Rb2/p130 is the dominating pocket protein in the p53–p21 DNA damage response pathway leading to senescence

Helmbold, H; Komm, Natascha; Deppert, Wolfgang; Bohn, Wolfgang

doi:10.1038/onc.2009.222

Cited by 50 publications

(41 citation statements)

References 37 publications

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“…lanes 4 and 5,6), consistent with the observation in Figure 1H. We also showed that the p53 target gene PAI-1 and p130, both of which are associated with p53-induced senescence (Kortlever et al 2006;Helmbold et al 2009), were induced by RNPC1 deficiency in the presence and absence of treatment with doxorubicin (Fig. 6A, cf.…”

Section: Loss Of Rnpc1 Induces P53 Expression Leading To P53-dependesupporting

confidence: 77%

Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas

Zhang¹,

Cho²,

Shu³

et al. 2011

Genes Dev.

117

183

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The p53 pathway is critical for tumor suppression, as the majority of human cancer has a faulty p53. Here, we identified RNPC1, a p53 target and a RNA-binding protein, as a critical regulator of p53 translation. We showed that ectopic expression of RNPC1 inhibited, whereas knockdown of RNPC1 increased, p53 translation under normal and stress conditions. We also showed that RNPC1 prevented cap-binding protein eIF4E from binding p53 mRNA via its C-terminal domain for physical interaction with eIF4E, and its N-terminal domain for binding p53 mRNA. Consistent with this, we found that RNPC1 directly binds to p53 59 and 39untranslated regions (UTRs). Importantly, we showed that RNPC1 inhibits ectopic expression of p53 in a dose-dependent manner via p53 59 or 39 UTR. Moreover, we showed that loss of RNPC1 in mouse embryonic fibroblasts increased the level of p53 protein, leading to enhanced premature senescence in a p53-dependent manner. Finally, to explore the clinical relevance of our finding, we showed that RNPC1 was frequently overexpressed in dog lymphomas, most of which were accompanied by decreased expression of wild-type p53. Together, we identified a novel p53-RNPC1 autoregulatory loop, and our findings suggest that RNPC1 plays a role in tumorigenesis by repressing p53 translation.

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Section: Loss Of Rnpc1 Induces P53 Expression Leading To P53-dependesupporting

confidence: 77%

Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas

Zhang¹,

Cho²,

Shu³

et al. 2011

Genes Dev.

117

183

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“…It is interesting to note that depletion of Rb resulted in a smaller but significant increase in proliferation, indicating that it also plays a role in controlling proliferation. Furthermore, the Rb family member p130 has been shown recently to be the major pocket protein required for replicative and DNA-damage-induced senescence downstream of p53-p21 and p16INK4A (Helmbold et al, 2009). Taken together, this suggests that accumulation of p130 is one of the mechanisms underlying the hypoproliferation observed in HFKs acutely depleted for p63.…”

Section: Discussionmentioning

confidence: 50%

“…By contrast, p107 depletion did not significantly affect proliferation alone or in p63-depleted cells, whereas Rb knockdown results in a smaller increase in proliferation and partial rescue of proliferation to ~70% that of scrambled control. This is interesting, because recent data indicate that p130 is the major pocket protein accumulated downstream of p53 and p21 in replicative and DNA-damage-induced senescence (Helmbold et al, 2009), whereas Rb and p107 levels are consistently decreased. Therefore, because of the p130-p53-p21 association and because we only observed an increase in p130 protein levels in the p63-depleted cells and p130 depletion resulted in greater and more significant rescue of proliferation in p63-depleted cells, we examined the effect of p130 depletion in organotypic raft cultures.…”

Section: Hypoproliferation In P63-depleted Cells Is Dependent On the mentioning

confidence: 86%

p63 maintains keratinocyte proliferative capacity through regulation of Skp2–p130 levels

McDade

Patel

McCance

2011

Journal of Cell Science

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p63 is a master regulator of proliferation and differentiation in stratifying epithelia, and its expression is frequently altered in carcinogenesis. However, its role in maintaining proliferative capacity remains unclear. Here, we demonstrate that hypoproliferation and loss of differentiation in organotypic raft cultures of primary neonatal human foreskin keratinocytes (HFKs) depleted of the α and β isoforms of p63 result from p53–p21-mediated accumulation of retinoblastoma (Rb) family member p130. Hypoproliferation in p63-depleted HFKs can be rescued by depletion of p53, p21CIP1 or p130. Furthermore, we identified the gene encoding S-phase kinase-associated protein 2 (Skp2), the recognition component of the SCFSkp2 E3 ubiquitin ligase, as a novel target of p63, potentially influencing p130 levels. Expression of Skp2 is maintained by p63 binding to a site in intron 2 and mRNA levels are downregulated in p63-depleted cells. Hypoproliferation in p63-depleted cells can be restored by re-expression of Skp2. Taken together, these results indicate that p63 plays a multifaceted role in maintaining proliferation in the mature regenerating epidermis, in addition to being required for differentiation.

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“…4C, compare lanes 1 and 3 with 2 and 4, respectively). We would like to mention that p21, PAI-1, and p130 are well-defined markers for p53-dependent cellular senescence (8,18).…”

Section: Lack Of Ninj1 Up-regulates P53 Expression Potentially Throughmentioning

confidence: 99%

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

Cho

Rossi

Jung

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The tumor suppressor protein p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest, apoptosis, and senescence. The nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a homophilic adhesion molecule and involved in nerve regeneration. Interestingly, Ninj1 is found to be overexpressed in human cancer, but its role in tumorigenesis is not clear. Here, we found that Ninj1 is transcriptionally regulated by p53 and can be induced by DNA damage in a p53-dependent manner. We also found that knockout or knockdown of Ninj1 increases p53 expression potentially through enhanced p53 mRNA translation. In addition, we found that Ninj1 deficiency suppresses cell proliferation but enhances apoptosis and premature senescence in a p53-dependent manner. Consistent with this, we found that mice heterozygous in ninj1 are hypersensitive to ionizing radiation-induced lethality, along with increased expression of p53 in thymus. Taken together, we provided evidence that Ninj1 is a p53 target and modulates p53 mRNA translation and p53-dependent premature senescence, cell proliferation, apoptosis, and radiationinduced mortality in vitro and in vivo. Thus, we postulate that as a membrane adhesion molecule, Ninj1 is an ideal target to regulate p53 activity via the p53-Ninj1 loop. cellular senescence | radiosensitivity

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Rb2/p130 is the dominating pocket protein in the p53–p21 DNA damage response pathway leading to senescence

Cited by 50 publications

References 37 publications

Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas

Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas

p63 maintains keratinocyte proliferative capacity through regulation of Skp2–p130 levels

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

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