Mage-A cancer/testis antigens inhibit p53 function by blocking its interaction with chromatin.
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.
Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
Lynnette
L
Marcar
Nicola J
NJ
Maclaine
Ted R
TR
Hupp
David W
DW
Meek
D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology*; D012516:Osteosarcoma / Q000235:genetics / Q000276:immunology*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000951:Antigens, Neoplasm; D002843:Chromatin; C420909:Mage-a2 antigen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53