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CMF1-Rb interaction promotes myogenesis in avian skeletal myoblasts.

ABSTRACT: CMF1 protein is expressed in developing striated muscle before the expression of contractile proteins, and depletion of CMF1 in myoblasts results in inability to express muscle-specific proteins. Previous studies of CMF1 identify a functional Rb-binding domain, which is conserved in the murine and human homologues. Here, we show that CMF1 binds Rb family members, while a CMF1 protein with deletion of the Rb-binding domain (Rb-del CMF1) does not. Myogenic cell lines over-expressing Rb-del CMF1 proliferate normally, but exhibit markedly impaired differentiation, including dramatically reduced contractile proteins gene expression and failure to fuse into myotubes. Furthermore, by quantitative real-time polymerase chain reaction, MyoD and Myf5 mRNA levels are comparable to wild-type, while myogenin and contractile protein mRNA levels are significantly attenuated. These data demonstrate that CMF1 regulates myocyte differentiation by interaction with Rb family members to induce expression of myogenic regulatory factors.

SUBMITTER: Robertson JB

PROVIDER: S-EPMC2854498 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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CMF1-Rb interaction promotes myogenesis in avian skeletal myoblasts.

Robertson J Brian JB Zhu Tianli T Nasreen Shampa S Kilkenny Dawn D Bader David D Dees Ellen E

Developmental dynamics : an official publication of the American Association of Anatomists 20080501 5

CMF1 protein is expressed in developing striated muscle before the expression of contractile proteins, and depletion of CMF1 in myoblasts results in inability to express muscle-specific proteins. Previous studies of CMF1 identify a functional Rb-binding domain, which is conserved in the murine and human homologues. Here, we show that CMF1 binds Rb family members, while a CMF1 protein with deletion of the Rb-binding domain (Rb-del CMF1) does not. Myogenic cell lines over-expressing Rb-del CMF1 pr ...[more]

PMID: 18425850

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Project description:BACKGROUND: The effects of transforming growth factor-beta (TGFβ) are mediated by the transcription factors Smad2 and Smad3. During adult skeletal myogenesis, TGFβ signaling inhibits the differentiation of myoblasts, and this can be reversed by treatment with retinoic acid (RA). In mesenchymal stem cells and preadipocytes, RA treatment can function in a non-classical manner by stimulating the expression of Smad3. Smad3 can bind to and prevent the bzip transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) from binding DNA response elements in target promoters, thereby affecting cell differentiation. In skeletal muscle, C/EBPβ is highly expressed in satellite cells and myoblasts and is downregulated during differentiation. Persistent expression of C/EBPβ in myoblasts inhibits their differentiation. METHODS: Using both C2C12 myoblasts and primary myoblasts, we examined the regulation of C/EBPβ expression and activity following treatment with TGFβ and RA. RESULTS: We demonstrate that treatment with RA upregulates Smad3, but not Smad2 expression in myoblasts, and can partially rescue the block of differentiation induced by TGFβ. RA treatment reduces C/EBPβ occupancy of the Pax7 and Smad2 promoters and decreased their expression. RA also inhibits the TGFβ-mediated phosphorylation of Smad2, which may also contribute to its pro-myogenic activities. TGFβ treatment of C2C12 myoblasts stimulates C/EBPβ expression, which in turn can stimulate Pax7 and Smad2 expression, and inhibits myogenesis. Loss of C/EBPβ expression in myoblasts partially restores differentiation in the presence of TGFβ. CONCLUSIONS: TGFβ acts, at least in part, to inhibit myogenesis by upregulating the expression of C/EBPβ, as treatment with RA or loss of C/EBPβ can partially rescue differentiation in TGFβ-treated cells. This work identifies a pro-myogenic role for Smad3, through the inhibition of C/EBPβ's actions in myoblasts, and reveals mechanisms of crosstalk between RA and TGFβ signaling pathways.

Dataset Information

CMF1-Rb interaction promotes myogenesis in avian skeletal myoblasts.

Publications

CMF1-Rb interaction promotes myogenesis in avian skeletal myoblasts.

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