Mdm2 promotes myogenesis through the ubiquitination and degradation of CCAAT/enhancer-binding protein β.
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 β (C/EBPβ) 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/EBPβ protein is rapidly down-regulated upon induction of myogenesis and this is not due to changes in Cebpb mRNA expression. Rather, loss of C/EBPβ protein is accompanied by an increase in Mdm2 expression, an E3 ubiquitin ligase. We demonstrate that Mdm2 interacts with, ubiquitinates and targets C/EBPβ 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/EBPβ 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/EBPβ, suggesting that the regulation of C/EBPβ turnover is a major role for Mdm2 in myoblasts. Taken together, we provide evidence that Mdm2 regulates entry into myogenesis by targeting C/EBPβ for degradation by the 26 S proteasome.
Mesh Terms:
Animals, CCAAT-Enhancer-Binding Protein-beta, Cell Differentiation, Cell Line, Gene Expression Regulation, Developmental, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Development, Muscle, Skeletal, MyoD Protein, Myoblasts, PAX7 Transcription Factor, Primary Cell Culture, Proteasome Endopeptidase Complex, Proteolysis, Proto-Oncogene Proteins c-mdm2, RNA, Small Interfering, Signal Transduction, Ubiquitination
Animals, CCAAT-Enhancer-Binding Protein-beta, Cell Differentiation, Cell Line, Gene Expression Regulation, Developmental, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Development, Muscle, Skeletal, MyoD Protein, Myoblasts, PAX7 Transcription Factor, Primary Cell Culture, Proteasome Endopeptidase Complex, Proteolysis, Proto-Oncogene Proteins c-mdm2, RNA, Small Interfering, Signal Transduction, Ubiquitination
J. Biol. Chem.
Date: Apr. 17, 2015
PubMed ID: 25720496
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