期刊
ONCOGENE
卷 23, 期 29, 页码 4975-4983出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1207657
关键词
hypoxia; anoxia; p53; HIF; tumor cells
资金
- NCI NIH HHS [P01-CA79862] Funding Source: Medline
- PHS HHS [66310] Funding Source: Medline
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 CoCl2, 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据