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RESEARCH PAPER

Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4

¹ H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA; ² Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA; ³ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA

Histone deacetylase 3 (HDAC3) is one of four members of the human class I HDACs that regulates gene expression by deacetylation of histones and nonhistone proteins. Early studies have suggested that HDAC3 activity is regulated by association with the corepressors N-CoR and SMRT. Here we demonstrate that, in addition to protein–protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser⁴²⁴, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity. Interestingly, unlike other class I HDACs, HDAC3 uniquely copurifies with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4_c/PP4_R1). Furthermore, HDAC3 complexes displayed protein phosphatase activity and a series of subsequent mutational analyses revealed that the N terminus of HDAC3 (residues 1–122) was both necessary and sufficient for HDAC3–PP4_c interactions. Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4_c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4_c. These findings therefore further highlight the importance of protein–protein interactions and extend the significance of dephosphorylation in the regulation of HDAC activity, as well as present a novel alternative pathway by which HDAC3 activity is regulated.

[Keywords: HDAC3; histone deacetylation; protein phosphatase; PP4]

Received December 2, 2004; revised version accepted February 7, 2005.

⁴ These authors contributed equally to this work.

⁵ Corresponding author.

E-MAIL setoe{at}moffitt.usf.edu; FAX (813) 979-7264.

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