title: Homeodomain-interacting protein kinase 2-dependent repression of myogenic differentiation is relieved by its caspase-mediated cleavage.
abstract: Differentiation of skeletal muscle cells is accompanied by drastic changes in gene expression programs that depend on activation and repression of genes at defined time points. Here we identify the serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) as a corepressor that inhibits myocyte enhancer factor 2 (MEF2)-dependent gene expression in undifferentiated myoblasts. Downregulation of HIPK2 expression by shRNAs results in elevated expression of muscle-specific genes, whereas overexpression of the kinase dampens transcription of these genes. HIPK2 is constitutively associated with a multi-protein complex containing histone deacetylase (HDAC)3 and HDAC4 that serves to silence MEF2C-dependent transcription in undifferentiated myoblasts. HIPK2 interferes with gene expression on phosphorylation and HDAC3-dependent deacetylation of MEF2C. Ongoing muscle differentiation is accompanied by elevated caspase activity, which results in caspase-mediated cleavage of HIPK2 following aspartic acids 916 and 977 and the generation of a C-terminally truncated HIPK2 protein. The short form of the kinase loses its affinity to the repressive multi-protein complex and its ability to bind HDAC3 and HDAC4, thus alleviating its repressive function for expression of muscle genes. This study identifies HIPK2 as a further protein that determines the threshold and kinetics of gene expression in proliferating myoblasts and during the initial steps of myogenesis.
authors.affiliation: Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, 35392 Giessen, Germany.
authors.forename: Laureano
authors.initials: L
authors.lastname: de la Vega
authors.forename: Juliane
authors.initials: J
authors.lastname: Hornung
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Maja
authors.initials: M
authors.lastname: Milanovic
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
mesh_terms: D000107:Acetylation; D000818:Animals; D001224:Aspartic Acid / Q000032:analysis; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D056970:Co-Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D064326:MEF2 Transcription Factors; D051379:Mice; D024510:Muscle Development / Q000235:genetics*; D032448:Myoblasts, Skeletal / Q000201:enzymology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D001224:Aspartic Acid; D002352:Carrier Proteins; D020169:Caspases; D056970:Co-Repressor Proteins; D006655:Histone Deacetylases; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D017346:Protein Serine-Threonine Kinases; D000099186:Histone Deacetylase 3; C578041:Mef2c protein, mouse; C492003:Hipk2 protein, mouse; C498618:Hdac5 protein, mouse