Proteasome-mediated degradation of the coactivator p300 impairs cardiac transcription

The transcription of tissue-specific genes is controlled by regulatory fact ors 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, dHAN D, and NKX2.5, three pivotal regulators of cardiac gene expression. Deliver y of exogenous p300, a coactivator of MEF2C and NKX2.5 in cardiomyocytes, r estored cardiac transcription despite the presence of doxorubicin, Furtherm ore, p300 also restored the accumulation of transcripts for MEF2C itself, I mportantly cardiocytes exposed to doxorubicin displayed reduced levels of p 300 proteins. This was not due to alterations in the level of p300 transcri pts; rather, and surprisingly, doxorubicin promoted selective degradation o f p300 mediated by the 26S-proteasome machinery. Doxorubicin had no effect on the general level of ubiquitinated proteins or on the levels of beta -ca tenin, a protein known to be degraded by proteasome-mediated degradation. T hese results provide evidence for a new mechanism of transcriptional repres sion caused by doxorubicin in which the selective degradation of p300 resul ts in reduced p300-dependent transcription, including production of MEF2C m RNA.