Translational research? Ribosome integrity and a new p53 tumor suppressor checkpoint

Opferman, Joseph T.; Zambetti, Gerard P.

doi:10.1038/sj.cdd.4401923

Cited by 24 publications

(16 citation statements)

References 25 publications

(28 reference statements)

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“…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). Therefore, the present results confirm that p53 stabilisation is the major mechanism by which an altered ribosomal biogenesis induces the arrest of cell cycle progression.…”

Section: Discussionsupporting

confidence: 75%

“…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%

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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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Section: Discussionsupporting

confidence: 75%

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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“…Presumably these were cells that had escaped the deletion. Whether the block in the cell cycle is caused by nucleolar disruption activating the p53 checkpoint response (39,41) or is due to an unknown mechanism that couples cell division and ribosome biogenesis (2,41) remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Dyskerin Ablation in Mouse Liver Inhibits rRNA Processing and Cell Division

Ge¹,

Rudnick²,

He³

et al. 2010

Molecular and Cellular Biology

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Dyskerin is a component of small nucleolar ribonucleoprotein complexes and acts as a pseudouridine synthase to modify newly synthesized ribosomal, spliceosomal, and possibly other RNAs. It is encoded by the DKC1 gene, the gene mutated in X-linked dyskeratosis congenita, and is also part of the telomerase complex. The yeast ortholog, Cbf5, is an essential protein, but in mammals the effect of dyskerin ablation at the cellular level is not known. Here we show that mouse hepatocytes can survive after induction of a Dkc1 deletion. In the absence of dyskerin, rRNA processing is inhibited with the accumulation of large precursors, and fibrillarin does not accumulate in nucleoli. A low rate of apoptosis is induced in the hepatocytes, which show an induction of the p53-dependent cell cycle checkpoint pathway. Signs of liver damage including an increase in serum alanine aminotransferase activity and a disordered structure at the histological and macroscopic levels are observed. In response to carbon tetrachloride administration, when wild-type hepatocytes mount a rapid proliferative response, those without dyskerin do not divide. We conclude that hepatocytes can survive without dyskerin but that the role of dyskerin in RNA modification is essential for cellular proliferation.

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“…Studies have presently demonstrated that ribosome biogenesis is connected with the p53 activation pathway (Pestov et al, 2001;Opferman and Zambetti, 2006). Ribosome biogenesis is initiated by ribosomal RNA (rRNA) synthesis and processing, followed by the assembly of rRNA with ribosomal proteins to make the ribosomal subunits.…”

Section: Introductionmentioning

confidence: 99%

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

2011

Oncogene

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The largest energy consumer in the cell is the ribosome biogenesis whose aberrancy elicits various diseases in humans. It has been recently revealed that p53 induction, along with cell cycle arrest, is related with abnormal ribosome biogenesis, but the exact mechanism still remains unknown. In this study, we have found that aberrant ribosome biogenesis activates two parallel cellular pathways, c-Myc and ASK1/p38, which result in p53 induction and G1 arrest. The c-Myc stabilizes p53 by rpL11-mediated HDM2 inhibition, and ASK1/p38 activates p53 by phosphorylation on serine 15 and 33. Our studies demonstrate the relationship between these two pathways and p53 induction. The changes caused by impaired ribosomal stress, such as p53 induction and G1 arrest, were completely disappeared by inhibition of either pathway. These findings suggest a monitoring mechanism of c-Myc and ASK1/p38 against abnormal ribosome biogenesis through controlling the stability and activity of p53 protein.

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Translational research? Ribosome integrity and a new p53 tumor suppressor checkpoint

Cited by 24 publications

References 25 publications

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

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

Dyskerin Ablation in Mouse Liver Inhibits rRNA Processing and Cell Division

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

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