November 2018: p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression

Posted by he28 at Apr 24, 2019 10:45 AM |
Studies carried out by researchers from Cambridge University supported by the Division of Biomedical Services led by Ivano Amelio's research group.

Expression in cancer cells of novel proteins generated by mutations in the TP53 gene is an important prognostic factor; however, how p53 mutants promote cancer progression is largely unknown. Here, we describe a molecular mechanism of gain-of-function by mutant p53 in hypoxic non-small cell lung cancer (NSCLC) cells. We identified the existence of a hypoxia-inducible factor-1 (HIF-1)/mutant p53 complex, exerting transcriptional control of a specific subset of protumorigenic genes, codifying for extracellular matrix (ECM) components. Employing in vivo cancer models and analyzing clinical material, we demonstrate that these ECM components substantially contribute to the synergistic protumorigenic activity of p53 mutants and HIF-1. Our data indicate that HIF-1/mutant p53 cross-talk is an innovative potential therapeutic target to treat advanced NSCLC.

Please visit the PNAS website for the full article.

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