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J. Biol. Chem., Vol. 283, Issue 24, 16416-16426, June 13, 2008

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RACK1 and CIS Mediate the Degradation of BimEL in Cancer Cells^*

Weizhou Zhang¹², George Zhi Cheng², Jianli Gong¹, Ulrich Hermanto, Cong Susan Zong^¶, Joseph Chan, Jin Quan Cheng^||, and Lu-Hai Wang³

From the Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, the Departments of Radiology and ^¶Molecular and Cellular Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas 77030, and the ^||Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612

RACK1 is a 7-WD motif-containing protein with numerous downstream effectors regulating various cellular functions. Using a yeast two-hybrid screen, we identified dynein light chain 1 as a novel interacting partner of RACK1. Additionally, we demonstrated that RACK1 formed a complex with DLC1 and Bim, specifically BimEL, in the presence of apoptotic agents. Upon paclitaxel treatment, RACK1, DLC1, and CIS mediated the degradation of BimEL through the ElonginB/C-Cullin2-CIS ubiquitin-protein isopeptide ligase complex. We further showed that RACK1 conferred paclitaxel resistance to breast cancer cells in vitro and in vivo. Finally, we observed an inverse correlation between CIS and BimEL levels in both ovarian and breast cancer cell lines and specimens. Our study suggests a role of RACK1 in protecting cancer cells from apoptosis by regulating the degradation of BimEL, which together with CIS could play an important role of drug resistance in chemotherapy.

Received for publication, March 26, 2008 , and in revised form, April 16, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA29339 (to L.-H. W.). 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–S6.

¹ Partially supported by Fellowship C021334 from the New York State Department of Health.

² Both authors contributed equally to this work.

³ To whom correspondence should be addressed: Dept. of Microbiology, 1 Gustave L. Levy Place, Box 1124, New York, NY 10029-6574. Tel.: 212-241-3759; Fax: 212-534-1684; E-mail: lu-hai.wang{at}mssm.edu.

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