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

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    Authors
    Xenaki, G
    Ontikatze, T
    Rajendran, R
    Stratford, Ian J
    Dive, Caroline
    Krstic-Demonacos, M
    Demonacos, Costas
    Affiliation
    School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
    Issue Date
    2008-10-02
    
    Metadata
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    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 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.
    Citation
    PCAF is an HIF-1alpha cofactor that regulates p53 transcriptional activity in hypoxia. 2008, 27 (44):5785-96 Oncogene
    Journal
    Oncogene
    URI
    http://hdl.handle.net/10541/68174
    DOI
    10.1038/onc.2008.192
    PubMed ID
    18574470
    Type
    Article
    Language
    en
    ISSN
    1476-5594
    ae974a485f413a2113503eed53cd6c53
    10.1038/onc.2008.192
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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