Serum response factor MADS box serine-162 phosphorylation switches proliferation and myogenic gene programs.
Phosphorylation of a cluster of amino acids in the serum response factor (SRF) "MADS box" alphaI coil DNA binding domain regulated the transcription of genes associated with proliferation or terminal muscle differentiation. Mimicking phosphorylation of serine-162, a target of protein kinase C-alpha, with an aspartic acid substitution (SRF-S162D) completely inhibited SRF-DNA binding and blocked alpha-actin gene transcription even in the presence of potent myogenic cofactors, while preserving c-fos promoter activity because of stabilization of the ternary complex via Elk-1. Introduction of SRF-S162D into SRF null ES cells permitted transcription of the c-fos gene but was unable to rescue expression of myogenic contractile genes. Transition of proliferating C2C12 myoblasts to postfusion myocytes after serum withdrawal was associated with a progressive decline in SRF-S162 phosphorylation and an increase in alpha-actin gene expression. Hence, the phosphorylation status of serine-162 in the alphaI coil may constitute a novel switch that directs target gene expression into proliferation or differentiation programs.
Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Center for Cardiovascular Development, Baylor College of Medicine, Houston, TX 77030, USA.
Dinakar
D
Iyer
David
D
Chang
Joe
J
Marx
Lei
L
Wei
Eric N
EN
Olson
Michael S
MS
Parmacek
Ashok
A
Balasubramanyam
Robert J
RJ
Schwartz
D000199:Actins / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016762:Genes, fos / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000235:genetics; D024510:Muscle Development / Q000235:genetics*; D009130:Muscle, Smooth / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011487:Protein Conformation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D026362:Serum Response Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
D000199:Actins; C494113:Elk1 protein, mouse; D026362:Serum Response Factor; D050807:ets-Domain Protein Elk-1; D001224:Aspartic Acid; D012694:Serine; D051571:Protein Kinase C-alpha