PMID:25720496

Citation	Fu, D, Lala-Tabbert, N, Lee, H and Wiper-Bergeron, N (2015) Mdm2 promotes myogenesis through the ubiquitination and degradation of CCAAT/enhancer-binding protein β. J. Biol. Chem. 290:10200-7
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 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.
Links	PubMed PMC4400335 Online version:10.1074/jbc.M115.638577
Keywords	Animals; CCAAT-Enhancer-Binding Protein-beta/genetics; CCAAT-Enhancer-Binding Protein-beta/metabolism; Cell Differentiation; Cell Line; Gene Expression Regulation, Developmental; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Development/genetics; Muscle, Skeletal/cytology; Muscle, Skeletal/growth & development; Muscle, Skeletal/metabolism; MyoD Protein/genetics; MyoD Protein/metabolism; Myoblasts/cytology; Myoblasts/metabolism; PAX7 Transcription Factor/genetics; PAX7 Transcription Factor/metabolism; Primary Cell Culture; Proteasome Endopeptidase Complex/metabolism; Proteolysis; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2/genetics; Proto-Oncogene Proteins c-mdm2/metabolism; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Signal Transduction; Ubiquitination
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:MDM2		GO:0042787: protein ubiquitination involved in ubiquitin-dependent protein catabolic process	ECO:0000315:		P		The organism Mus Musculus and the protein is MDM2. Figure 4B is a ubiquitination assay that shows that MDM2 ubiquitinates C/EBPβ (CCAAT-enhancer-binding protein). Figure 4 shows that "Mdm2 ubiquitinates and targets C/EBPβ for degradation"	complete CACAO 13030
MOUSE:MDM2		GO:0051149: positive regulation of muscle cell differentiation	ECO:0000315:		P		The organism is Mus Musculus and the protein is MDM2. Figure 5B shows that mice lacking MDM2 have 90% less cell differential compared to the control group with MDM2. this shows that presence of MDM2 positively regulates muscle cell differentiation since the loss of MDM2 shows much less muscle cell differentiation	complete CACAO 13031

References

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