Degradation of Mcl-1 by β-TrCP Mediates Glycogen Synthase Kinase 3-Induced Tumor Suppression and Chemosensitization

• DOI: 10.1128/mcb.00620-06
• Publication Date: 2007-03-27T01:04:47Z
• Authors: Qingqing Ding; Xianghuo He; Jung-Mao Hsu; Weiya Xia; Chun-Te Chen; Long-Yuan Li; Dung-Fang Lee; Jaw-Ching Liu; Qing Zhong; Xiaodong Wang; Mien-Chie Hung
• Keywords: Mice, Knockout; 0301 basic medicine; Proteasome Endopeptidase Complex; Glycogen Synthase Kinase 3 beta; Mice, Nude; Antineoplastic Agents; Apoptosis; beta-Transducin Repeat-Containing Proteins; Neoplasm Proteins; Glycogen Synthase Kinase 3; Mice; 03 medical and health sciences; Proto-Oncogene Proteins c-bcl-2; Neoplasms; Animals; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Female; Phosphorylation; Cells, Cultured

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-3beta associates with and phosphorylates Mcl-1 at one consensus motif ((155)STDG(159)SLPS(163)T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 with the E3 ligase beta-TrCP, and beta-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-3beta and then cannot be ubiquitinated by beta-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3beta and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by beta-TrCP is an essential mechanism for GSK-3beta-induced apoptosis and contributes to GSK-3beta-mediated tumor suppression and chemosensitization.