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Molecular and Cellular Biology, January 2005, p. 525-532, Vol. 25, No. 2
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.2.525-532.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Jihong Chen,1 Jonathan R. St-Germain,1 and Qiao Li1,2*

Ottawa Health Research Institute,1 Departments of Cellular and Molecular Medicine and of Medicine, University of Ottawa, Ottawa, Ontario, Canada2

Received 18 August 2004/ Returned for modification 7 September 2004/ Accepted 18 October 2004

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 B56{gamma} regulatory subunits of protein phosphatase 2A. The B56{gamma}3 regulatory and catalytic subunits of protein phosphatase 2A interact with p300. Overexpression of the B56{gamma}3 subunit leads to proteasome-mediated p300 degradation and represses p300-dependent transcriptional activation, which requires the B56{gamma}3 interaction domain of p300. Conversely, silencing of the B56{gamma} 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.

* Corresponding author. Mailing address: Ottawa Health Research Institute, 725 Parkdale Ave., Ottawa, Ontario, Canada K1Y 4E9. Phone: (613) 798-5555, ext. 13454. Fax: (613) 761-5036. E-mail: qli{at}ohri.ca.

Molecular and Cellular Biology, January 2005, p. 525-532, Vol. 25, No. 2
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.2.525-532.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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