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

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.
Mesh Terms:
Animals, Antineoplastic Agents, Apoptosis, Cells, Cultured, Female, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Mice, Mice, Knockout, Mice, Nude, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins, Neoplasms, Phosphorylation, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-bcl-2, beta-Transducin Repeat-Containing Proteins
Mol. Cell. Biol.
Date: Jun. 01, 2007
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