The transcriptional co-activators CREB-binding protein (CBP) and p300 play a critical role in cardiac hypertrophy that is dependent on their histone acetyltransferase activity.
The CBP and p300 proteins are transcriptional co-activators that are involved in a variety of transcriptional pathways in development and in response to specific signaling pathways. We have previously demonstrated that the ability of both these factors to stimulate transcription is greatly enhanced by treatment of cardiac cells with the hypertrophic agent phenylephrine (PE). Here, we show that inhibition of either CBP or p300 with antisense or dominant negative mutant constructs inhibits PE-induced hypertrophy as assayed by atrial naturetic protein production, cardiac cell protein:DNA ratio and cell size. Furthermore, we show that overexpression of CBP or p300 can induce hypertrophy and that this effect requires their histone acetyltransferase (HAT) activity. Moreover, we show that PE can directly enhance CBP HAT activity and that artificial enhancement of HAT activity is sufficient to induce hypertrophy. Hence, CBP and p300 play an essential role in hypertrophy induced by PE, and this effect is mediated via PE-induced enhancement of their HAT activity. This is the first time a role for these factors, and their HAT activity, in hypertrophy has been directly demonstrated.
Gusterson
Rosalind J
RJ
Institute of Child Health, University College London, 30 Guilford St., London WC1N 1EH, United Kingdom.
Jazrawi
Elen
E
Adcock
Ian M
IM
Latchman
David S
DS
D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D050882:CREB-Binding Protein; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002469:Cell Separation; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D050881:E1A-Associated p300 Protein; D005434:Flow Cytometry; D005799:Genes, Dominant; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D051548:Histone Acetyltransferases; D006984:Hypertrophy; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000166:cytology; D009687:Nuclear Proteins / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D002316:Cardiotonic Agents; D016895:Culture Media, Serum-Free; D008164:Luminescent Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D049452:Green Fluorescent Proteins; D010656:Phenylephrine; D008156:Luciferases; D000123:Acetyltransferases; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat; D051548:Histone Acetyltransferases