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首页> 外文期刊>Nature >Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha.
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Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha.

机译：缺氧诱导因子1alpha稳定野生型p53。

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Although hypoxia (lack of oxygen in body tissues) is perhaps the most physiological inducer of the wild-type p53 gene, the mechanism of this induction is unknown. Cells may detect low oxygen levels through a haem-containing sensor protein. The hypoxic state can be mimicked by using cobalt chloride and the iron chelator desferrioxamine: like hypoxia, cobalt chloride and desferrioxamine activate hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulates the transcription of several genes that are associated with hypoxia. Here we show that these treatments induce accumulation of wild-type p53 through HIF-1alpha-dependent stabilization of p53 protein. Induction of p53 does not occur in either a mutant hepatoma cell line that is unable to induce HIF-1alpha or embryonic stem cells derived from mice lacking HIF-1beta. HIF-1alpha is found in p53 immunoprecipitates from MCF7 cells that express wild-type p53 and are either hypoxic or have been exposed to desferrioxamine. Similarly, anti-haemagglutinin immunoprecipitates from lysates of normoxic PC3M cells that had been co-transfected with haemagglutinin-tagged HIF-1alpha and wild-type p53 also contain p53. Transfection of normoxic MCF7 cells with HIF-1alpha stimulates a co-transfected p53-dependent reporter plasmid and increases the amount of endogenous p53. Our results suggest that hypoxic induction of transcriptionally active wild-type p53 is achieved as a result of the stabilization of p53 by its association with HIF-1alpha.
机译：尽管缺氧（人体组织中缺氧）可能是野生型p53基因的最生理诱导剂，但这种诱导的机制尚不清楚。细胞可以通过含血红素的传感器蛋白检测低氧水平。缺氧状态可以通过使用氯化钴和铁螯合剂去铁胺来模拟：像缺氧一样，氯化钴和去铁胺激活缺氧诱导因子1α（HIF-1alpha），从而刺激与缺氧相关的几个基因的转录。在这里，我们显示这些治疗通过p53蛋白的HIF-1alpha依赖性诱导诱导野生型p53的积累。在不能诱导HIF-1alpha的突变肝癌细胞系或衍生自缺乏HIF-1beta的小鼠的胚胎干细胞中，不会发生p53的诱导。在表达野生型p53的MCF7细胞的p53免疫沉淀物中发现了HIF-1alpha，该细胞要么低氧，要么已暴露于去铁敏。类似地，来自常氧PC3M细胞裂解物的抗血凝素免疫沉淀物已经被血凝素标记的HIF-1alpha和野生型p53共转染，也含有p53。用HIF-1alpha转染常氧MCF7细胞会刺激共转染p53依赖的报告质粒，并增加内源性p53的量。我们的结果表明，由于p53与HIF-1alpha缔合而使p53稳定，从而实现了对转录活性野生型p53的低氧诱导。

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