Failure to Phosphorylate the Retinoblastoma Gene Product in Senescent Human Fibroblasts

Stein, Gretchen H.; Beeson, Mary; Gordon, Lena

doi:10.1126/science.2166342

Cited by 349 publications

(164 citation statements)

References 33 publications

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“…The activation of E2F is sufficient to commit cells to undergo DNA replication; thus, E2F is crucial in the control of cellular proliferation (58). Replicative senescence has been described as irreversible growth arrest occurring after many culture passages, with the overexpression of cyclin-dependent kinase inhibitors, including p16 ink4a (p16) and p21 cip/waf1 (p21), leading to pRb hypophosphorylation (56,59). This hypophosphorylation of pRb in senescent cells binds and inhibits E2F, resulting in the suppression of E2F-responsive genes (60,61).…”

Section: Discussionmentioning

confidence: 99%

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Chang¹,

Jin

Yoon

et al. 2008

Molecular Cancer Research

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DNA damage and mutations in the genome increase with age. To determine the potential mechanisms of senescence-dependent increases in genomic instability, we analyzed DNA mismatch repair (MMR) efficiency in young and senescent human colonic fibroblast and human embryonic lung fibroblast. It was found that MMR activity is significantly reduced in senescent cells. Western blot and immunohistochemistry analysis revealed that hMSH2 and MSH6 protein (MutSA complex), which is a known key component in the MMR pathway, is markedly down-regulated in senescent cells. Moreover, the addition of purified MutSA to extracts from senescent cells led to the restoration of MMR activity. Semiquantitative reverse transcription-PCR analysis exhibited that MSH2 mRNA level is reduced in senescent cells. In addition, a decrease in E2F transcriptional activity in senescent cells was found to be crucial for MSH2 suppression. E2F1 small interfering RNA expression reduced hMSH2 expression and MMR activity in young human primary fibroblast cells. Importantly, expression of E2F1 in quiescent cells restored the MSH2 expression as well as MMR activity, whereas E2F1-infected senescent cells exhibited no restoration of MSH2 expression and MMR activity. These results indicate that the suppression of E2F1 transcriptional activity in senescent cells lead to stable repression of MSH2, followed by a induction of MutSA dysfunction, which results in a reduced cellular MMR capacity in senescent cells. (Mol Cancer Res 2008;6(6):978 -89)

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Section: Discussionmentioning

confidence: 99%

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Chang¹,

Jin

Yoon

et al. 2008

Molecular Cancer Research

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“…As widely reported, p21 WAF1 belongs to a class of regulatory proteins that inhibit the action of cyclin-dependent kinases in cell cycle progression (Xiong et al, 1993) and pRb acts in the G1-phase of the cell cycle, regulating the expression of a bank of genes that mediate progression of the cell through the growth cycle (Paggi et al, 1995). Several lines of evidence indicate that both p21 WAF1 and pRb may also play a positive role in the di erentiation of a variety of cell types (Stein et al, 1990;Chen et al, 1995;Wang et al, 1996;Parker et al, 1995;Yang et al, 1995). Our data are consistent with the previously reported association between phenylacetate-induced growth arrest in MCF-7 cells and enhanced expression of p21 WAF1 and dephosphorylation of the retinoblastoma protein where p21 WAF1 induction was required for accumulation of the hypophosphorylated pRb (Gorospe et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of c-erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation

et al. 1998

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c-erbB-2, a member of the tyrosine kinase oncogene family, is overexpressed in about 30% of human breast tumors where it correlates with poor prognosis. In vitro studies have suggested that increased expression of the receptor plays an important role in malignant progression. To better understand the direct e ects of p185 HER2 overexpression, a human c-erbB-2 expression vector was transfected into the hormone-dependent MCF-7 human breast carcinoma cell line and cell growth was analysed. Unexpectedly, colony formation assay revealed a reduction in the number and size of colonies as compared with mock-transfected cells. In hormone-deprived medium, c-erbB-2 transfected cells acquired growth capability, consistent with previous reports. By contrast, two c-erbB-2-transfected clones grown in complete medium showed a reduced proliferation rate despite the activation of a fully functional oncoprotein capable of autophosphorylation and induction of the MAPK pathway. The number of c-erbB-2-overexpressing cells in the S phase of the cell cycle was about one-half the number of control and mock-transfected cells. Also, overexpression of c-erbB-2 induced overexpression of p21 WAF1 , pRB hypophosphorylation and a mature di erentiated cell phenotype with production of lipid droplets. Functional inactivation of p185 HER2 by means of a speci®c single chain antibody indicated the c-erbB-2-dependence of the observed alterations. These data show that the exogenous overexpression of the c-erbB-2 gene in hormonedependent breast cancer cells inhibits proliferation and induces di erentiation.

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“…pRb phosphorylation, 40 together with the presence of G1 cyclins (cyclins D1 and E1) 27 and the lack of mitotic cyclins (cyclin B1), 41 is an early-recognized hallmark of senescence. Very soon after its discovery, p16 Ink4a (p16), another pRb regulator that specifically inhibits the cyclin D1-associated kinases Cdk4 and Cdk6, was also implicated in senescence 28,[42][43][44] (Fig.…”

Section: Senescence As An Irreversible G1 Arrestmentioning

confidence: 99%