The p38alpha/beta mitogen-activated protein kinases mediate recruitment of CREB-binding protein to preserve fast myosin heavy chain IId/x gene activity in myotubes.
J Biol Chem
; 282(10): 7265-75, 2007 Mar 09.
Article
em En
| MEDLINE
| ID: mdl-17210568
ABSTRACT
In skeletal muscle, the transformation of fast into slow fiber type is accompanied by shifts in fiber type-specific gene expression that includes down-regulation of the adult fast fiber myosin heavy chain IId/x (MyHCIId/x) gene. Here, we report that the mitogen-activated protein kinases (MAPKs) p38alpha/beta regulate MyHCIId/x gene expression. Electrical stimulation of rabbit skeletal muscle cells with a slow fiber type activity pattern and treatment of C2C12 myotubes with Ca(2+)-ionophore inhibited p38alpha/beta MAPKs and reduced fast fiber type MyHC protein expression and promoter activity. Pharmacological inhibition of p38alpha/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 p38alpha/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 Ca(2+)-ionophore-treated myotubes, CBP was absent in complex formation at that site. Taken together, the data indicate that p38alpha/beta MAPKs-mediated coactivator recruitment at a proximal MEF-2 site is important for MyHCIId/x gene regulation in skeletal muscle.
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Base de dados:
MEDLINE
Assunto principal:
Fibras Musculares Esqueléticas
/
Cadeias Pesadas de Miosina
/
Proteína Quinase 11 Ativada por Mitógeno
/
Proteína Quinase 14 Ativada por Mitógeno
/
Proteína de Ligação a CREB
Limite:
Animals
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Alemanha