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  • Original Paper
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Hypoxia attenuates the p53 response to cellular damage

Abstract

The tumour suppressor activity of p53 in vivo can be subject to pressure from the physiological stress of hypoxia and we report on the development of a cell system to define the p53-dependent stages in the adaptation of cells to hypoxia. p53+/+ cells exposed to hypoxia exhibited a transient arrest in G2/M, but escaped from this checkpoint and entered a long-term G0/G1 arrest. By contrast, isogenic p53-null cells exposed to hypoxic conditions exhibited a 6–10-fold higher level of apoptosis, suggesting that p53 acts as a survival factor under limiting oxygen concentrations. Surprisingly, hypoxia-dependent growth arrest in p53+/+ cells did not result in either p21WAF1 or HIF-1 protein stabilization, but rather promoted a significant decrease in Ser392-site phosphorylation at the CK2/FACT site. However, chemically induced anoxia induced Ser392-site phosphorylation as well as stabilization of both p53 and HIF-1 proteins. In contrast to hypoxia, 5-flourouracil (5-FU)-induced p53-dependent cell death correlated with enhanced Ser392 phosphorylation of p53 and elevated p21WAF1 protein levels. Hypoxia inhibited 5-FU-induced p53-dependent cell death and attenuated p53 phosphorylation at the ATM and CK2/FACT phosphorylation sites. Although anoxia activates the p53 response, hypoxia silences the p53 transactivation pathway and identifies a physiological signalling model to study mechanisms of p53 inactivation under hypoxic conditions.

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Acknowledgements

This research was funded by the UK Medical Research Council (Career Establishment Grant) and a Programme Grant from the Cancer Research UK. We thank Dr Anna Woodward for critical reading of this manuscript.

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Correspondence to Ted R Hupp.

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Achison, M., Hupp, T. Hypoxia attenuates the p53 response to cellular damage. Oncogene 22, 3431–3440 (2003). https://doi.org/10.1038/sj.onc.1206434

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