Mcl-1 integrates the opposing actions of signaling pathways that mediate survival and apoptosis
Program in Molecular Medicine
3T3 Cells; Amino Acid Substitution; Animals; Apoptosis; Base Sequence; Cell Survival; DNA Primers; Glycogen Synthase Kinase 3; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Mutagenesis, Site-Directed; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Recombinant Proteins; Signal Transduction; Ultraviolet Rays
Life Sciences | Medicine and Health Sciences
Mcl-1 is a member of the Bcl2-related protein family that is a critical mediator of cell survival. Exposure of cells to stress causes inhibition of Mcl-1 mRNA translation and rapid destruction of Mcl-1 protein by proteasomal degradation mediated by a phosphodegron created by glycogen synthase kinase 3 (GSK3) phosphorylation of Mcl-1. Here we demonstrate that prior phosphorylation of Mcl-1 by the c-Jun N-terminal protein kinase (JNK) is essential for Mcl-1 phosphorylation by GSK3. Stress-induced Mcl-1 degradation therefore requires the coordinated activity of JNK and GSK3. Together, these data establish that Mcl-1 functions as a site of signal integration between the proapoptotic activity of JNK and the prosurvival activity of the AKT pathway that inhibits GSK3.
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Citation: Mol Cell Biol. 2009 Jul;29(14):3845-52. Epub 2009 May 11. Link to article on publisher's site