Critical role for p53-serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters

Jayne Loughery, Miranda Cox, Linda M. Smith, David W. Meek (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    120 Citations (Scopus)
    159 Downloads (Pure)

    Abstract

    The p53 tumour suppressor is induced by various stress stimuli and coordinates an adaptive gene expression programme leading to growth arrest or cell death. Some stimuli, such as DNA damage, lead to rapid and substantial multisite phosphorylation of p53, nucleated initially through phosphorylation of serine 15. Other stimuli, such as hyper-proliferation, do not stimulate p53-phosphorylation, raising questions regarding the physiological role for phosphorylation. Here, we show that a basal level of Ser15 phosphorylation occurs in both unstimulated cells and cells stimulated pharmacologically to induce p53. p53 in which Ser15 is substituted by alanine (S15A) fails to mediate p53-dependent transcription or growth arrest but can be rescued by substitution with aspartate (S15D: a phospho-mimic). Chromatin immunoprecipitation (ChIP) analyses show that, while wt- and S15A-p53 are detectable on the CDKN1A (p21) promoter (as a representative p53-responsive promoter), S15A-p53 does not stimulate histone acetylation (a measure of chromatin relaxation), nor is its recruitment stimulated, in response to a DNA damage or pharmacological stimulus. These data demonstrate that Ser15 phosphorylation is required for p53 function in the physiological context of p53-responsive promoters and suggest a key and possibly universal role even for low levels of this modification in promoting p53-transcription function.
    Original languageEnglish
    Pages (from-to)7666-7680
    Number of pages15
    JournalNucleic Acids Research
    Volume42
    Issue number12
    Early online date13 Jun 2014
    DOIs
    Publication statusPublished - 8 Jul 2014

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