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J. Biol. Chem., Vol. 279, Issue 29, 30800-30806, July 16, 2004

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Vgl-4, a Novel Member of the Vestigial-like Family of Transcription Cofactors, Regulates ₁-Adrenergic Activation of Gene Expression in Cardiac Myocytes^*

Hsiao-Huei Chen, Steven J. Mullett, and Alexandre F. R. Stewart

From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213

Cardiac and skeletal muscle genes are regulated by the transcriptional enhancer factor (TEF-1) family of transcription factors. In skeletal muscle, TEF-1 factors interact with a skeletal muscle-specific cofactor called Vestigial-like 2 (Vgl-2) that is related to the Drosophila protein Vestigial. Here, we characterize Vgl-4, the only member of the Vestigial-like family expressed in the heart. Unlike other members of the Vgl family that have a single TEF-1 interaction domain called the tondu (TDU) motif, Vgl-4 has two TDU motifs in its carboxyl-terminal domain. Like other Vgl factors, Vgl-4 physically interacts with TEF-1 in an immunoprecipitation assay. Vgl-4 functionally interacts with TEF-1 and also with myocyte enhancer factor 2 in a mammalian two-hybrid assay. Overexpression of Vgl-4 in cardiac myocytes interfered with the basal expression and ₁-adrenergic receptor-dependent activation of a TEF-1-dependent skeletal -actin promoter. In cardiac myocytes cultured in serum and in serum-free medium, a myc-tagged Vgl-4 protein was located in the nucleus and cytoplasm but was exported from the nucleus when cells were treated with ₁-adrenergic receptor agonist. A chimeric nuclear-retained Vgl-4 protein inhibited ₁-adrenergic receptor-dependent activation. In contrast, deletion of the TDU motifs of Vgl-4 prevented Vgl-4 nuclear localization, relieved Vgl-4 interference of basal activity, and enhanced ₁-adrenergic up-regulation of the skeletal -actin promoter. Nuclear export of Vgl-4 is dependent on the nuclear exportin CRM-1. These results suggest that Vgl-4 modulates the activity of TEF-1 factors and counteracts ₁-adrenergic activation of gene expression in cardiac myocytes.

Received for publication, January 7, 2004 , and in revised form, April 1, 2004.

^* This work was supported by a grant from the Muscular Dystrophy Association. 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.

To whom correspondence should be addressed: Cardiovascular Institute, University of Pittsburgh, Pittsburgh, 1704.3 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15213. Tel.: 412-383-9761; Fax: 412-383-8997; E-mail: stewartaf{at}upmc.edu.

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