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J. Biol. Chem., Vol. 278, Issue 37, 35241-35247, September 12, 2003

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Cdc42 Promotes G₁ Progression through p70 S6 Kinase-mediated Induction of Cyclin E Expression^*

Margaret M. Chou  , Jeffrey M. Masuda-Robens ¶ and Meryl L. Gupta ||

From the Department of Cell and Developmental Biology and ^¶Department of Pharmacology, University of Pennsylvania School of Medicine and the ^||School of Veterinary Medicine, Philadelphia, Pennsylvania 19104

The Rho family GTPase Cdc42 is recognized for its role in cellular proliferation and transformation. However, the mechanism by which it promotes cell cycle progression has remained undefined. Using an inducible expression system, we show that constitutively active Cdc42 (Cdc42V12) is sufficient by itself to induce anchorage-independent but not mitogen-independent growth in NIH3T3 cells. However, Cdc42V12 markedly accelerates activation of cyclin E-Cdk2 in response to mitogen. These effects were highly specific, as the kinetics of cyclin D-Cdk4 activation was unaltered. Cdc42V12 promotes Cdk2 activation by selectively inducing cyclin E expression without affecting other regulatory proteins such as the p27 Cdk inhibitor or Cdc25A. Furthermore, Cdc42V12 was able to activate a reporter gene driven by the cyclin E promoter in the absence of exogenous mitogen or adhesion. Cyclin E induction was sensitive to rapamycin but not inhibitors of mitogen-activated protein kinases, implicating p70 S6 kinase (p70S6k) as the relevant mediator. Consistent with this notion, wild type and constitutively active alleles of p70S6k were sufficient to activate the cyclin E promoter. In sum, these studies provide novel insights into the mechanism by which Cdc42 promotes G₁ progression.

Received for publication, May 19, 2003 , and in revised form, June 30, 2003.

^* This work was supported by the Leukemia and Lymphoma Society, American Cancer Society Grant RPG CCG-98408, National Institutes of Health Grant RO1 CA81415–01A1 and Training Grant RR07065, and by the Merck Foundation. 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.

To whom correspondence should be addressed: Dept. of Cell and Developmental Biology, 421 Curie Blvd. Bldg. BRBII/III, Rm. 1011, Philadelphia, PA 19104. Tel.: 215-573-4126; Fax: 215-898-9871; E-mail: mmc{at}mail.med.upenn.edu.

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