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de la Vega, L.* ; Hornung, J.* ; Kremmer, E. ; Milanovic, M.* ; Schmitz, M.L.*

Homeodomain-interacting protein kinase 2-dependent repression of myogenic differentiation is relieved by its caspase-mediated cleavage.

Nucleic Acids Res. 41, 5731-5745 (2013)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Skeletal-muscle Differentiation ; Myocyte Enhancer Factor-2 ; Mef2 Transcription Factor ; Ii Histone Deacetylases ; Dna-damage ; Terminal Differentiation ; Hdac4 Deacetylase ; Genotoxic Stress ; Class Iihdacs ; Hipk2

ISSN (print) / ISBN 0305-1048

e-ISSN 1362-4962

Journal Nucleic Acids Research

Quellenangaben Volume: 41, Issue: 11, Pages: 5731-5745

Publisher Oxford University Press

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Molecular Immunology (IMI)