C/EBPβ cooperates with RB:E2F to implement RasV12-induced cellular senescence

Sebastian, Thomas; Malı́k, Radek; Thomas, Sara; Sage, Julien; Johnson, Peter F.

doi:10.1038/sj.emboj.7600789

Cited by 140 publications

(180 citation statements)

References 62 publications

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“…Inhibition of E2F transcription factors by Rb is an important pro‐senescence process (Mallette, Goumard, Gaumont‐Leclerc, Moiseeva & Ferbeyre, 2004; Narita et al., 2003; Sebastian, Malik, Thomas, Sage & Johnson, 2005). Our data support the view that plasma membrane depolarization promotes senescence through the Rb pathway, as repressed mitotic genes are known E2F targets and the inhibition of Rb prevents senescence induced by plasma membrane depolarization.…”

Section: Discussionmentioning

confidence: 99%

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

et al. 2018

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SummaryOncogenic signals lead to premature senescence in normal human cells causing a proliferation arrest and the elimination of these defective cells by immune cells. Oncogene‐induced senescence (OIS) prevents aberrant cell division and tumor initiation. In order to identify new regulators of OIS, we performed a loss‐of‐function genetic screen and identified that the loss of SCN9A allowed cells to escape from OIS. The expression of this sodium channel increased in senescent cells during OIS. This upregulation was mediated by NF‐κB transcription factors, which are well‐known regulators of senescence. Importantly, the induction of SCN9A by an oncogenic signal or by p53 activation led to plasma membrane depolarization, which in turn, was able to induce premature senescence. Computational and experimental analyses revealed that SCN9A and plasma membrane depolarization mediated the repression of mitotic genes through a calcium/Rb/E2F pathway to promote senescence. Taken together, our work delineates a new pathway, which involves the NF‐κB transcription factor, SCN9A expression, plasma membrane depolarization, increased calcium, the Rb/E2F pathway and mitotic gene repression in the regulation of senescence. This work thus provides new insight into the involvement of ion channels and plasma membrane potential in the control of senescence.

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Section: Discussionmentioning

confidence: 99%

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

et al. 2018

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“…C/EBPb is translated into two different isoforms: LAP (C/EBPb, p44, p42) and LIP (p20) (Calkhoven et al, 2000;Zahnow, 2009). The LAP:LIP ratio is assumed to regulate cell proliferation through the LAPmediated repression of E2F target genes (Sebastian et al, 2005). Lamb et al (2003) suggested that CCND1 acts similar to LIP by counteracting LAP (C/EBPbeta) functions.…”

Section: Discussionmentioning

confidence: 99%

The RNA-binding protein La contributes to cell proliferation and CCND1 expression

et al. 2010

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The La protein is an essential RNA-binding protein implicated in different aspects of RNA metabolism. Herein, we report that small interfering (siRNA)-mediated La depletion reduces cell proliferation of different cell lines concomitant with a reduction in cyclin D1 (CCND1) protein. To exclude off-target effects we demonstrate that exogenous La expression in La-depleted cells restores cell proliferation and CCND1 protein levels. In contrast, proliferation of immortalized CCND1 knockout cells is not affected by La depletion, supporting a functional coherence between La, CCND1 and proliferation. Furthermore, we document by reversible in vivo crosslinking and ribonucleoprotein (RNP) immunoprecipitation an association of the La protein with CCND1 messengerRNA and that CCND1 internal ribosome entry site (IRES)-dependent translation is modulated by La protein level within the cell. In addition, we show elevated La protein expression in cervical cancer tissue and its correlation with aberrant CCND1 protein levels in cervical tumor tissue lysates. In conclusion, this study establishes a role of La in cell proliferation and CCND1 expression and demonstrates for the first time an overexpression of the RNA-binding protein La in solid tumors.

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“…[13][14][15] However, it is now becoming clear that Ras oncogene can also induce senescence via p53-independent pathways such as CCAAT/enhancerbinding protein-b, or ones mediated by p63. 16,17 Apoptosis-stimulating protein of p53 (ASPP) 2 belongs to the evolutionarily conserved ASPP family of proteins that were initially identified through their ability to bind to, and regulate, the apoptotic function of p53 and its family members p63 and p73. 18 Two different ASPP2 transgenic mouse models were generated, expressing either exon 3-or exons 10-17-deleted ASPP2 genes.…”

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confidence: 99%

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

et al. 2010

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Oncogene-induced senescence represents a key tumor suppressive mechanism. Here, we show that Ras oncogene-induced senescence can be mediated by the recently identified haploinsufficient tumor suppressor apoptosis-stimulating protein of p53 (ASPP) 2 through a novel and p53/p19 Arf /p21 waf1/cip1 -independent pathway. ASPP2 suppresses Ras-induced small ubiquitin-like modifier (SUMO)-modified nuclear cyclin D1 and inhibits retinoblastoma protein (Rb) phosphorylation. The lysine residue, K33, of cyclin D1 is a key site for this newly identified regulation. In agreement with the fact that its nuclear localization is required for its oncogenic activity, we show that nuclear cyclin D1 is far more potent than wild-type (WT) cyclin D1 in bypassing Ras-induced senescence. Thus, this study identifies SUMO modification as a positive regulator of nuclear cyclin D1, and reveals a new way by which cell cycle entry and senescence are regulated. Cell Death and Differentiation (2011) 18, 304-314; doi:10.1038/cdd.2010; published online 27 August 2010Cellular senescence is an irreversible cell cycle arrest and one of the major cellular processes that suppress tumor growth. Cyclin-dependent kinases (CDKs) are among the main regulators of cellular senescence, predominantly achieved through their phosphorylation of the retinoblastoma protein (Rb), preventing it from binding and inhibiting the E2F family of transcription factors that are involved in cell cycle progression. Deregulation of CDK pathways is common in the development of human cancers. Amplification and overexpression of cyclin D1, a regulatory subunit of CDK4/CDK6, has been observed in around 50% of human breast and esophageal cancers. 1,2 Interestingly, however, elevation of cyclin D1 alone is not sufficient to induce tumor growth in vivo, 3,4 partly owing to the fact that the cyclin D1/CDK4 or cyclin D1/CDK6 complex needs to locate in the nucleus to phosphorylate Rb during S-phase to promote cell proliferation. 5,6 Nuclear export, coupled with ubiquitin-dependent destruction of cyclin D1 in the cytoplasm during S-phase, is one of the best known mechanisms of cyclin D1/CDK4 kinase activity control. Hence, nuclear accumulation of cyclin D1 may be a key mechanism by which cyclin D1 exerts its oncogenic effects. In agreement with this, overexpression of mutant cyclin D1 (D1T286A), defective in phosphorylation-mediated nuclear export and subsequent proteolysis, induces cell transformation in vitro and triggers B-cell lymphoma in vivo. 6,7 Furthermore, transgenic mice overexpressing the same mutant, driven by mouse mammary tumor virus (MMTV) promoter (MMTV-D1T286A), developed mammary adenocarcinoma with a shorter latency relative to mice overexpressing wild-type (WT) cyclin D1 (MMTV-D1). 8 These observations support the notion that the subcellular localization of cyclin D1 is critical in controlling its tumorigenicity. Identifying the molecular mechanisms that regulate the nuclear localization of cyclin D1 is, therefore, vital for our better understanding of tumor development....

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C/EBPβ cooperates with RB:E2F to implement RasV12-induced cellular senescence

Cited by 140 publications

References 62 publications

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

The RNA-binding protein La contributes to cell proliferation and CCND1 expression

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

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