This Article Full Text Full Text (PDF) Supplemental material Other Versions of this Article: MCB.00620-06v1 27/11/4006    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ding, Q. Articles by Hung, M.-C. Search for Related Content PubMed PubMed Citation Articles by Ding, Q. Articles by Hung, M.-C.

 Previous Article  |  Next Article 

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 ^,

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 Hung^1,2,4,5*

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.

Published ahead of print on 26 March 2006.

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

Q.D. and X.H. contributed equally to this work.

This article has been cited by other articles:

• Ding, Q., Huo, L., Yang, J.-Y., Xia, W., Wei, Y., Liao, Y., Chang, C.-J., Yang, Y., Lai, C.-C., Lee, D.-F., Yen, C.-J., Chen, Y.-J. R., Hsu, J.-M., Kuo, H.-P., Lin, C.-Y., Tsai, F.-J., Li, L.-Y., Tsai, C.-H., Hung, M.-C. (2008). Down-regulation of Myeloid Cell Leukemia-1 through Inhibiting Erk/Pin 1 Pathway by Sorafenib Facilitates Chemosensitization in Breast Cancer. Cancer Res. 68: 6109-6117 [Abstract] [Full Text]  
• Plotnikov, A., Li, Y., Tran, T. H., Tang, W., Palazzo, J. P., Rui, H., Fuchs, S. Y. (2008). Oncogene-Mediated Inhibition of Glycogen Synthase Kinase 3{beta} Impairs Degradation of Prolactin Receptor. Cancer Res. 68: 1354-1361 [Abstract] [Full Text]  
• Germain, M., Duronio, V. (2007). The N Terminus of the Anti-apoptotic BCL-2 Homologue MCL-1 Regulates Its Localization and Function. J. Biol. Chem. 282: 32233-32242 [Abstract] [Full Text]  
• De Biasio, A., Vrana, J. A., Zhou, P., Qian, L., Bieszczad, C. K., Braley, K. E., Domina, A. M., Weintraub, S. J., Neveu, J. M., Lane, W. S., Craig, R. W. (2007). N-terminal Truncation of Antiapoptotic MCL1, but Not G2/M-induced Phosphorylation, Is Associated with Stabilization and Abundant Expression in Tumor Cells. J. Biol. Chem. 282: 23919-23936 [Abstract] [Full Text]