Ras Links Growth Factor Signaling to the Cell Cycle Machinery via Regulation of Cyclin D1 and the Cdk Inhibitor p27<sup><i>KIP1</i></sup>

Aktaş, Hüseyin; Cai, Hong; Cooper, Geoffrey M.

doi:10.1128/mcb.17.7.3850

Cited by 388 publications

(338 citation statements)

References 48 publications

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“…The H322 cell line used in this study has a wild type ras. The ras protein has also been reported to be involved in the regulation of cyclin D1 and the CDK inhibitor, p27 KIP1 (Aktas et al, 1997). Pathways downsteam of ras are involved in cellular responses to stress.…”

Section: Discussionmentioning

confidence: 99%

Dual effect of erbB-2 depletion on the regulation of DNA repair and cell cycle mechanisms in non-small cell lung cancer cells

et al. 1998

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Overexpression of the erbB-2 tyrosine kinase receptor, p185 erbB-2 , is a common alteration in non-small cell lung cancer (NSCLC) and has been associated with poor prognosis and a tumor drug resistance phenotype. In this study, we have examined the consequences of erbB-2 depletion on DNA repair, cell cycle, and apoptosis using a panel of NSCLC cell lines constitutively overexpressing erbB-2 receptor. Depletion of the erbB-2 was achieved using the tyrosine kinase inhibitor CP127,374 which promotes erbB-2 degradation. Treatment with CP127,374 concentrations which deplete erbB-2 and inhibit tyrosine phosphorylation resulted in downregulation of DNA repair mechanisms and cell accumulation at G1 phase of the cell cycle. G1 arrest was observed in cells with mutated p53 as well as cells lacking p53 protein, suggesting a p53-independent mechanisms. NSCLC cells which overexpress erbB-2 were more resistant to cisplatin-induced cytotoxicity in comparison to cells expressing low levels of erbB-2. Treatment with CP127,374 alone did not result in any induction of apoptosis. A combination of CP127,374 and cisplatin, however, was more potent in cell growth inhibition and induction of apoptosis compared to treatment with cisplatin alone. Together, our results further support a pivotal role of erbB-2 signaling in the regulatory balance between DNA repair, cell cycle checkpoints and apoptosis; all these mechanisms are essential determinants for tumor cell destiny following chemotherapy stress.

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Section: Discussionmentioning

confidence: 99%

Dual effect of erbB-2 depletion on the regulation of DNA repair and cell cycle mechanisms in non-small cell lung cancer cells

et al. 1998

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“…It appears that the signals from Ga 12/13 are translated into growth-promoting signals by the small GTPases Ras, Rac, and Rho. It has been reported that Ras, Rho, Rac, and CDC42 play an essential role in cell cycle progression from G1 to S phase (Aktas et al, 1997;Takuwa and Takuwa, 1997;Olson et al, 1995;Hirai et al, 1997). An additional role for Rac in progression from G2 to M phase has been also identi®ed (Moore et al, 1997).…”

Section: Ga 12/13 : the Gep Oncogenes?mentioning

confidence: 99%

Regulation of cell proliferation by G proteins

Dhanasekaran

Tsim²,

Dermott³

et al. 1998

Oncogene

136

107

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G Proteins provide signal transduction mechanisms to seven transmembrane receptors. Recent studies have indicated that the a-subunits as well as the bg-subunits of these proteins regulate several critical signaling pathways involved in cell proliferation, di erentiation and apoptosis. Of the 17 a-subunits that have been cloned, at least ten of them have been shown to couple mitogenic signaling in ®broblast cells. Activating mutations in Ga s , Ga i2 , and Ga 12 have been correlated with di erent types of tumors. In addition, the ability of the bg-subunits to activate mitogenic pathways in di erent cell-types has been de®ned. The present review brie¯y summarizes the diverse and novel signaling pathways regulated by the a-as well as the bg-subunits of G proteins in regulating cell proliferation.

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“…In general, oncogenic Ras subverts mitogenic signaling in the process of mediating transformation. Specifically, Ras utilizes signaling through the MEK/ERK pathway to stimulate cyclin D1 expression/function (Filmus et al, 1994;Aktas et al, 1997;Crespo and Leon, 2000). It has been shown that oncogenic transformation through Ras in cell culture and animal models is dependent on cyclin D1 (Liu et al, 1995;Peeper et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular context

et al. 2009

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The retinoblastoma tumor suppressor, RB, is a key regulator of cellular proliferation that is functionally inactivated at high frequency in human cancer. Although RB has been extensively studied with regard to tumor etiology, loss of tumor-suppressor function often occurs relatively late in tumor progression. Therefore, inactivation of RB could have a profound impact on the behavior of tumors driven by discrete oncogenes. Here, collaboration between Ras or c-Myc deregulation and RB functional state was investigated in a model of conditional genetic deletion to decipher the effects related to disease progression. These studies showed that RB loss had a robust impact on mitogen dependence, anchorage dependence and overall survival, which was significantly modified by oncogene activation. Specifically, RB deficiency predisposed c-Myc-expressing cells to cell death and reduced overall tumorigenic proliferation. In contrast, RB deficiency exacerbated the tumorigenic behavior of Ras-transformed cells in both the model system and human tumor cell lines. As these tumors exhibited highly aggressive behavior, the possibility of exploiting the intrinsic sensitivity to cell death with RB loss was evaluated. Particularly, although Ras-transformed, RB-deficient cells bypassed the G1-checkpoint elicited by pharmacological activation of the p53 pathway, they were also highly sensitized to cell death. Altogether, these data suggest that the impact of RB deletion is dependent on the oncogene milieu, and can directly contribute to transformed phenotypes and response to therapeutic intervention.

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Ras Links Growth Factor Signaling to the Cell Cycle Machinery via Regulation of Cyclin D1 and the Cdk Inhibitor p27^KIP1

Cited by 388 publications

References 48 publications

Dual effect of erbB-2 depletion on the regulation of DNA repair and cell cycle mechanisms in non-small cell lung cancer cells

Dual effect of erbB-2 depletion on the regulation of DNA repair and cell cycle mechanisms in non-small cell lung cancer cells

Regulation of cell proliferation by G proteins

Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular context

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Ras Links Growth Factor Signaling to the Cell Cycle Machinery via Regulation of Cyclin D1 and the Cdk Inhibitor p27KIP1

Cited by 388 publications

References 48 publications

Dual effect of erbB-2 depletion on the regulation of DNA repair and cell cycle mechanisms in non-small cell lung cancer cells

Dual effect of erbB-2 depletion on the regulation of DNA repair and cell cycle mechanisms in non-small cell lung cancer cells

Regulation of cell proliferation by G proteins

Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular context

Contact Info

Product

Resources

About

Ras Links Growth Factor Signaling to the Cell Cycle Machinery via Regulation of Cyclin D1 and the Cdk Inhibitor p27^KIP1