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J. Biol. Chem., Vol. 280, Issue 31, 28749-28760, August 5, 2005

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Alternative Pre-mRNA Splicing Governs Expression of a Conserved Acidic Transactivation Domain in Myocyte Enhancer Factor 2 Factors of Striated Muscle and Brain^*

Bangmin Zhu¶, Bindu Ramachandran, and Tod Gulick||

From the Diabetes Research Laboratory, Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts 02129 and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

Myocyte enhancer factor 2 (MEF2) transcription factors play pivotal roles in striated muscle, neuron, and lymphocyte gene expression and are targets of stress- and calcium-mediated signaling. All MEF2 gene products have a common DNA binding and dimerization domain, but MEF2 transcripts are alternatively spliced among coding exons to produce splicing isoforms. In vertebrate MEF2A, -C, and -D, a splice versus no-splice option gives forms that include or exclude a short domain that we designate . We show that mRNAs containing are expressed predominantly in striated muscle and brain and that splicing to include is induced during myocyte differentiation. MEF2 + isoforms are more robust than - forms in activating MEF2-responsive reporters despite similar expression levels. One-hybrid transcription assays using Gal4-MEF2 fusions show similar distinctions in the transactivation produced by + versus - isoforms in all cell types tested, including myocytes. function is position-independent and exists in all MEF2 splicing variant contexts. The activity is not due to cis effects on MEF2 DNA binding or dimerization nor are established transcription factor or coactivator interactions involved. Each MEF2 domain contains multiple acidic residues, mutation of which abolishes function. Despite a location between the p38 MAPK docking domain and Thr phosphoacceptors of MEF2A and MEF2C, inclusion of does not influence responses of these factors to this signaling pathway. Thus, a conserved pattern of alternative splicing in vertebrate MEF2 genes generates an acidic activation domain in MEF2 proteins selectively in tissues where MEF2 target genes are highly expressed.

Received for publication, March 7, 2005 , and in revised form, April 12, 2005.

^* This work was supported in part by American Heart Association Grant 0150622N, Juvenile Diabetes Foundation Grant 1998-224, Clinical Nutrition Research Center at Harvard Grant P30 DK40561, and National Institutes of Health Grants DK55875 and HL72713. 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.

^¶ Present address: Ben May Institute for Cancer Research, University of Chicago, 5841 S. Maryland Ave., Box MC6027, Chicago, IL 60637.

^|| Supported by NIDDK Independent Scientist Award DK02461 and by a grant from the Vivien Krantz Memorial Fund. To whom correspondence should be addressed: Diabetes Research Laboratory, Massachusetts General Hospital, CNY 149 8219, Charlestown, MA 02129. Tel.: 617-724-2356; Fax: 617-726-9452; E-mail: gulick{at}helix.mgh.harvard.edu.

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