Mdm2 promotes myogenesis through the ubiquitination and degradation of CCAAT/enhancer-binding protein ß.
J Biol Chem
; 290(16): 10200-7, 2015 Apr 17.
Article
em En
| MEDLINE
| ID: mdl-25720496
ABSTRACT
Myogenesis is a tightly regulated differentiation process during which precursor cells express in a coordinated fashion the myogenic regulatory factors, while down-regulating the satellite cell marker Pax7. CCAAT/Enhancer-binding protein ß (C/EBPß) is also expressed in satellite cells and acts to maintain the undifferentiated state by stimulating Pax7 expression and by triggering a decrease in MyoD protein expression. Herein, we show that C/EBPß protein is rapidly down-regulated upon induction of myogenesis and this is not due to changes in Cebpb mRNA expression. Rather, loss of C/EBPß protein is accompanied by an increase in Mdm2 expression, an E3 ubiquitin ligase. We demonstrate that Mdm2 interacts with, ubiquitinates and targets C/EBPß for degradation by the 26 S proteasome, leading to increased MyoD expression. Knockdown of Mdm2 expression in myoblasts using a shRNA resulted in high C/EBPß levels and a blockade of myogenesis, indicating that Mdm2 is necessary for myogenic differentiation. Primary myoblasts expressing the shMdm2 construct were unable to contribute to muscle regeneration when grafted into cardiotoxin-injured muscle. The differentiation defect imposed by loss of Mdm2 could be partially rescued by loss of C/EBPß, suggesting that the regulation of C/EBPß turnover is a major role for Mdm2 in myoblasts. Taken together, we provide evidence that Mdm2 regulates entry into myogenesis by targeting C/EBPß for degradation by the 26 S proteasome.
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Assunto principal:
Músculo Esquelético
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Regulação da Expressão Gênica no Desenvolvimento
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Proteína beta Intensificadora de Ligação a CCAAT
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Desenvolvimento Muscular
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Mioblastos
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Proteínas Proto-Oncogênicas c-mdm2
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2015
Tipo de documento:
Article