Cited by 881Cell death mechanisms and regulationPI3K/AKT/mTOR signaling in cancerWnt/β-catenin signaling in development and cancer

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

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Maurer, Ulrich, Charvet, Céline, Wagman, Allan S., Dejardin, Emmanuel, Green, Douglas R.·2006·Molecular Cell

Abstract

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.

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Authors
Maurer, U., Charvet, C., Wagman, A. S., Dejardin, E., & Green, D. R.
Affiliations
  • La Jolla Institute for Immunology (US)
  • University of Liège (BE)
Corresponding author
  • Maurer, Ulrich
  • Green, Douglas R.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2006-03
Volume
21
Issue
6
Pages
749-760
ISSN
1097-2765 (ISSN-L)
OpenAlex
W2152876030
Cited by
881
References
71
Citations by year
2026: 10 · 2025: 18 · 2024: 16 · 2023: 35 · 2022: 33 · 2021: 41 · 2020: 31 · 2019: 26 · 2018: 39 · 2017: 48 · 2016: 41 · 2015: 48 · 2014: 51 · 2013: 71 · 2012: 62
FWCI
23.68
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
Funders
  • National Institutes of Health (AI44828, CA-69381, AI40646, GM52735)
  • National Cancer Institute (CA 69381, P01CA069381)
  • National Institute of General Medical Sciences (GM-52735)
  • National Institute of Allergy and Infectious Diseases (R01AI040646, AI40646, AI44828)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
glycogen synthase kinase-3, Mcl-1, mitochondrial outer membrane permeabilization, apoptosis, protein phosphorylation, ubiquitination, protein degradation, IL-3 withdrawal, PI3K signaling, Akt signaling, cytochrome c release
MeSH terms
Amino Acid Sequence, Animals, Cell Line, Cell Survival, Humans, Interleukin-3, Molecular Sequence Data, Neoplasm Proteins, Permeability, Phosphorylation, Time Factors, Transfection, Apoptosis, Sequence Homology, Amino Acid, Proto-Oncogene Proteins c-bcl-2, Phosphatidylinositol 3-Kinases, Glycogen Synthase Kinase 3, Cytochromes c, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, Mitochondrial Membranes, Mice, Myeloid Cell Leukemia Sequence 1 Protein

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