B56 Regulatory Subunit of Protein Phosphatase 2A Mediates Valproic Acid-Induced p300 Degradation

Abstract

Transcriptional coactivator p300 is required for embryonic development and cell proliferation. Valproic acid, a histone deacetylase inhibitor, is widely used in the therapy of epilepsy and bipolar disorder. However, it has intrinsic teratogenic activity through unidentified mechanisms. We report that valproic acid stimulates proteasome-dependent p300 degradation through augmentation of gene expression of the B56γ regulatory subunits of protein phosphatase 2A. The B56γ3 regulatory and catalytic subunits of protein phosphatase 2A interact with p300. Overexpression of the B56γ3 subunit leads to proteasome-mediated p300 degradation and represses p300-dependent transcriptional activation, which requires the B56γ3 interaction domain of p300. Conversely, silencing of the B56γ subunit expression by RNA interference increases the stability and transcriptional activity of the coactivator. Our study establishes the functional interaction between protein phosphatase 2A and p300 activity and provides direct evidence for signal-dependent control of p300 function.

ACKNOWLEDGMENTS

We thank V. Giguere, M. O. Hottiger, M. A. Ikeda, and T. Perlmann for plasmids. We also thank C. Kamibayashi for antibody and M. A. R. Abed for expertise.

This work was supported in part by operating grants from Canadian Institutes of Health Research (CIHR) and The Cancer Research Society, Inc. During the course of this study, Q.L. was supported by scholarships from CIHR.