Ahmed, A; (2011) Regulation of p53-dependent cell death responses in normoxia and hypoxia. Doctoral thesis , UCL (University College London).

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Abstract

Hypoxia, defined as low oxygen tension, is a common characteristic of growing tumours. Tumour cells adapt to their hypoxic microenvironment by inducing angiogenesis and escaping cell death. In doing so, tumour cells become resistant to radiotherapy and many forms of chemotherapy. Hypoxia signalling and angiogenesis is mediated by the hypoxia-inducible factor (HIF) transcriptional complex. HIF can crosstalk to the p53 tumour suppressor protein, a critical regulator of cell cycle and cell death responses to stress. This study aims to understand how cell death responses are regulated in tumour cells by HIF and p53, in normoxia and in hypoxia. Recently, activation of p53 by the small molecule RITA has been investigated. Flow cytometry, comet assays and western blot analysis have been used to reveal a novel p53-dependent DNA damage response that activates cell cycle checkpoints, and induces significant cell death of hypoxic tumour cells. Activation of p53 also achieves anti-angiogenic effects, both in vitro and in vivo by inhibition of HIF-1α protein synthesis and HIF target genes, including VEGF. The MEK-ERK MAPK pathway has also been investigated as a critical modulator of p53-dependent cell death in normoxia and hypoxia. Inhibition of MEK1/2 by the MAPK signalling inhibitor PD98059 significantly inhibits p53 induction and cell death responses by RITA. The anti-tumour effect of p53 activation in response to RITA is therefore dependent on MEK-ERK signalling. By understanding p53 interactions with HIF signalling, and the role of p53 in responding to DNA damage and apoptotic signals, this study has potential to improve the therapeutic targeting of resistant tumours with deregulated angiogenic and cell death pathways.

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