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Molecular and Cellular Biology, December 2000, p. 8643-8654, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Proteasome-Mediated Degradation of the Coactivator p300 Impairs Cardiac Transcription

Coralie Poizat,1 Vittorio Sartorelli,2 Gene Chung,1 Robert A. Kloner,3,4 and Larry Kedes1,4,*

Institute for Genetic Medicine and Department of Biochemistry & Molecular Biology1 and Department of Medicine,4 Keck School of Medicine of the University of Southern California, and The Heart Institute, Good Samaritan Hospital and Division of Cardiology,3 Los Angeles, California, and Laboratory of Physical Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 208922

Received 23 March 2000/Returned for modification 8 May 2000/Accepted 29 August 2000

The transcription of tissue-specific genes is controlled by regulatory factors and cofactors and is suppressed in cardiac cells by the antineoplastic agent doxorubicin. Here we show that exposure of cultured cardiomyocytes to doxorubicin resulted in the rapid depletion of transcripts for MEF2C, dHAND, and NKX2.5, three pivotal regulators of cardiac gene expression. Delivery of exogenous p300, a coactivator of MEF2C and NKX2.5 in cardiomyocytes, restored cardiac transcription despite the presence of doxorubicin. Furthermore, p300 also restored the accumulation of transcripts for MEF2C itself. Importantly, cardiocytes exposed to doxorubicin displayed reduced levels of p300 proteins. This was not due to alterations in the level of p300 transcripts; rather, and surprisingly, doxorubicin promoted selective degradation of p300 mediated by the 26S-proteasome machinery. Doxorubicin had no effect on the general level of ubiquitinated proteins or on the levels of beta -catenin, a protein known to be degraded by proteasome-mediated degradation. These results provide evidence for a new mechanism of transcriptional repression caused by doxorubicin in which the selective degradation of p300 results in reduced p300-dependent transcription, including production of MEF2C mRNA.

* Corresponding author. Mailing address: Institute for Genetic Medicine, USC School of Medicine, 2250 Alcazar Street, Los Angeles, CA 90033. Phone: (323) 442-1144. Fax: (323) 442-2764. E-mail: kedes{at}hsc.usc.edu.

Molecular and Cellular Biology, December 2000, p. 8643-8654, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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