title: Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy.
abstract: Hypertrophy is a basic cellular response to a variety of stressors and growth factors, and has been best characterized in myocytes. Pathologic hypertrophy of cardiac myocytes leads to heart failure, a major cause of death and disability in the developed world. Several cytosolic signaling pathways have been identified that transduce prohypertrophic signals, but to date, little work has focused on signaling pathways that might negatively regulate hypertrophy. Herein, we report that glycogen synthase kinase-3beta (GSK-3beta), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase-dependent protein kinase that phosphorylates GSK-3beta on ser 9. Using adenovirus-mediated gene transfer of GSK-3beta containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3beta is required for cardiomyocytes to undergo hypertrophy. Furthermore, our data suggest that GSK-3beta regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. The identification of GSK-3beta as a transducer of antihypertrophic signals suggests that novel therapeutic strategies to treat hypertrophic diseases of the heart could be designed that target components of the GSK-3 pathway.
authors.affiliation: Cardiology Division, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02129-2060, USA.
authors.forename: S
authors.initials: S
authors.lastname: Haq
authors.forename: G
authors.initials: G
authors.lastname: Choukroun
authors.forename: Z B
authors.initials: ZB
authors.lastname: Kang
authors.forename: H
authors.initials: H
authors.lastname: Ranu
authors.forename: T
authors.initials: T
authors.lastname: Matsui
authors.forename: A
authors.initials: A
authors.lastname: Rosenzweig
authors.forename: J D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: A
authors.initials: A
authors.lastname: Alessandrini
authors.forename: J
authors.initials: J
authors.lastname: Woodgett
authors.forename: R
authors.initials: R
authors.lastname: Hajjar
authors.forename: A
authors.initials: A
authors.lastname: Michael
authors.forename: T
authors.initials: T
authors.lastname: Force
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010656:Phenylephrine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D019332:Endothelin-1; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D010656:Phenylephrine; D019869:Phosphatidylinositol 3-Kinases; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3