PCAF is an HIF-1alpha cofactor that regulates p53 transcriptional activity in hypoxia.
The p53 tumour suppressor is involved in several crucial cellular functions including cell-cycle arrest and apoptosis. p53 stabilization occurs under hypoxic and DNA damage conditions. However, only in the latter scenario is stabilized p53 capable of inducing the expression of its pro-apoptotic targets. Here we present evidence that under hypoxia-mimicking conditions p53 acetylation is reduced to a greater extent at K320 site targeted by P300/CBP-associated factor (PCAF) than at K382 site targeted by p300/CBP. The limited amounts of acetylated p53 at K320 are preferentially recruited to the promoter of the p21(WAF-1/CIP-1) gene, which appears to be unaffected by hypoxia, but are not recruited to the BID promoter and hence p53 is incapable of upregulating pro-apoptotic BID in hypoxic conditions. As the K320 p53 acetylation is the site predominantly affected in hypoxia, the PCAF histone acetyltransferase activity is the key regulator of the cellular fate modulated by p53 under these conditions. In addition, we provide evidence that PCAF acetylates hypoxia-inducible factor-1alpha (HIF-1alpha) in hypoxic conditions and that the acetylated HIF-1alpha is recruited to a particular subset of its targets. In conclusion, PCAF regulates the balance between cell-cycle arrest and apoptosis in hypoxia by modulating the activity and protein stability of both p53 and HIF-1alpha.
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
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Xenaki
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Ontikatze
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Rajendran
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Stratford
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Dive
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Krstic-Demonacos
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Demonacos
D000107:Acetylation; D017209:Apoptosis / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D050759:Cyclin-Dependent Kinase Inhibitor p21; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C493956:CDKN1A protein, human; C497442:HIF1A protein, human