Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

Deisenroth, Chad; Zhang, Yi

doi:10.1038/onc.2010.189

Cited by 270 publications

(275 citation statements)

References 76 publications

(79 reference statements)

Supporting

Mentioning

266

Contrasting

Unclassified

Order By: Relevance

“…We demonstrated that a downregulation of rRNA synthesis induced by silencing the POLR1A gene coding for the RNA polymerase I catalytic subunit stabilised p53 without giving rise either to structural changes in the nucleolar components or leakage of the nucleolar proteins to the nucleoplasm. As we found that, according to the available evidence (see reviews by Zhang and Lu, 2009;Deisenroth and Zhang, 2010), the inhibition of the synthesis of rRNA was associated with an increased binding of rpL5 and rpL11 to MDM2, we investigated whether p53 stabilisation also occurred in experimental models in which the synthesis of rRNA and ribosomal proteins was reduced at the same time, such as in cells after serum deprivation or exposure to rapamycin (O'Mahony et al, 1992;Mahajan, 1994;Glibetic et al, 1995;Hannan et al, 2003;Caldarola et al, 2004;Gera et al, 2004;Bilanges et al, 2007). The data obtained, showing no p53 stabilisation in either conditions, indicated that p53 was stabilised only when the reduction of rRNA synthesis was not accompanied by a similar variation in the synthesis of ribosomal proteins, that is, when a relative increase in ribosomal protein availability for MDM2 binding was induced.…”

Section: Introductionmentioning

confidence: 61%

“…Recently, the disruption of ribosome biogenesis has been shown to cause p53 stabilisation, as a consequence of the release from the nucleolus of several ribosomal proteins that bind to MDM2 and relieve its inhibitory activity toward p53 (see the reviews by Zhang and Lu, 2009;Deisenroth and Zhang, 2010). In fact, the large subunit ribosome proteins rpL5, rpL11 and rpL23 were all reported to bind MDM2, thus inducing p53 stabilisation by inhibiting its E3 ubiquitin ligase function (Lohrum et al, 2003;Zhang et al, 2003;Bhat et al, 2004;Jin et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

et al. 2011

View full text Add to dashboard Cite

Data on the relationship between ribosome biogenesis and p53 function indicate that the tumour suppressor can be activated by either nucleolar disruption or ribosomal protein defects. However, there is increasing evidence that the induction of p53 does not always require these severe cellular changes, and data are still lacking on a possible role of ribosome biogenesis in the downregulation of p53. Here, we studied the effect of the up-and downregulation of the rRNA transcription rate on p53 induction in mammalian cells. We found that a downregulation of rRNA synthesis, induced by silencing the POLR1A gene coding for the RNA polymerase I catalytic subunit, stabilised p53 without altering the nucleolar integrity in human cancer cells. p53 stabilisation was due to the inactivation of the MDM2-mediated p53 degradation by the binding of ribosomal proteins no longer used for ribosome building. p53 stabilisation did not occur when rRNA synthesis downregulation was associated with a contemporary reduction of protein synthesis. Furthermore, we demonstrated that in three different experimental models characterised by an upregulation of rRNA synthesis, cancer cells treated with insulin or exposed to the insulin-like growth factor 1, rat liver stimulated by cortisol and regenerating rat liver after partial hepatectomy, the p53 protein level was reduced due to a lowered ribosomal protein availability for MDM2 binding. It is worth noting that the upregulation of rRNA synthesis was responsible for a decreased p53-mediated response to cytotoxic stresses. These findings demonstrated that the balance between rRNA and ribosomal protein synthesis controls the function of p53 in mammalian cells, that p53 can be induced without the occurrence of severe changes of the cellular components controlling ribosome biogenesis, and that conditions characterised by an upregulated rRNA synthesis are associated with a reduced p53 response.

show abstract

Section: Introductionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

et al. 2011

View full text Add to dashboard Cite

show abstract

“…The inhibition of Pol I transcription was shown to trigger a phenomenon called "nucleolar stress" that leads to the translocation of ribosomal proteins from nucleolus to nucleoplasm, where some of them, for example, rpL5 and rpL11, will bind to MDM2, triggering its dissociation from and thus activation of p53. 13 Thus, by sustaining high levels of Pol I transcription, cancer cells maintain nucleolar integrity and hence promote the suppression of p53.…”

mentioning

confidence: 99%

Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics

Haddach¹,

Schwaebe²,

Michaux³

et al. 2012

ACS Med. Chem. Lett.

129

109

View full text Add to dashboard Cite

Accelerated proliferation of solid tumor and hematologic cancer cells is linked to accelerated transcription of rDNA by the RNA polymerase I (Pol I) enzyme to produce elevated levels of rRNA (rRNA). Indeed, upregulation of Pol I, frequently caused by mutational alterations among tumor suppressors and oncogenes, is required for maintenance of the cancer phenotype and forms the basis for seeking selective inhibitors of Pol I as anticancer therapeutics. 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (CX-5461, 7c) has been identified as the first potent, selective, and orally bioavailable inhibitor of RNA Pol I transcription with in vivo activity in tumor growth efficacy models. The preclinical data support the development of CX-5461 as an anticancer drug with potential for activity in several types of cancer.

show abstract

“…All of these observations show that the rate of cellular proliferation can be adjusted by the rate of ribosome biogenesis. Our finding that continuous expression of NOLC1 under normal growth conditions is attuned by p53 implies that p53 exerts its influence over the ribosome biogenesis pathway; it adjusts the cellular growth and acts in a positive feedback loop of the RP-Hdm2-p53 pathway 26 to limit ribosome assembly and cellular proliferation under stress conditions. In accordance, p53 upregulation leads to NOLC1 downregulation.…”

Section: Discussionmentioning

confidence: 86%

“…These genes are positioned upstream of the mature ribosome subunits that are known to activate the ribosomal protein (RP)-Hdm2-p53 pathway (reviewed in ref. 26), but downstream of the ribosomal RNA transcription machinery. There are more than 170 ribosome assembly factors 27 and the finding that only a small number of them induce p53 in our screen indicates that p53 monitors specific steps in the assembly process.…”

Section: Genome-scale Synthetic Interaction Rnai Screen With Tp53mentioning

confidence: 99%

A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly

et al. 2011

View full text Add to dashboard Cite

TP53(tumour protein 53) is one of the most frequently mutated genes in human cancer and its role during cellular transformation has been studied extensively. However, the homeostatic functions of p53 are less well understood. Here, we explore the molecular dependency network of TP53 through an RNAi-mediated synthetic interaction screen employing two HCT116 isogenic cell lines and a genome-scale endoribonuclease-prepared short interfering RNA library. We identify a variety of TP53 synthetic interactions unmasking the complex connections of p53 to cellular physiology and growth control. Molecular dissection of the TP53 synthetic interaction with UNRIP indicates an enhanced dependency of TP53-negative cells on small nucleolar ribonucleoprotein (snoRNP) assembly. This dependency is mediated by the snoRNP chaperone gene NOLC1 (also known as NOPP140 ), which we identify as a physiological p53 target gene. This unanticipated function of TP53 in snoRNP assembly highlights the potential of RNAi-mediated synthetic interaction screens to dissect molecular pathways of tumour suppressor genes.More than 30 years of intense research on the tumour suppressor gene TP53 has revealed its relevance in many aspects of tumour biology (reviewed in ref. 1). It is now well established that p53 (the protein product of TP53) activation leads to the execution of a complex genetic program that limits cellular proliferation and leads to senescence or apoptosis 2,3 . Several lines of evidence have pointed to an under-appreciated homeostasis function of p53 in normal, unstressed cells 4 . As a transcription factor, p53 can mediate the expression levels of its target genes, thereby adjusting cellular homeostasis of basic metabolism 5 , balance of reactive oxygen species 6,7 , stem cell identity and reprogramming 8 and animal reproduction 9 . These data establish an important role for p53 in cellular homeostasis and indicate that p53-loss-of-function cells become genetically rewired in a way that discriminates them from wild-type cells, a premise that could be explored for the identification of possible p53 genetic dependencies.Synthetic interaction screens have led the way in identifying new and unanticipated functional interactions between seemingly unrelated protein complexes in yeast 10,11 . In mammalian cells, RNA interference (RNAi)-based synthetic interaction screens are a promising approach to dissect genetic dependencies and the first studies on mammalian synthetic interactions of oncogenes have demonstrated the power of this approach 12,13 . Furthermore, synthetic lethal screens have identified genes that sensitize cells to different chemical drugs 14,15 . Several synthetic interactions with tumour suppressor genes have also been published 11,16 , but to our knowledge a genome-scale survey for synthetic interactions of a tumour suppressor gene has not been reported. Here, we present the results of a systematic investigation of TP53 genetic dependencies and characterize in molecular detail a homeostatic function of p53 in snoRNP biogen...

show abstract

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

Cited by 270 publications

References 76 publications

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics

A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly

Contact Info

Product

Resources

About