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Molecular and Cellular Biology, September 2004, p. 8264-8275, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8264-8275.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Phosphorylation and Alternative Pre-mRNA Splicing Converge To Regulate Myocyte Enhancer Factor 2C Activity

Bangmin Zhu and Tod Gulick*

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

Received 15 February 2004/ Returned for modification 5 April 2004/ Accepted 11 June 2004

Myocyte enhancer factor 2 (MEF2) transcription factors play pivotal roles in cardiac, muscle, and neuron gene expression. All products of MEF2 genes have a common amino-terminal DNA binding and dimerization domain, but the four vertebrate MEF2 gene transcripts are alternatively spliced among coding exons to produce splicing isoforms. In MEF2C alone, alternative splice acceptors in the last exon give forms that include or exclude a short domain that we designate {gamma}. We show that MEF2C is expressed exclusively as {gamma}– isoforms in heart tissue and predominantly as {gamma}– in other adult tissues and in differentiating myocytes. MEF2C {gamma}– isoforms are much more robust than {gamma}+ forms in activating MEF2-responsive reporters in transfected fibroblasts despite indistinguishable expression levels, and they better synergize with MyoD in promoting myogenic conversion. One-hybrid transcription assays using Gal4-MEF2C fusions give similar distinctions between {gamma}– and {gamma}+ isoforms in all cell types tested, including myocytes. Cis effects of {gamma} on MEF2C DNA binding, dimerization, protein stability, or response to CaM or p38 mitogen-activated protein kinase signaling are not apparent, and the isolated {gamma} domain represses transcription when fused to Gal4. One phosphoserine residue is present within the {gamma} domain according to tandem mass spectrometry, and mutation of this residue abolishes {gamma}-mediated transrepression. A similar activity is present in the constitutive {gamma} domain and serine phosphoacceptor of MEF2A. Our findings indicate that {gamma} functions autonomously as a phosphoserine-dependent transrepressor to downregulate transactivation function of MEF2 factors and that alternative splicing and serine phosphorylation converge to provide complex combinatorial control of MEF2C activity.

* Corresponding author. Mailing address: Diabetes Research Laboratory, Massachusetts General Hospital, MGH East, CNY 149 8219, Charlestown, MA 02129. Phone: (617) 724-2356. Fax: (617) 726-9452. E-mail: gulick{at}helix.mgh.harvard.edu.

Molecular and Cellular Biology, September 2004, p. 8264-8275, Vol. 24, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.18.8264-8275.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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