The RNA helicase p68 modulates expression and function of the Delta 133 isoform(s) of p53, and is inversely associated with Delta 133p53 expression in breast cancer

H. C. Moore, L. B. Jordan, S. E. Bray, L. Baker, P. R. Quinlan, C. A. Purdie, A.M. Thompson, J-C Bourdon, F.V. Fuller-Pace (Lead / Corresponding author)

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    24 Citations (Scopus)

    Abstract

    The RNA helicase p68 is a potent co-activator of p53-dependent transcription in response to DNA damage. Previous independent studies have indicated that p68 and the Delta 133p53 isoforms, which modulate the function of full-length p53, are aberrantly expressed in breast cancers. Here we identify a striking inverse association of p68 and Delta 133p53 expression in primary breast cancers. Consistent with these findings, small interfering RNA depletion of p68 in cell lines results in a p53-dependant increase of Delta 133p53 in response to DNA damage, suggesting that increased Delta 133p53 expression could result from downregulation of p68 and provide a potential mechanistic explanation for our observations in breast cancer. Delta 133p53 alpha, which has been shown to negatively regulate the function of full-length p53, reciprocally inhibits the ability of p68 to stimulate p53-dependent transcription from the p21 promoter, suggesting that Delta 133p53 alpha may be competing with p68 to regulate p53 function. This hypothesis is underscored by our observations that p68 interacts with the C-terminal domain of p53, co-immunoprecipitates 133p53 alpha from cell extracts and interacts only with p53 molecules that are able to form tetramers. These data suggest that p68, p53 and 133p53 alpha may form part of a complex feedback mechanism to regulate the expression of Delta 133p53, with consequent modification of p53-mediated transcription, and may modulate the function of p53 in breast and other cancers that harbour wild-type p53. Oncogene (2010) 29, 6475-6484; doi:10.1038/onc.2010.381; published online 6 September 2010

    Original languageEnglish
    Pages (from-to)6475-6484
    Number of pages10
    JournalOncogene
    Volume29
    Issue number49
    DOIs
    Publication statusPublished - Dec 2010

    Keywords

    • breast cancer
    • p68 RNA helicase
    • p53
    • Delta 133p53
    • gene expression/regulation
    • TUMOR-SUPPRESSOR P53
    • ESTROGEN-RECEPTOR-ALPHA
    • TRANSCRIPTIONAL COACTIVATOR
    • RIBOSOMAL-RNA
    • DNA-DAMAGE
    • BOX
    • PROTEINS
    • GENE
    • DIFFERENTIATION
    • ACTIVATION

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