Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 282, Issue 10, Pages 7265-7275Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M609076200
Keywords
-
Categories
Ask authors/readers for more resources
In skeletal muscle, the transformation of fast into slow fib type is accompanied by shifts in fiber type-specific gene expression that includes down-regulation of the adult fast fiber myosin heavy chain Ild/x (MyHCIId/x) gene. Here, we report that the mitogen-activated protein kinases (MAPKs) p38 alpha/beta regulate MyHCIId/x gene expression. Electrical stimulation of rabbi skeletal muscle cells with a slow fiber type activity pattern an treatment of C2C12 myotubes with Ca2+-ionophore inhibited p38 alpha/beta MAPKs and reduced fast fiber type MyHC protein expression and promoter activity. Pharmacological inhibition of p38 alpha/beta also down-regulated MyHCII gene expression. In controls, binding of the myocyte enhancer factor-2 (MEF-2) isoforms C and D as a heterodimer to a proximal consensus site within the MyHCIId/x promoter and recruitment of a transcriptional coactivator, the CREB-binding protein CBP, were observed. Overexpression of wild type MEF-2C but not of a MEF-2C mutant that cannot be phosphorylated by p38 induced promoter activity. Mutation of the MEF-2-binding site decreased the inducing effect of overexpressed CBP. Inhibition of p38 alpha/beta MAPKs abolished CBP binding, whereas enforced induction of p38 by activated MAPK kinase 6 (MKK6EE) enhanced binding of CBP and increased promoter activity. Furthermore, knockdown of endogenous CBP by RNA interference eliminated promoter activation by MEF-2C or MKK6EE. In electrical stimulated and Ca2+-ionophore-treated myotubes, CBP was absent in complex formation at that site. Taken together, the data indicate that p38 alpha/beta MAPKs-mediated coactivator recruitment at a proximal MEF-2 site is important for MyHCIId/x gene regulation in skeletal muscle.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available