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J. Biol. Chem., Vol. 280, Issue 10, 8756-8764, March 11, 2005

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Indole-3-Carbinol (I3C) Inhibits Cyclin-dependent Kinase-2 Function in Human Breast Cancer Cells by Regulating the Size Distribution, Associated Cyclin E Forms, and Subcellular Localization of the CDK2 Protein Complex^*

Hanh H. Garcia, Gloria A. Brar, David H. H. Nguyen, Leonard F. Bjeldanes¶, and Gary L. Firestone||

From the Department of Molecular and Cell Biology and The Cancer Research Laboratory and the ^¶Department of Nutritional Sciences and Toxicology, The University of California at Berkeley, Berkeley, California 94720

Indole-3-carbinol (I3C), a dietary compound found in cruciferous vegetables, induces a robust inhibition of CDK2 specific kinase activity as part of a G₁ cell cycle arrest of human breast cancer cells. Treatment with I3C causes a significant shift in the size distribution of the CDK2 protein complex from an enzymatically active 90 kDa complex to a larger 200 kDa complex with significantly reduced kinase activity. Co-immunoprecipitations revealed an increased association of both a 50 kDa cyclin E and a 75 kDa cyclin E immunoreactive protein with the CDK2 protein complex under I3C-treated conditions, whereas the 90 kDa CDK2 protein complexes detected in proliferating control cells contain the lower molecular mass forms of cyclin E. I3C treatment caused no change in the level of CDK2 inhibitors (p21, p27) or in the inhibitory phosphorylation states of CDK2. The effects of I3C are specific for this indole and not a consequence of the cell cycle arrest because treatment of MCF-7 breast cancer cells with either the I3C dimerization product DIM or the anti-estrogen tamoxifen induced a G₁ cell cycle arrest with no changes in the associated cyclin E or subcellular localization of the CDK2 protein complex. Taken together, our results have uncovered a unique effect of I3C on cell cycle control in which the inhibition of CDK2 kinase activity is accompanied by selective alterations in cyclin E composition, size distribution, and subcellular localization of the CDK2 protein complex.

Received for publication, July 14, 2004 , and in revised form, December 15, 2004.

^* This study was supported by National Institutes of Health Public Health Service Grant CA102360 from the NCI, National Institutes of Health and by Grant 9WB-0148 awarded by the California Breast Cancer Research Program. 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 Predoctoral Fellowship DAMD17-01-1-0175 awarded from the United States Department of Defense Breast Cancer Research Program.

^|| To whom correspondence should be addressed: Dept. of Molecular and Cell Biology, 591 LSA, The University of California at Berkeley, Berkeley, CA 94720-3200. Tel.: 510-642-8319; Fax: 510-643-6791; E-mail: glfire{at}berkeley.edu.

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