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J. Biol. Chem., Vol. 283, Issue 17, 11280-11292, April 25, 2008

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Cyclin E and SV40 Small t Antigen Cooperate to Bypass Quiescence and Contribute to Transformation by Activating CDK2 in Human Fibroblasts^*

Elena Sotillo¹, Judit Garriga, Alison Kurimchak, and Xavier Graña²

From the Fels Institute for Cancer Research and Molecular Biology and Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Cyclin E overexpression is observed in multiple human tumors and linked to poor prognosis. We have previously shown that ectopic expression of cyclin E is sufficient to induce mitogen-independent cell cycle entry in a variety of tumor/immortal cell lines. Here we have investigated the rate-limiting step leading to cell cycle entry in quiescent normal human fibroblasts (NHF) ectopically expressing cyclin E. We found that in serum-starved NHF, cyclin E forms inactive complexes with CDK2 and fails to induce DNA synthesis. Coexpression of SV40 small t antigen (st), but not other tested oncogenes, efficiently induces mitogen-independent CDK2 phosphorylation on Thr-160, CDK2 activation, and DNA synthesis. Additionally, in contact-inhibited NHF ectopically expressing cyclin E, st induces cell cycle entry, continued proliferation, and foci formation. Coexpression of cyclin E and st also bypasses G₀/G₁ arrests induced by CDK inhibitors. Although CDK2 is dispensable for G₀/G₁ cell cycle entry and normal proliferation in mammals, CDK2 activity is an essential rate-limiting step in NHF with deregulated cyclin E expression and altered PP2A activity, which endows primary cells with transformed features. Consequently, CDK2 could be targeted therapeutically in tumors that involve these alterations. These data also suggest that alterations prior to cyclin E deregulation facilitate proliferation of tumor cells by bypassing mitogenic requirements and negative regulation by adjacent cells.

Received for publication, November 5, 2007 , and in revised form, February 13, 2008.

^* This work was supported in part by grant projects under National Institutes of Health (NIH) Grant CA095569 (to X. G. and J. G.) and NIH Career Development Award K02 AI01823 (to X. G.). Facilities used for this work were supported in part by NIH Shared Resources for Cancer Research Grant R24 CA88261-01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported in part by a postdoctoral fellowship from the Ministry of Education and Culture of Spain.

² To whom correspondence should be addressed: Temple University School of Medicine, AHP Bldg. Rm. 308, 3307 N. Broad St., Philadelphia, PA 19140. Fax: 215-707-5562; E-mail: xavier{at}temple.edu.

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