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

Abstract

<div>Abstract<p>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 <i>p21, MDM2</i>, and <i>PUMA</i> 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. <i>Cancer Res; 70(24); 10362–70. ©2010 AACR.</i></p></div>