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Mage-A Cancer/Testis Antigens Inhibit p53 Function by Blocking Its Interaction with Chromatin

Mage-A Cancer/Testis Antigens Inhibit p53 Function by Blocking Its Interaction with Chromatin

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Authors

  • Lynnette Marcar
  • Nicola J. MacLaine
  • Ted R. Hupp
  • David W. Meek (Lead / Corresponding author)

Research units

    Info

    Original languageEnglish
    Pages10362-10370
    Number of pages9
    JournalCancer Research
    Journal publication date15 Dec 2010
    Journal number24
    Volume70
    DOIs
    StatePublished

    Abstract

    The p53 tumor suppressor plays a major protective role in tumor prevention by coordinating changes in gene expression that lead to the elimination of cancer cells. Mage-A proteins comprise a family of metastasis-associated transcriptional regulators that potently inhibit p53 function. Here, we show that Mage-A interacts with 3 distinct peptides each of which is located within the DNA binding surface of the core domain of p53 and encompasses amino acids that are critical for site-specific DNA binding. These data suggest that Mage-A may block the association of p53 with its cognate sites in chromatin. Consistent with this idea, silencing of Mage-A expression leads to upregulation of several p53-responsive genes in a p53-dependent manner and stimulates by several fold the interaction of p53 with the p21, MDM2, and PUMA promoters. Notably, these effects can occur in the absence of genotoxic stress, leading in a p53-dependent manner, to cell-cycle delay and increased cell death. These data reveal a novel mechanism by which Mage-A proteins may suppress the p53 transcriptional program during tumor development and highlight the p53/Mage-A interaction as a prospective therapeutic target. Cancer Res; 70( 24); 10362-70. (C)2010 AACR.

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