p53 cannot be induced by hypoxia alone but responds to the hypoxic microenvironment
p53 cannot be induced by hypoxia alone but responds to the hypoxic microenvironment
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DOI：
10.1038/sj.onc.1207657
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发表时间：
2004-06-24
期刊：
影响因子：
8
通讯作者：
Simon, MC
中科院分区：
文献类型：
--
作者：
Pan, Y;Oprysko, PR;Simon, MC
由于血液供应不足，实体瘤常含有缺氧亚区。在这些区域，细胞可以经历依赖于P53的凋亡。因此，低氧被认为是P53积聚和激活的生理刺激。在这样的环境中，p53突变细胞表现出选择性生长优势。P53的低氧调节被认为是低氧诱导因子(HIF)依赖的；然而，对于低氧(O-2)本身是否以及在多大程度上提高P53蛋白的稳定性，仍存在争议。在这里，我们研究了几个表达不同HIF-α蛋白的细胞系对低氧和低氧模拟物的P53反应。大多数细胞在低氧模拟物如甲磺酸去铁胺和CoCl2的作用下表现出高水平的P53，而与其HIF-α蛋白表达谱无关。然而，在从1.5%到不到0.02%的O-2水平范围内，我们未能在任何被测试的细胞系中观察到P53积聚或P53核转位。只有在缺氧和酸中毒/营养剥夺的组合处理后，一些细胞才显示出P53的诱导。我们的结果表明，虽然低氧在体内诱导了P53的积累，但由于低氧的巴斯德效应(而不是低氧本身)引起的酸中毒等继发性效应是P53积累所必需的。因此，在细胞的缺氧反应中，HIF-1α和P53蛋白的表达不是偶联的。
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.