Degradation of Mcl-1 by B-TrCP Mediates Glycogen Synthase Kinase 3-Induced Tumor Suppression and Chemosensitization
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Qingqing Ding,1‡ Xianghuo He,1,6‡ Jung-Mao Hsu,1,2 Weiya Xia,1 Chun-Te Chen,1,2 Long-Yuan Li,1,4,5 Dung-Fang Lee,1,2 Jaw-Ching Liu,1 Qing Zhong,3 Xiaodong Wang,3 and Mien-Chie Hung1,2,4,5*
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 770301; Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas 770302; Howard Hughes Medical Institute and Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 753903; Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan, Republic of China4; Asia University, Taichung 413, Taiwan, Republic of China5; and State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai 200032, People’s Republic of China6 Received 10 April 2006/Returned for modification 12 June 2006/Accepted 14 March 2007

Apoptosis is critical for embryonic development, tissue homeostasis, and tumorigenesis and is determined largely by the Bcl-2 family of antiapoptotic and prosurvival regulators. Here, we report that glycogen synthase kinase 3 (GSK-3) was required for Mcl-1 degradation, and we identified a novel mechanism for proteasomemediated Mcl-1 turnover in which GSK-3B associates with and phosphorylates Mcl-1 at one consensus motif (155STDG159SLPS163T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 with the
E3 ligase B-TrCP, and B-TrCP then facilitates the ubiquitination and degradation of phosphorylated Mcl-1. A variant of Mcl-1 (Mcl-1-3A), which abolishes the phosphorylations by GSK-3B and then cannot be ubiquitinated by B-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3B and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by B-TrCP is an essential mechanism for GSK-3B-induced apoptosis and contributes to GSK-3B-mediated tumor suppression and chemosensitization.