| First Author | Fu D | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 16 | Pages | 10200-7 |
| PubMed ID | 25720496 | Mgi Jnum | J:222127 |
| Mgi Id | MGI:5643999 | Doi | 10.1074/jbc.M115.638577 |
| Citation | Fu D, et al. (2015) Mdm2 promotes myogenesis through the ubiquitination and degradation of CCAAT/enhancer-binding protein beta. J Biol Chem 290(16):10200-7 |
| abstractText | 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 beta (C/EBPbeta) 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/EBPbeta protein is rapidly down-regulated upon induction of myogenesis and this is not due to changes in Cebpb mRNA expression. Rather, loss of C/EBPbeta protein is accompanied by an increase in Mdm2 expression, an E3 ubiquitin ligase. We demonstrate that Mdm2 interacts with, ubiquitinates and targets C/EBPbeta 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/EBPbeta 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/EBPbeta, suggesting that the regulation of C/EBPbeta turnover is a major role for Mdm2 in myoblasts. Taken together, we provide evidence that Mdm2 regulates entry into myogenesis by targeting C/EBPbeta for degradation by the 26 S proteasome. |
