Inhibition of P53 Tumour Suppressor Function by Metastasis-Associated Mage-A Proteins

MAGE-A (melanoma antigen) proteins comprise a 12-member sub-family of cancer/testis antigens, so called because, physiologically, they are expressed almost exclusively in the testis, but during the development of a range of cancers (including melanoma where they were initially discovered) their expression is re-activated and is tightly associated with malignancy (i.e. with invasion and metastasis). Experimental evidence supports the idea that they are actually drivers of the malignant phenotype. We, and others, have established that several MAGE-A proteins are potent inhibitors of the p53 tumour suppressor.

The hypothesis of the present study is that inhibition of p53 tumour suppressor function by MAGE-A proteins is a feature of cancer cell development that contributes towards malignancy. The aim of the project is to identify amino acids in MAGE-A2 that are required to make contact with p53 and/or other key regulators of the p53 network. A series of MAGE-A2 mutants will be tested for their ability to associate with p53 in vitro (pulldown assays) and in cultured cells (co-immunoprecipitation assays). They shall also be tested functionally to determine whether they can mediate inhibition of p53 function/signalling and whether they are able to block p53-mediated apoptosis. Based on these analyses, further fine-tuning analysis will be conducted by generating and testing appropriate point mutations. These analyses will be an integral component of ongoing studies aimed at establishing the mechanism of p53 inhibition by MAGE-A and identifying interacting regions/domains that can be explored as potential therapeutic targets.

Dr David Meek
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