Doedens Andrew, Johnson Randall S
Molecular Biology Section, Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.
Methods Enzymol. 2007;435:87-105. doi: 10.1016/S0076-6879(07)35005-2.
The hypoxia-inducible factor (HIF) is a heterodimeric basic helix-loop-helix (bHLH) transcription factor that controls the mammalian cellular transcriptional response to low oxygen tension by up-regulating genes including glycolytic enzymes and angiogenic factors, such as the vascular endothelial growth factor (VEGF). Under normal oxygen tensions, the pathway is negatively regulated by posttranslational proteasomal degradation of HIF-alpha (alpha) subunits in a pathway requiring prolyl-hydroxylase domain (PHD) containing enzyme modification followed by von-Hippel Lindau (VHL) tumor suppressor polyubiquitination (pVHL). Murine knockouts of HIF, pVHL, PHD, and VEGF have demonstrated the essential role of these hypoxic response pathway proteins in development. Conditional deletion of these genes in a wide range of tissues has further shown that ablation or overexpression of the pathway has profound in vivo effects, with important implications for physiology, pathology, and tumor biology. This review aims to summarize the insights garnered from key murine knockouts and transgenics involving components of the HIF hypoxia response pathway.
缺氧诱导因子（HIF）是一种异二聚体碱性螺旋-环-螺旋（bHLH）转录因子，它通过上调包括糖酵解酶和血管生成因子（如血管内皮生长因子（VEGF））在内的基因，来控制哺乳动物细胞对低氧张力的转录反应。在正常氧张力下，该途径通过HIF-α亚基的翻译后蛋白酶体降解而受到负调控，此过程需要含脯氨酰羟化酶结构域（PHD）的酶修饰，随后是冯-希佩尔-林道（VHL）肿瘤抑制因子的多聚泛素化（pVHL）。HIF、pVHL、PHD和VEGF的小鼠基因敲除已证明这些缺氧反应途径蛋白在发育中的重要作用。在多种组织中对这些基因进行条件性缺失进一步表明，该途径的缺失或过表达在体内具有深远影响，对生理学、病理学和肿瘤生物学具有重要意义。本综述旨在总结从涉及HIF缺氧反应途径组成部分的关键小鼠基因敲除和转基因研究中获得的见解。
