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J. Biol. Chem., Vol. 279, Issue 52, 54676-54686, December 24, 2004

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SMRT and N-CoR Corepressors Are Regulated by Distinct Kinase Signaling Pathways^*

Brian A. Jonas and Martin L. Privalsky

From the Section of Microbiology, Division of Biological Sciences, University of California, Davis, California 95616

N-CoR and SMRT are corepressor paralogs that partner with and mediate transcriptional repression by a wide variety of metazoan transcription factors, including nuclear hormone receptors. Although encoded by distinct genetic loci, N-CoR and SMRT share substantial sequence interrelatedness, form analogous assemblies with histone deacetylases and auxiliary factors, can interact with overlapping sets of transcription factor partners, and exert overlapping functions in cells. SMRT is subject to negative regulation by MAPK signaling pathways operating downstream of growth factor and stress signaling pathways. We report here that whereas activation of MEKK1 leads to phosphorylation of SMRT, its dissociation from its transcription factor partners in vivo and in vitro, and its redistribution from the cell nucleus to a cytoplasmic compartment, N-CoR is refractory to all these forms of regulation. In contrast to this MAPK cascade, other signal transduction pathways operating downstream of growth factor/cytokine receptors appear able to affect both corepressor paralogs. Our results indicate that SMRT and N-CoR are embedded in distinct regulatory networks and that the two corepressors interpret growth factor, cytokine, differentiation, and prosurvival signals differently.

Received for publication, September 2, 2004 , and in revised form, October 14, 2004.

^* This work was supported in part by United States Public Health Service Grant DK53528 from NIDDK, National Institutes of Health. 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 United States Public Health Service Predoctoral Training Award T32GM07377 from the NIGMS, National Institutes of Health/University of California Davis Physician Scientist Training Program.

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

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