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Molecular and Cellular Biology, April 2005, p. 2673-2687, Vol. 25, No. 7
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.7.2673-2687.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phosphorylation-Dependent Degradation of p300 by Doxorubicin-Activated p38 Mitogen-Activated Protein Kinase in Cardiac Cells

Coralie Poizat,1* Pier Lorenzo Puri,2,3 Yan Bai,1 and Larry Kedes1

Institute for Genetic Medicine and Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles,1 The Burnham Institute, La Jolla,2 California, and Laboratory of Gene Expression, Dulbecco Telethon Institute at Fondazione A. Cesalpino, Institute of Cell Biology and Tissue Engineering, Rome, Italy3

Received 6 May 2004/ Returned for modification 12 July 2004/ Accepted 27 December 2004

p300 and CBP are general transcriptional coactivators implicated in different cellular processes, including regulation of the cell cycle, differentiation, tumorigenesis, and apoptosis. Posttranslational modifications such as phosphorylation are predicted to select a specific function of p300/CBP in these processes; however, the identification of the kinases that regulate p300/CBP activity in response to individual stimuli and the physiological significance of p300 phosphorylation have not been elucidated. Here we demonstrate that the cardiotoxic anticancer agent doxorubicin (adriamycin) induces the phosphorylation of p300 in primary neonatal cardiomyocytes. Hyperphosphorylation precedes the degradation of p300 and parallels apoptosis in response to doxorubicin. Doxorubicin-activated p38 kinases {alpha} and ß associate with p300 and are implicated in the phosphorylation-mediated degradation of p300, as pharmacological blockade of p38 prevents p300 degradation. p38 phosphorylates p300 in vitro at both the N and C termini of the protein, and enforced activation of p38 by the constitutively active form of its upstream kinase (MKK6EE) triggers p300 degradation. These data support the conclusion that p38 mitogen-activated protein kinase regulates p300 protein stability and function in cardiomyocytes undergoing apoptosis in response to doxorubicin.

* Corresponding author. Mailing address: Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, 2250 Alcazar St., CSC 245, Los Angeles, CA 90033. Phone: (323) 442-2099. Fax: (323) 442-2764. E-mail: poizat{at}usc.edu.

Molecular and Cellular Biology, April 2005, p. 2673-2687, Vol. 25, No. 7
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.7.2673-2687.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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