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首页> 外文期刊>Molecular and Cellular Biology >Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin
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Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin

机译：雷帕霉素哺乳动物靶标对缺氧诱导因子1α表达和功能的调节

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Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor containing an inducibly expressed HIF-1α subunit and a constititutively expressed HIF-1β subunit. Under hypoxic conditions, the HIF-1α subunit accumulates due to a decrease in the rate of proteolytic degradation, and the resulting HIF-1α-HIF-1β heterodimers undergo posttranslational modifications that promote transactivation. Recent studies suggest that amplified signaling through phosphoinositide 3-kinase, and its downstream target, mTOR, enhances HIF-1-dependent gene expression in certain cell types. In the present study, we have explored further the linkage between mTOR and HIF-1 in PC-3 prostate cancer cells treated with hypoxia or the hypoxia mimetic agent, CoCl2. Pretreatment of PC-3 cells with the mTOR inhibitor, rapamycin, inhibited both the accumulation of HIF-1α and HIF-1-dependent transcription induced by hypoxia or CoCl2. Transfection of these cells with wild-type mTOR enhanced HIF-1 activation by hypoxia or CoCl2, while expression of a rapamycin-resistant mTOR mutant rendered both HIF-1α stabilization and HIF-1 transactivating function refractory to inhibition by rapamycin. Studies with GAL4-HIF-1α fusion proteins pinpointed the oxygen-dependent degradation domain as a critical target for the rapamycin-sensitive, mTOR-dependent signaling pathway leading to HIF-1α stabilization by CoCl2. These studies position mTOR as an upstream activator of HIF-1 function in cancer cells and suggest that the antitumor activity of rapamycin is mediated, in part, through the inhibition of cellular responses to hypoxic stress.
机译：缺氧诱导因子1（HIF-1）是一种异二聚体转录因子，包含一个诱导表达的HIF-1α亚基和一个组成性表达的HIF-1β亚基。在缺氧条件下，由于蛋白水解降解速率的降低，HIF-1α亚基会积累，所得的HIF-1α-HIF-1β异二聚体会经历翻译后修饰，从而促进反式激活。最近的研究表明，通过磷酸肌醇3-激酶及其下游靶标mTOR放大的信号传导增强了某些细胞类型中HIF-1依赖性基因的表达。在本研究中，我们进一步探讨了缺氧或缺氧模拟剂CoCl 2 处理的PC-3前列腺癌细胞中mTOR与HIF-1之间的联系。用mTOR抑制剂雷帕霉素预处理PC-3细胞可抑制缺氧或CoCl 2 诱导的HIF-1α和HIF-1依赖性转录的积累。用野生型mTOR转染这些细胞可增强缺氧或CoCl 2 对HIF-1的激活，而表达雷帕霉素抗性mTOR突变体则使HIF-1α稳定和HIF-1反激活功能对雷帕霉素的抑制作用。 GAL4-HIF-1α融合蛋白的研究指出，氧依赖性降解结构域是雷帕霉素敏感，mTOR依赖性信号转导途径导致CoCl 2 稳定HIF-1α的关键靶标。这些研究将mTOR定位为癌细胞中HIF-1功能的上游激活剂，并表明雷帕霉素的抗肿瘤活性部分是通过抑制细胞对低氧应激的应答来介导的。

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