title: Cross-talk between glycogen synthase kinase 3β (GSK3β) and p38MAPK regulates myocyte enhancer factor 2 (MEF2) activity in skeletal and cardiac muscle.
abstract: Characterizing the signaling network that controls MEF2 transcription factors is crucial for understanding skeletal and cardiac muscle gene expression. Glycogen synthase kinase 3β (GSK3β) regulates MEF2 activity indirectly through reciprocal regulation of p38MAPK. Cross-talk between GSK3β and p38MAPK regulates MEF2 activity in skeletal and cardiac muscle. Understanding cross-talk in the signaling network converging at MEF2 control has therapeutic implications in cardiac and skeletal muscle pathology. Glycogen synthase kinase 3β (GSK3β) is a known regulator of striated muscle gene expression suppressing both myogenesis and cardiomyocyte hypertrophy. Since myocyte enhancer factor 2 (MEF2) proteins are key transcriptional regulators in both systems, we assessed whether MEF2 is a target for GSK3β. Pharmacological inhibition of GSK3β resulted in enhanced MEF2A/D expression and transcriptional activity in skeletal myoblasts and cardiac myocytes. Even though in silico analysis revealed GSK3β consensus (S/T)XXX(S/T) sites on MEF2A, a subsequent in vitro kinase assay revealed that MEF2A is only a weak substrate. However, we did observe a posttranslational modification in MEF2A in skeletal myoblasts treated with a GSK3β inhibitor which coincided with increased p38MAPK phosphorylation, a potent MEF2A activator, indicating that GSK3β inhibition may de-repress p38MAPK. Heart specific excision of GSK3β in mice also resulted in up-regulation of p38MAPK activity. Interestingly, upon pharmacological p38MAPK inhibition (SB203580), GSK3β inhibition loses its effect on MEF2 transcriptional activity suggesting potent cross-talk between the two pathways. Thus we have documented that cross-talk between p38MAPK and GSK3β signaling converges on MEF2 activity having potential consequences for therapeutic modulation of cardiac and skeletal muscle gene expression.
authors.affiliation: Department of Biology, York University, 4700 Keele St., Toronto, Ontario, Canada M3J 1P3.
authors.forename: M G
authors.initials: MG
authors.lastname: Dionyssiou
authors.forename: N B
authors.initials: NB
authors.lastname: Nowacki
authors.forename: S
authors.initials: S
authors.lastname: Hashemi
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: A
authors.initials: A
authors.lastname: Kerr
authors.forename: R G
authors.initials: RG
authors.lastname: Tsushima
authors.forename: J C
authors.initials: JC
authors.lastname: McDermott
mesh_terms: D000818:Animals; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007093:Imidazoles / Q000494:pharmacology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology; D032446:Myoblasts; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D010766:Phosphorylation; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D015533:Transcriptional Activation; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D018006:Myogenic Regulatory Factors; D011725:Pyridines; C465539:SB202494; D013844:Thiazoles; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D008156:Luciferases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C093642:SB 203580