p53 cannot be induced by hypoxia alone but responds to the hypoxic microenvironment

Solid tumors frequently contain hypoxic subregions due to insufficient blood supply. In these domains, cells can undergo p53-dependent apoptosis. Therefore, hypoxia has been implicated as a physiological stimulus for p53 accumulation and activation. In such an environment, p53 mutant cells exhibit a selective growth advantage. Hypoxic regulation of p53 has been proposed to be hypoxia inducible factor (HIF) dependent; however, controversy remains over whether and to what extent low oxygen (O(2)) tension by itself enhances p53 protein stability. Here, we examined the p53 response to hypoxia and hypoxia mimetics in several cell lines expressing different HIF-alpha proteins. Most cells exhibited elevated levels of p53 in response to hypoxia mimetics such as deferoxamine mesylate and CoCl(2), regardless of their HIF-alpha protein expression profile. However, over a range of O(2) levels, from 1.5% to less than 0.02%, we failed to observe p53 accumulation or p53 nuclear translocation in any cell lines tested. Only after treatment with a combination of hypoxia and acidosis/nutrient deprivation did some cells exhibit p53 induction. Our results suggest that, although hypoxia induces p53 accumulation in vivo, secondary effects such as acidosis caused by a hypoxic Pasteur effect (instead of low O(2) by itself) are necessary for p53 accumulation. Therefore, the expression of HIF-1alpha and p53 proteins is not coupled during the cellular hypoxia response.