title: 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 G(0)/G(1) 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 p21(WAF1) or HIF-1 protein stabilization, but rather promoted a significant decrease in Ser(392)-site phosphorylation at the CK2/FACT site. However, chemically induced anoxia induced Ser(392)-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 Ser(392) phosphorylation of p53 and elevated p21(WAF1) 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.
authors.affiliation: The Cancer Research UK Laboratories, Department of Molecular and Cellular Pathology, The University of Dundee, Dundee, DD1 9SY, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Achison
authors.forename: Ted R
authors.initials: TR
authors.lastname: Hupp
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D005472:Fluorouracil / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D010766:Phosphorylation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D005472:Fluorouracil