title: Intracellular calcium and myosin isoform transitions. Calcineurin and calcium-calmodulin kinase pathways regulate preferential activation of the IIa myosin heavy chain promoter.
abstract: Intracellular calcium levels can have profound effects on muscle biology via alterations in gene expression. In particular, intracellular calcium levels increase during muscle activation and are thought to underlie fast-to-slow shifts in muscle gene expression. In the present work, we determined that increased intracellular calcium has a significant effect on the activity of the adult fast myosin heavy chain (MyHC) promoters in the order of MyHC IIa>> IId/x > IIb. We have identified the pathways by which the calcium signal mediates increased activation of the MyHC IIa promoter. Inhibition of calcineurin or calcium-calmodulin kinase greatly attenuates ionophore-induced activation of the MyHC IIa promoter, whereas protein kinase C inhibitors have no effect. Inhibition and overexpression studies with members of the mitogen-activated protein kinase family reveal roles for MEK1/MEK2 and MEKK1, but not p38 or phosphatidylinositol 3-kinase. Downstream mediators of these effects are the activities of the MEF-2 and NFAT transcription factors, whose binding sites in the MyHC IIa promoter are required for calcium-induced activation of the MyHC IIa promoter.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA. allendl@stripe.colorado.edu
authors.forename: David L
authors.initials: DL
authors.lastname: Allen
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Leinwand
mesh_terms: D000818:Animals; D001665:Binding Sites; D000001:Calcimycin / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D007476:Ionophores / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; C491779:Elf4 protein, mouse; D004791:Enzyme Inhibitors; D007476:Ionophores; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; D000001:Calcimycin; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin; D018995:Myosin Heavy Chains; D002118:Calcium