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PCAF is an HIF-1α cofactor that regulates p53 transcriptional activity in hypoxia

Oncogene volume 27, pages 5785–5796 (2008)Cite this article

Abstract

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 p21WAF-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-1α (HIF-1α) in hypoxic conditions and that the acetylated HIF-1α 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-1α.

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Acknowledgements

We thank W El-Deiry for providing the BID-p53-Luc reporter construct; I Talianidis for the Flag-PCAF and Flag-PCAF-ΔHAT constructs; T Halazonetis for the p53K320R expression vector; K Williams for the HIF-1α-responsive reporters of VEGF-Luc, CA-IX-Luc, PGK-1-Luc and LDH-A-Luc; M Blaylock and the Paterson Institute for Cancer Research for assistance with FACS analysis. Our research was supported by the School of Pharmacy, University of Manchester (CD), Cancer Research UK (CDive), MRC programme grant (G0500366) to IJS and Wellcome Trust (069024) to MKD.

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  1. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK

    G Xenaki, T Ontikatze, R Rajendran, I J Stratford, C Dive & C Demonacos

  2. Paterson Institute for Cancer Research, University of Manchester, Manchester, UK

    C Dive

  3. Faculty of Life Sciences, University of Manchester, Manchester, UK

    M Krstic-Demonacos

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  1. G Xenaki
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Correspondence to C Demonacos.

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Xenaki, G., Ontikatze, T., Rajendran, R. et al. PCAF is an HIF-1α cofactor that regulates p53 transcriptional activity in hypoxia. Oncogene 27, 5785–5796 (2008). https://doi.org/10.1038/onc.2008.192

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