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J. Biol. Chem., Vol. 281, Issue 46, 35070-35080, November 17, 2006

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-Actinin 4 Potentiates Myocyte Enhancer Factor-2 Transcription Activity by Antagonizing Histone Deacetylase 7^*

Sharmistha Chakraborty, Erin L. Reineke¹, Minh Lam, Xiaofang Li², Yu Liu, Chengzhuo Gao, Simran Khurana, and Hung-Ying Kao, An American Cancer Society Research Scholar³

From the Department of Biochemistry, School of Medicine, Case Western Reserve University and the Research Institute of University Hospitals of Cleveland and the Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106

Histone deacetylase 7 (HDAC7) is a member of class IIa HDACs that regulate myocyte enhancer factor-2 (MEF2)-mediated transcription and participate in multiple cellular processes such as T cell apoptosis. We have identified -actinin 1 and 4 as class IIa HDAC-interacting proteins. The interaction domains are mapped to C terminus of -actinin 4 and amino acids 72-172 of HDAC7. A point mutation in HDAC7 that disrupts its association with MEF2A also disrupts its association with -actinin 4, indicating that MEF2A and -actinin 4 binding sites largely overlap. We have also isolated a novel splice variant of -actinin 4 that is predominantly localized in the nucleus, a pattern distinct from the full-length -actinin 4, which is primarily distributed in the cytoplasm and plasma membrane. Using small interfering RNA, chromatin immunoprecipitation, and transient transfection assays, we show that -actinin 4 potentiates expression of TAF55, a putative MEF2 target gene. Loss of MEF2A interaction correlates with loss of the ability of -actinin 4 to potentiate TAF55 promoter activity. Ectopic expression of -actinin 4, but not the mutant defective in MEF2A association, leads to disruption of HDAC7·MEF2A association and enhancement of MEF2-mediated transcription. Taken together, we have identified a novel mechanism by which HDAC7 activity is negatively regulated and uncovered a previously unknown function of -actinin 4.

Received for publication, March 16, 2006 , and in revised form, September 14, 2006.

^* This project was supported by American Heart Association Grant 0330311N and NIDDK, National Institutes of Health Grant R01 DK62985 (to H.-Y. K.). 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.

¹ Supported by the Case Comprehensive Cancer Center, NCI, National Institutes of Health Research Oncology Training Grant T32 CA059366-11.

² Present address: College of Life Science, East China Normal University, 3663 N. Zhongshan Rd., Shanghai 200062, China.

³ To whom correspondence should be addressed: Dept. of Biochemistry and the Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Tel.: 216-368-1150; Fax: 216-368-1597; E-mail: hxk43{at}po.cwru.edu.

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