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J. Biol. Chem., Vol. 280, Issue 9, 7493-7503, March 4, 2005

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Alternative mRNA Splicing of SMRT Creates Functional Diversity by Generating Corepressor Isoforms with Different Affinities for Different Nuclear Receptors^*

Michael L. Goodson, Brian A. Jonas, and Martin L. Privalsky

From the Sections of Microbiology and Molecular and Cellular Biology, University of California, Davis, California 95616

Many eukaryotic transcription factors are bimodal in their regulatory properties and can both repress and activate expression of their target genes. These divergent transcriptional properties are conferred through recruitment of auxiliary proteins, denoted coactivators and corepressors. Repression plays a particularly critical role in the functions of the nuclear receptors, a large family of ligand-regulated transcription factors involved in metazoan development, differentiation, reproduction, and homeostasis. The SMRT corepressor interacts directly with nuclear receptors and serves, in turn, as a platform for the assembly of a larger corepressor complex. We report here that SMRT is expressed in cells by alternative mRNA splicing to yield two distinct variants or isoforms. We designate these isoforms SMRT and SMRT and demonstrate that these isoforms have significantly different affinities for different nuclear receptors. These isoforms are evolutionarily conserved and are expressed in a tissue-specific manner. Our results suggest that differential mRNA splicing serves to customize corepressor function in different cells, allowing the transcriptional properties of nuclear receptors to be adapted to different contexts.

Received for publication, October 8, 2004 , and in revised form, December 23, 2004.

^* This work was supported in part by United States Public Health Service Grant DK53538 from NIDDK. 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.

Supported by National Institutes of Health Grant 5F32DK062654-02 and a fellowship from the Pharmaceutical Research and Manufacturers of America Foundation.

To whom correspondence should be addressed: Section of Microbiology, Div. of Biological Sciences, One Shields Ave., University of California, Davis, CA 95616. Tel.: 530-752-3013; Fax: 530-752-9014; E-mail: mlprivalsky{at}ucdavis.edu.

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