Regulation of cellular senescence by Rb2/p130

Helmbold, H; Deppert, Wolfgang; Bohn, Wolfgang

doi:10.1038/sj.onc.1209613

Cited by 23 publications

(23 citation statements)

References 90 publications

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“…Given that we found HP1-g expression in p53-deficient tissue in our model, the Rb pathway may be involved in the ability of p16 to promote senescence. The Rb2/p130 protein, which is a member of the Rb family, is also reported to mediate the senescent growth arrest (Helmbold et al, 2006). Similar to pRb, Rb2/p130 is hyperphosphorylated by cyclin D/cdk4 or 6 and cyclin E or A/cdk2 complexes and considered acting as a master regulator of pRb in a sustained senescent arrest.…”

Section: Discussionmentioning

confidence: 99%

Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

et al. 2008

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Aurora A mitotic kinase is frequently overexpressed in various human cancers and is widely considered to be an oncoprotein. However, the cellular contexts in which Aurora A induces malignancy in vivo are still unclear. We previously reported a mouse model in which overexpression of human Aurora A in the mammary gland leads to small hyperplastic changes but not malignancy because of the induction of p53-dependent apoptosis. To study the additional factors required for Aurora A-associated tumorigenesis, we generated a new Aurora A overexpression mouse model that lacks p53. We present evidence here that Aurora A overexpression in primary mouse embryonic fibroblasts (MEFs) that lack p53 overrides postmitotic checkpoint and leads to the formation of multinucleated polyploid cells. Induction of Aurora A overexpression in the mammary glands of p53-deficient mice resulted in development of precancerous lesions that were histologically similar to atypical ductal hyperplasia in human mammary tissue and showed increased cellular senescence and p16 expression. We further observed DNA damage in p53-deficient primary MEFs after Aurora A overexpression. Our results suggest that Aurora A overexpression in mammary glands is insufficient for the development of malignant tumors in p53-deficient mice because of the induction of cellular senescence. Both p53 and p16 are critical in preventing mammary gland tumorigenesis in the Aurora A overexpression mouse model.

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Section: Discussionmentioning

confidence: 99%

Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

et al. 2008

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“…We showed that ectopic expression of RNPC1a markedly increased the number of cells that stained positive with senescence-associated ␤-galactosidase (SA-␤-Gal) (Fig. 9B) concomitantly with increased expression of senescence markers p130 and DEC1 (14) (Fig. 9A, compare lanes 1 and 3 with 2 and 4, respectively).…”

Section: Rnpc1mentioning

confidence: 96%

p73 Expression Is Regulated by RNPC1, a Target of the p53 Family, via mRNA Stability

Yan

Zhang

et al. 2012

Molecular and Cellular Biology

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p73, a p53 family tumor suppressor, is expressed as TA and ⌬N isoforms. Due to the role of p73 in tumor suppression and neural development, its expression and activity are tightly regulated by multiple mechanisms, including transcription and posttranslational modifications. Here, we found that p73 mRNA stability is regulated by RNPC1, an RNA binding protein and a target of the p53 family. We also showed that a CU-rich element in the 3= untranslated region of p73 is recognized by and responsive to RNPC1. To explore the physiological significance of RNPC1-regulated p73 expression, we showed that the loss of RNPC1 in p53-null mouse embryonic fibroblasts leads to reduced expression of p73, along with decreased expression of p21, p130, and ␥-H2A.X, and consequently a decreased number of senescent cells. Furthermore, we observed that knockdown of TAp73 or p21, another target of RNPC1, attenuates the inhibitory effect of RNPC1 on cell proliferation and premature senescence, whereas combined knockdown of TAp73 and p21 completely abolishes it. Due to the fact that RNPC1 is a target of p73, the mutual regulation between p73 and RNPC1 constitutes a novel feed-forward loop, which might be explored as a target for tumors without a functional p53.

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“…Activation of the Rb pathway has been implicated in senescence and there is experimental evidence that pRb may play a direct role in gene silencing during induction of senescence (29,35). Because pRb levels are dramatically reduced in nutlintreated cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic p53 Activation Blocks Cell Cycle Progression but Fails to Induce Senescence in Epithelial Cancer Cells

Huang

Deo

Xia

et al. 2009

Molecular Cancer Research

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Cellular senescence is a stress-induced state of irreversible growth arrest thought to act as a barrier to cancer development. The p53 tumor suppressor is a critical mediator of senescence and recent in vivo studies have suggested that p53-induced senescence may contribute to tumor clearance by the immune system. Recently developed MDM2 antagonists, the nutlins, are effective p53 activators and potent antitumor agents in cells with functional apoptotic pathways. However, they only block cell cycle progression in cancer cells with compromised p53 apoptotic signaling. We use nutlin-3a as a selective probe to study the role of p53 activation in senescence using a panel of eight epithelial cancer cell lines and primary epithelial cells. Our results reveal that the MDM2 antagonist can induce a senescence-like state in all tested cell lines, but it is reversible and cells resume proliferation upon drug removal and normalization of p53 control. Retinoblastoma family members (pRb, p107, and p130) previously implicated in gene silencing during fibroblasts senescence were found down-regulated in cells with nutlin-induced senescence-like phenotype, suggesting a mechanism for its reversibility. Therefore, selective p53 pathway activation is insufficient for induction of true senescence in epithelial cells in vitro. However, elevated expression of several inflammatory cytokines in cancer cells with nutlin-induced senescence-like phenotype suggests a possible in vivo benefit of p53-activating therapies.

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Regulation of cellular senescence by Rb2/p130

Cited by 23 publications

References 90 publications

Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

p73 Expression Is Regulated by RNPC1, a Target of the p53 Family, via mRNA Stability

Pharmacologic p53 Activation Blocks Cell Cycle Progression but Fails to Induce Senescence in Epithelial Cancer Cells

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