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J. Biol. Chem., Vol. 280, Issue 26, 24363-24370, July 1, 2005

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Rac-GAP-dependent Inhibition of Breast Cancer Cell Proliferation by 2-Chimerin^*

Chengfeng Yang, Ying Liu, Federico Coluccio Leskow, Valerie M. Weaver¶, and Marcelo G. Kazanietz||

From the Department of Pharmacology and ^¶Department of Pathology and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160

2-Chimerin is a member of the "non-protein kinase C" intracellular receptors for the second messenger diacylglycerol and the phorbol esters that is yet poorly characterized, particularly in the context of signaling pathways involved in proliferation and cancer progression. 2-Chimerin possesses a C-terminal Rac-GAP (GTPase-activating protein) domain that accelerates the hydrolysis of GTP from the Rac GTPase, leading to its inactivation. We found that 2-chimerin messenger levels are significantly down-regulated in human breast cancer cell lines as well as in breast tumors. Adenoviral delivery of 2-chimerin into MCF-7 breast cancer cells leads to inhibition of proliferation and G₁ cell cycle arrest. Mechanistic studies show that the effect involves the reduction in Rac-GTP levels, cyclin D1 expression, and retinoblastoma dephosphorylation. Studies using the mutated forms of 2-chimerin revealed that these effects were entirely dependent on its C-terminal GAP domain and Rac-GAP activity. Moreover, MCF-7 cells stably expressing active Rac (V12Rac1) but not RhoA (V14RhoA) were insensitive to 2-chimerin-induced inhibition of proliferation and cell cycle progression. The modulation of G₁/S progression by 2-chimerin not only implies an essential role for Rac in breast cancer cell proliferation but also raises the intriguing possibility that diacylglycerol-regulated non-protein kinase C pathways can negatively impact proliferation mechanisms controlled by Rho GTPases.

Received for publication, October 12, 2004 , and in revised form, March 16, 2005.

^* This work was supported by Grants RO1-CA74197 (National Institutes of Health) and RPG-97-092-06-CNE (American Cancer Society) (to M. G. K.). 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.

Supported by a postdoctoral fellowship from the Department of Defense Breast Cancer Research Program (DAMD17-03-1-0469).

^|| To whom correspondence should be addressed: Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, 816 Biomedical Research Bldg. II/III, 421 Curie Blvd., Philadelphia, PA 19104-6160. Tel.: 215-898-0253; Fax: 215-573-9004; E-mail: marcelo{at}spirit.gcrc.upenn.edu.

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