Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 27, Issue 11, Pages 4006-4017Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00620-06
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Funding
- NCI NIH HHS [CA 099031, P30 CA016672, CA 109311, R01 CA109311, P01 CA099031, CA 16672] Funding Source: Medline
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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-3 beta 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-3 beta 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-3 beta and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by P-TrCP is an essential mechanism for GSK-3 beta-induced apoptosis and contributes to GSK-3 beta-mediated tumor suppression and chemosensitization.
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