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

Donati, Giulio; Brighenti, Elisa; Vici, Manuela; Mazzini, Giuliano; Trerè, Davide; Montanaro, Lorenzo; Derenzini, Massimo

doi:10.1242/jcs.086074

Cited by 83 publications

(83 citation statements)

References 43 publications

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“…Recent evidence uncovered novel stress-response pathways, which function independently of p53 and still result in cell cycle arrest and/or apoptosis. For instance, a nucleolar stress response in p53-silenced HCT116 cancer cells induces forced interaction of the ribosomal protein RpL11 with MDM2 resulting in E2F-1 degradation and cell cycle arrest (8). Further steps into this direction are required, as only a few p53-independent pathways are identified.…”

mentioning

confidence: 99%

The Wnt Target Protein Peter Pan Defines a Novel p53-independent Nucleolar Stress-Response Pathway

Pfister

Keil

Kühl

2015

Journal of Biological Chemistry

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Background: Peter Pan (PPAN) localizes to nucleoli and functions in ribosome biogenesis. Results: PPAN localizes also to mitochondria, and PPAN knockdown triggers p53-independent mitochondrial apoptosis and nucleolar stress as observed by de-stabilization of nucleophosmin. Conclusion: PPAN orchestrates a p53-independent stress-response pathway by coupling nucleolar stress induction to the mitochondrial apoptosis. Significance: Novel insight into the anti-apoptotic role of the ribosome processing factor PPAN is provided.

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mentioning

confidence: 99%

The Wnt Target Protein Peter Pan Defines a Novel p53-independent Nucleolar Stress-Response Pathway

Pfister

Keil

Kühl

2015

Journal of Biological Chemistry

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“…In human cancer cell lines, p53-independent mechanisms linking ribosome biogenesis defects to cell cycle arrest have been reported. 44,45 Interestingly, binding of RPL11 to MDM2 was shown to inhibit its E2F1-stabilizing activity, thereby hindering cell cycle progression. 44 Increased binding of RPL11 to MDM2 consecutive to ribosome biogenesis dysfunction could therefore potentially interfere with other p53-independent functions of MDM2 such as inhibition of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…44,45 Interestingly, binding of RPL11 to MDM2 was shown to inhibit its E2F1-stabilizing activity, thereby hindering cell cycle progression. 44 Increased binding of RPL11 to MDM2 consecutive to ribosome biogenesis dysfunction could therefore potentially interfere with other p53-independent functions of MDM2 such as inhibition of apoptosis. [46][47][48] So far, such functions has been described in cell lines and it will be interesting in future studies to evaluate their contribution to the phenotype of NleVilcKO; p53KO mice.…”

Section: Discussionmentioning

confidence: 99%

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

et al. 2015

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International audienceRibosome biogenesis is an essential cellular process. Its impairment is associated with developmental defects and increased risk of cancer. The in vivo cellular responses to defective ribosome biogenesis and the underlying molecular mechanisms are still incompletely understood. In particular, the consequences of impaired ribosome biogenesis within the intestinal epithelium in mammals have not been investigated so far. Here we adopted a genetic approach to investigate the role of Notchless (NLE), an essential actor of ribosome biogenesis, in the adult mouse intestinal lineage. Nle deficiency led to defects in the synthesis of large ribosomal subunit in crypts cells and resulted in the rapid elimination of intestinal stem cells and progenitors through distinct types of cellular responses, including apoptosis, cell cycle arrest and biased differentiation toward the goblet cell lineage. Similar observations were made using the rRNA transcription inhibitor CX-5461 on intestinal organoids culture. Importantly, we found that p53 activation was responsible for most of the cellular responses observed, including differentiation toward the goblet cell lineage. Moreover, we identify the goblet cell-specific marker Muc2 as a direct transcriptional target of p53. Nle-deficient ISCs and progenitors disappearance persisted in the absence of p53, underlying the existence of p53-independent cellular responses following defective ribosome biogenesis. Our data indicate that NLE is a crucial factor for intestinal homeostasis and provide new insights into how perturbations of ribosome biogenesis impact on cell fate decisions within the intestinal epithelium

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“…Elevated rRNA concentrations are commonly seen in human cancers associated with enhanced protein synthesis and accelerated cell proliferation (19,39). For example, increased rRNA transcription and ribosomal biogenesis were observed in cancers subject to c-Myc activation (17,18).…”

Section: Attenuated Protein Synthesis Upon Hspc111 and Rtcd1 Reductionmentioning

confidence: 99%

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Zhang

Yin

Wang

et al. 2014

Molecular Cancer Research

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Activation of c-Myc plays a decisive role in the development of many human cancers. As a transcription factor, cMyc facilitates cell growth and proliferation by directly transcribing a multitude of targets, including rRNAs and ribosome proteins. However, how to elucidate the deregulation of rRNAs and ribosome proteins driven by c-Myc in cancer remains a significant challenge and thus warrants close investigation. In this report, a crucial role for the HSPC111 (NOP16) multiprotein complex in governing ribosomal biogenesis and tumor growth was determined. It was discovered that enhanced HSPC111 expression paralleled the upregulation of c-Myc and was directly regulated by c-Myc in breast cancer cells. Knockdown of HSPC111 dramatically reduced the occurrence of tumorigenesis in vivo, and largely restrained tumor cell growth in vitro and in vivo. In stark contrast, HSPC111 overexpression significantly promoted tumor cell growth. Biochemically, it was demonstrated that RNA 3 0 -phosphate cyclase (RTCD1/RTCA) interacted with HSPC111, and RTCD1 was involved in the HSPC111 multiprotein complex in regulating rRNA production and ribosomal biogenesis. Moreover, HSPC111 and RTCD1 synergistically modulated cell growth and cellular size through commanding rRNA synthesis and ribosome assembly coupled to protein production. Finally, overall survival analysis revealed that concomitant upregulation of HSPC111 and RTCD1 correlated with the worst prognosis in a breast cancer cohort.Implications: Inhibition of HSPC111-dependent ribosomal biosynthesis and protein synthesis is a promising therapeutic strategy to diminish breast cancer tumor progression. Mol Cancer Res; 12(4); 583-94. Ó2014 AACR. IntroductionBreast cancer is by far the most common cancer among women and the leading cause of cancer-related deaths worldwide. The primary tumor and metastases to distant organs often cause significant morbidity and mortality. Numerous studies suggest that the oncogene c-Myc plays a crucial role in the development and progression of breast cancer. Along with its partner protein Max, c-Myc regulates an estimated 10% to 15% of genes in the human genome, and globally reprograms cells and drives proliferation (1-3). Aberrant regulation and overexpression of c-Myc are observed in most tumor types,

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

Cited by 83 publications

References 43 publications

The Wnt Target Protein Peter Pan Defines a Novel p53-independent Nucleolar Stress-Response Pathway

The Wnt Target Protein Peter Pan Defines a Novel p53-independent Nucleolar Stress-Response Pathway

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

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