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Molecular and Cellular Biology, June 2007, p. 4006-4017, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.00620-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Degradation of Mcl-1 by ß-TrCP Mediates Glycogen Synthase Kinase 3-Induced Tumor Suppression and Chemosensitization{triangledown} ,{dagger}

Qingqing Ding,1,{ddagger} Xianghuo He,1,6,{ddagger} 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 77030,1 Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas 77030,2 Howard Hughes Medical Institute and Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390,3 Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan, Republic of China,4 Asia University, Taichung 413, Taiwan, Republic of China,5 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 proteasome-mediated Mcl-1 turnover in which GSK-3ß 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 ß-TrCP, and ß-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-3ß and then cannot be ubiquitinated by ß-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3ß and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by ß-TrCP is an essential mechanism for GSK-3ß-induced apoptosis and contributes to GSK-3ß-mediated tumor suppression and chemosensitization.

* Corresponding author. Mailing address: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 792-3668. Fax: (713) 794-0209. E-mail: mhung{at}mdanderson.org

{triangledown} Published ahead of print on 26 March 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Q.D. and X.H. contributed equally to this work.

Molecular and Cellular Biology, June 2007, p. 4006-4017, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.00620-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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