Degradation of Mcl-1 by β-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization

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

Research output: Contribution to journalArticle

280 Scopus citations

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-3β associates with and phosphorylates Mcl-1 at one consensus motif (155STDG 159SLPS163T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 with the E3 ligase β-TrCP, and β-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-3β and then cannot be ubiquitinated by β-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3β and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by β-TrCP is an essential mechanism for GSK-3β-induced apoptosis and contributes to GSK-3β-mediated tumor suppression and chemosensitization.

Original languageEnglish (US)
Pages (from-to)4006-4017
Number of pages12
JournalMolecular and cellular biology
Volume27
Issue number11
DOIs
StatePublished - Jun 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Ding, Q., He, X., Hsu, J. M., Xia, W., Chen, C. T., Li, L. Y., Lee, D. F., Liu, J. C., Zhong, Q., Wang, X., & Hung, M. C. (2007). Degradation of Mcl-1 by β-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Molecular and cellular biology, 27(11), 4006-4017. https://doi.org/10.1128/MCB.00620-06