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Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1.

We investigated the role of glycogen synthase kinase-3 (GSK-3), which is inactivated by AKT, for its role in the regulation of apoptosis. Upon IL-3 withdrawal, protein levels of MCL-1 decreased but were sustained by pharmacological inhibition of GSK-3, which prevented cytochrome c release and apoptosis. MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1. A phosphorylation-site mutant (MCL-1(S159A)), expressed in IL-3-dependent cells, showed enhanced stability upon IL-3 withdrawal and conferred increased protection from apoptosis compared to wild-type MCL-1. The results demonstrate that the control of MCL-1 stability by GSK-3 is an important mechanism for the regulation of apoptosis by growth factors, PI3K, and AKT.

Pubmed ID: 16543145

Authors

  • Maurer U
  • Charvet C
  • Wagman AS
  • Dejardin E
  • Green DR

Journal

Molecular cell

Publication Data

March 17, 2006

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI40646
  • Agency: NIAID NIH HHS, Id: AI44828
  • Agency: NCI NIH HHS, Id: CA69381
  • Agency: NIGMS NIH HHS, Id: GM52735

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Cytochromes c
  • Glycogen Synthase Kinase 3
  • Humans
  • Interleukin-3
  • Mice
  • Mitochondrial Membranes
  • Molecular Sequence Data
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Permeability
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2
  • Sequence Homology, Amino Acid
  • Time Factors
  • Transfection