specific drugs target the activity of eIF4E. Indeed, the antitumor action of mTOR complex 1 (mTORc1) blockers like rapamycin relies on their capability to inhibit eIF4E assembly into functional eIF4F complexes. eIF4E biology, from its inception to recent pharmacological targeting, is proof-of-principle that translational control is druggable. The case for eIF4E is not isolated. The translational machinery is involved in the biology of cancer through many other mechanisms. First, untranslated sequences on mRNAs as well as noncoding RNAs regulate the translational efficiency of mRNAs that are central for tumor progression. Second, other initiation factors like eIF6 show a tumorigenic potential by acting downstream of oncogenic pathways. Third, genetic alterations in components of the translational apparatus underlie an entire class of inherited syndromes known as 'ribosomopathies' that are associated with increased cancer risk. Taken together, data suggest that in spite of their evolutionary conservation and ubiquitous nature, variations in the activity and levels of ribosomal proteins and translation factors generate highly specific effects. Beside, as the structures and biochemical activities of several noncoding RNAs and initiation factors are known, these factors may be amenable to rational pharmacological targeting. The future is to design highly specific drugs targeting the translational apparatus.

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S6-Haploinsufficiency Activates the p53 Tumor Suppressor

Cited by 37 publications

References 53 publications

PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression

PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression

Selective inhibition of rRNA transcription downregulates E2F-1: a new p53-independent mechanism linking cell growth to cell proliferation

Translation factors and ribosomal proteins control tumor onset and progression: how?

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