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J. Biol. Chem., Vol. 280, Issue 43, 36037-36046, October 28, 2005

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7 Integrin Expression Is Negatively Regulated by EF1 during Skeletal Myogenesis^*

From the Department of Cell and Tissue Biology, University of California, San Francisco, California 94143

7 integrin levels increase dramatically as myoblasts differentiate to myotubes. A negative regulatory element with putative sites for EF1 is present in the 7 proximal promoter region. To define the role of EF1 in regulating 7 integrin expression, we overexpressed EF1 in C2C12 myoblasts. This resulted in a major down-regulation of 7 protein expression. Promoter assays revealed that C2C12 myoblasts transfected with EF1 showed a decrease in activity of the 2.8-kb 7 promoter fragment, indicating regulation of 7 integrin at the transcriptional level. We have identified two E-box-like sites for EF1 in the negative regulatory region. Mutation of these sites enhanced 7 promoter activity, indicating that these sites function in repression. MYOD, an activator of 7 integrin transcription, can compete with EF1 for binding at these sites in gel shift assay. By using chromatin immunoprecipitation, we demonstrated a reciprocal binding of EF1 and MYOD to this regulatory element depending on the stage of differentiation: EF1 is preferentially bound in myoblasts to this region, whereas MYOD is bound in myotubes. The N-terminal region of EF1 is necessary for 7 repression, and this region also binds the co-activator p300/CBP. Importantly, we found that the p300/CBP co-activator can overcome repression by EF1, suggesting that EF1 can titrate limiting amounts of this co-activator. These findings suggest that EF1 has a role in suppressing integrin expression in myoblasts by displacing MYOD and competing for p300/CBP co-activator.

Received for publication, August 8, 2005

^* This work was supported by National Institutes of Health Grant DE015404 (to R. H. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cell and Tissue Biology, University of California, Box 0640, C-640, 521 Parnassus Ave., San Francisco, CA 94143-0640. Tel.: 415-476-3275; Fax: 415-476-1499; E-mail: Randall.Kramer{at}ucsf.edu.

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