Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge.
Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge.
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DOI：
10.1111/cas.13483
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发表时间：
2018-03
期刊：
影响因子：
5.7
通讯作者：
Harada H
中科院分区：
文献类型：
--
作者：
Koyasu S;Kobayashi M;Goto Y;Hiraoka M;Harada H
缺氧诱导因子1（HIF-1）是与细胞对缺氧的适应性反应相关的多种基因的转录激活因子。HIF-1活性调节系统的功能障碍与包括恶性肿瘤在内的多种疾病的发病机制有关，因此，迫切需要阐明HIF-1活化的分子机制，以开发新的抗癌策略。氧依赖性和泛素介导的HIF-1调节亚基（HIF-1α）蛋白水解的重要性于1997年首次报道。从那时起，越来越多的证据表明，HIF-1α即使在常氧条件下也可能变得稳定和活跃;例如，当某些基因中与疾病相关的遗传和功能改变触发HIF-1的异常激活时，无论氧气条件如何。我们在此回顾了自1997年以来近二十年的知识，从传统的氧和蛋白水解依赖性机制到癌症相关遗传和功能改变介导机制的最新信息，对HIF-1活性的调节机制进行了研究。
Hypoxia‐inducible factor 1 (HIF‐1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF‐1 activity have been implicated in the pathogenesis of various diseases including malignant tumors and, thus, elucidating the molecular mechanisms underlying the activation of HIF‐1 is eagerly desired for the development of novel anti‐cancer strategies. The importance of oxygen‐dependent and ubiquitin‐mediated proteolysis of the regulatory subunit of HIF‐1 (HIF‐1α) was first reported in 1997. Since then, accumulating evidence has shown that HIF‐1α may become stable and active even under normoxic conditions; for example, when disease‐associated genetic and functional alterations in some genes trigger the aberrant activation of HIF‐1 regardless of oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF‐1 activity from conventional oxygen‐ and proteolysis‐dependent mechanisms to up‐to‐the‐minute information on cancer‐associated genetic and functional alteration‐mediated mechanisms.
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