University of Cambridge > Talks.cam > Cellular Genetic Disease Seminar > The p53 family in the cancer cell response to hypoxia

The p53 family in the cancer cell response to hypoxia

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Host: Dr Paolo D'Avino (ppd21@cam.ac.uk)

The p53 family of tumour suppressors (p53, p73, p63) has an essential role in the response to cellular stress and somatic cells largely rely on p53 and its siblings to overcome toxic insult and to maintain homeostasis. Inactivation of p53 (i.e. TP53 gene mutations) and deregulation of p73 and p63 are frequently observed in cancer, altering the response to cellular stressors and consequent direct implications for disease pathogenesis. Hypoxia (reduced O2) is a tumour microenvironmental factor commonly observed in advanced cancers. Hypoxia and its major regulator the Hypoxia-inducible Factor-1 (HIF-1) have long been associated with resistance to therapy, metastasis, and poor survival rates in cancer patients.

Our work demonstrated that the tumour suppressor TAp73 opposes HIF -1 activation in cancer cells, resulting in reduced angiogenesis and tumor progression. This new mechanism of control of HIF -1 protein stability has clinical implications as TAp73/HIF-1 axis correlates with stage and prognosis of the disease. The complexity of the interplay between the p53 family and the HIF -1 was further highlighted by our discovery of novel gain-of-function effect of p53 mutants in hypoxic tumours. We demonstrated that p53 mutants impinge on the HIF -1 transcriptional capability regulating a selective hypoxic-gene expression reponse, involved in pro-tumorigenic non-cell-autonomous functions. Overall our findings shed light on the complex interfamily crosstalk p53 family/HIF indicating this as a molecular axis of major relevance in cancer pathogenesis.

This talk is part of the Cellular Genetic Disease Seminar series.

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