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Molecular and Cellular Biology, September 2000, p. 6904-6912, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Regulation of Histone Deacetylase 4 by Binding of 14-3-3 Proteins

Audrey H. Wang,1 Michael J. Kruhlak,2 Jiong Wu,3 Nicholas R. Bertos,1 Marko Vezmar,1 Barry I. Posner,3 David P. Bazett-Jones,2 and Xiang-Jiao Yang1,*

Molecular Oncology Group, Department of Medicine, McGill University Health Centre,1 and Polypeptide Hormone Laboratory, Faculty of Medicine, McGill University,3 Montréal, Québec H3A 1A1, and Department of Cell Biology and Anatomy, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1,2 Canada

Received 22 February 2000/Returned for modification 4 April 2000/Accepted 22 June 2000

Histone (de)acetylation is important for the regulation of fundamental biological processes such as gene expression and DNA recombination. Distinct classes of histone deacetylases (HDACs) have been identified, but how they are regulated in vivo remains largely unexplored. Here we describe results demonstrating that HDAC4, a member of class II human HDACs, is localized in the cytoplasm and/or the nucleus. Moreover, we have found that HDAC4 interacts with the 14-3-3 family of proteins that are known to bind specifically to conserved phosphoserine-containing motifs. Deletion analyses suggested that S246, S467, and S632 of HDAC4 mediate this interaction. Consistent with this, alanine substitutions of these serine residues abrogated 14-3-3 binding. Although these substitutions had minimal effects on the deacetylase activity of HDAC4, they stimulated its nuclear localization and thus led to enhanced transcriptional repression. These results indicate that 14-3-3 proteins negatively regulate HDAC4 by preventing its nuclear localization and thereby uncover a novel regulatory mechanism for HDACs.

* Corresponding author. Mailing address: Molecular Oncology Group, Royal Victoria Hospital, Room H5.41, McGill University Health Centre, 687 Pine Ave. West, Montréal, Québec H3A 1A1, Canada. Phone: (514) 842-1231 ext. 4490. Fax: (514) 843-1478. E-mail: yangxj{at}lan1.molonc.mcgill.ca.

Molecular and Cellular Biology, September 2000, p. 6904-6912, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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