Vgl-4, a novel member of the vestigial-like family of transcription cofactors, regulates alpha1-adrenergic activation of gene expression in cardiac myocytes.
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 alpha1-adrenergic receptor-dependent activation of a TEF-1-dependent skeletal alpha-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 alpha1-adrenergic receptor agonist. A chimeric nuclear-retained Vgl-4 protein inhibited alpha1-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 alpha1-adrenergic up-regulation of the skeletal alpha-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 alpha1-adrenergic activation of gene expression in cardiac myocytes.
Mesh Terms:
Actins, Amino Acid Motifs, Amino Acid Sequence, Animals, Blotting, Northern, Cell Nucleus, Cells, Cultured, DNA, DNA-Binding Proteins, Fibroblasts, Gene Expression Regulation, Humans, Mice, Molecular Sequence Data, Muscle Proteins, Mutation, Myocardium, Myocytes, Cardiac, Nuclear Proteins, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Protein Biosynthesis, Protein Structure, Tertiary, RNA, Messenger, Rats, Receptors, Adrenergic, alpha-1, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Signal Transduction, Tissue Distribution, Transcription Factors, Transfection, Two-Hybrid System Techniques
Actins, Amino Acid Motifs, Amino Acid Sequence, Animals, Blotting, Northern, Cell Nucleus, Cells, Cultured, DNA, DNA-Binding Proteins, Fibroblasts, Gene Expression Regulation, Humans, Mice, Molecular Sequence Data, Muscle Proteins, Mutation, Myocardium, Myocytes, Cardiac, Nuclear Proteins, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Protein Biosynthesis, Protein Structure, Tertiary, RNA, Messenger, Rats, Receptors, Adrenergic, alpha-1, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Signal Transduction, Tissue Distribution, Transcription Factors, Transfection, Two-Hybrid System Techniques
J. Biol. Chem.
Date: Jul. 16, 2004
PubMed ID: 15140898
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