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

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2007 Mar 28

PMID 17387146

Citations 224

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

Affiliations

Soon will be listed here.

Abstract

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.

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