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Molecular and Cellular Biology, June 2009, p. 3355-3366, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.00227-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Direct Interaction between Myocyte Enhancer Factor 2 (MEF2) and Protein Phosphatase 1{alpha} Represses MEF2-Dependent Gene Expression{triangledown} ,{dagger}

R. L. S. Perry,1 C. Yang,1,{ddagger} N. Soora,1 J. Salma,1 M. Marback,1 L. Naghibi,1 H. Ilyas,1 J. Chan,1 J. W. Gordon,1 and J. C. McDermott1,2*

Department of Biology,1 CRMS Department of Chemistry, York University, 4700 Keele St., Toronto, Ontario, Canada M3J 1P32

Received 12 February 2008/ Returned for modification 14 April 2008/ Accepted 1 April 2009

The myocyte enhancer factor 2 (MEF2) transcription factors play important roles in neuronal, cardiac, and skeletal muscle tissues. MEF2 serves as a nuclear sensor, integrating signals from several signaling cascades through protein-protein interactions with kinases, chromatin remodeling factors, and other transcriptional regulators. Here, we report a novel interaction between the catalytic subunit of protein phosphatase 1{alpha} (PP1{alpha}) and MEF2. Interaction occurs within the nucleus, and binding of PP1{alpha} to MEF2 potently represses MEF2-dependent transcription. The interaction utilizes uncharacterized domains in both PP1{alpha} and MEF2, and PP1{alpha} phosphatase activity is not obligatory for MEF2 repression. Moreover, a MEF2-PP1{alpha} regulatory complex leads to nuclear retention and recruitment of histone deacetylase 4 to MEF2 transcription complexes. PP1{alpha}-mediated repression of MEF2 overrides the positive influence of calcineurin signaling, suggesting PP1{alpha} exerts a dominant level of control over MEF2 function. Indeed, PP1{alpha}-mediated repression of MEF2 function interferes with the prosurvival effect of MEF2 in primary hippocampal neurons. The PP1{alpha}-MEF2 interaction constitutes a potent locus of control for MEF2-dependent gene expression, having potentially important implications for neuronal cell survival, cardiac remodeling in disease, and terminal differentiation of vascular, cardiac, and skeletal muscle.

* Corresponding author. Mailing address: Department of Biology, York University, 4700 Keele St., Toronto, Ontario, Canada M3J 1P3. Phone: (416) 736-2100, ext. 30389. Fax: (416) 736-5698. E-mail: jmcderm{at}yorku.ca

{triangledown} Published ahead of print on 13 April 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Mass Spectrometry Facility, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Molecular and Cellular Biology, June 2009, p. 3355-3366, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.00227-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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