Reference : Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization an...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1
Maurer, Ulrich [> > > >]
Charvet, Céline [> > > >]
Wagman, Allan [> > > >]
Dejardin, Emmanuel mailto [Université de Liège - ULiège > > Virologie - Immunologie >]
Green, Douglas [> > > >]
Molecular Cell
Cell Press
Yes (verified by ORBi)
[en] apoptosis, Mcl-1
[en] 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 MCLA. 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 MCLA stability by GSK-3 is an important mechanism for the regulation of apoptosis by growth factors, PI3K, and AKT.

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