Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models.
Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models.
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DOI：
10.1242/dmm.021865
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发表时间：
2015-11
影响因子：
4.3
通讯作者：
van Eeden FJ
中科院分区：
文献类型：
--
作者：
Elks PM;Renshaw SA;Meijer AH;Walmsley SR;van Eeden FJ
低水平的组织氧（缺氧）是从癌症到感染的多种疾病的生理特征。氧敏感性羟化酶是感受细胞缺氧的重要酶，它调节缺氧诱导因子α（HIF-α）转录因子的蛋白质稳定性。当稳定时，HIF-α与其辅因子结合靶基因启动子中的HIF应答元件（HRE），以协调响应低氧环境的广泛转录程序。今年是HIF-1α转录因子发现20周年，近年来，HIF介导的缺氧反应越来越被认为是决定癌症、炎性疾病和细菌感染等疾病结局的重要过程。动物模型揭示了HIF在疾病中的作用，并揭示了涉及多种细胞类型的复杂控制机制，这些观察结果可能在更简单的体外系统中被遗漏。这些发现强调了需要新的疾病全生物体模型来阐明这些复杂的调控机制。在这篇综述中，我们讨论了我们对斑马鱼疾病模型研究中出现的疾病中缺氧和HIF的理解的最新进展。这些模型的发现将HIF确定为疾病过程中不可或缺的参与者。他们还强调了HIF通路的组成部分及其靶点，作为从癌症到传染病的潜在治疗靶点。由HIF介导的缺氧信号传导是许多疾病过程中的关键途径。在这里，我们审查目前的知识HIF信号和疾病，专注于最近的研究结果从斑马鱼模型。
A low level of tissue oxygen (hypoxia) is a physiological feature of a wide range of diseases, from cancer to infection. Cellular hypoxia is sensed by oxygen-sensitive hydroxylase enzymes, which regulate the protein stability of hypoxia-inducible factor α (HIF-α) transcription factors. When stabilised, HIF-α binds with its cofactors to HIF-responsive elements (HREs) in the promoters of target genes to coordinate a wide-ranging transcriptional programme in response to the hypoxic environment. This year marks the 20th anniversary of the discovery of the HIF-1α transcription factor, and in recent years the HIF-mediated hypoxia response is being increasingly recognised as an important process in determining the outcome of diseases such as cancer, inflammatory disease and bacterial infections. Animal models have shed light on the roles of HIF in disease and have uncovered intricate control mechanisms that involve multiple cell types, observations that might have been missed in simpler in vitro systems. These findings highlight the need for new whole-organism models of disease to elucidate these complex regulatory mechanisms. In this Review, we discuss recent advances in our understanding of hypoxia and HIFs in disease that have emerged from studies of zebrafish disease models. Findings from such models identify HIF as an integral player in the disease processes. They also highlight HIF pathway components and their targets as potential therapeutic targets against conditions that range from cancers to infectious disease. Summary: Hypoxia signalling, mediated by HIF, is a crucial pathway in many disease processes. Here, we review current knowledge of HIF signalling and disease, focusing on recent findings from zebrafish models.