Scheuermann Thomas H, Yang Jinsong, Zhang Lei, Gardner Kevin H, Bruick Richard K
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Methods Enzymol. 2007;435:3-24. doi: 10.1016/S0076-6879(07)35001-5.
Hypoxia-inducible factors (HIFs) are key transcriptional regulators of genes involved in cellular adaptation to reduced oxygen availability through effects on anaerobic metabolism, oxygen delivery, angiogenesis, and cellular survival and proliferation. As such, HIFs contribute to the pathogenesis of diseases in which oxygen availability is compromised, notably ischemia and tumorigenesis. Though tremendous progress has been made in elucidating the mechanisms underlying O(2)-dependent regulation of HIF by Fe(II)- and 2-oxoglutarate-dependent dioxygenases, HIF induction can be uncoupled from these modes of regulation in diseases such as cancer. Consequently, renewed interest has developed in understanding the structure/function relationships of individual P(er)/ARNT/S(im) (PAS) domains that are important for maintaining transcriptionally active HIF complexes, regardless of the manner by which HIF is induced. This review highlights strategies for the biophysical and biochemical characterization of the PAS domains found within both HIF subunits and provides a platform for future efforts to exploit these domains in therapeutic settings.
缺氧诱导因子（HIFs）是通过影响无氧代谢、氧输送、血管生成以及细胞存活和增殖来参与细胞适应低氧环境相关基因的关键转录调节因子。因此，HIFs参与了氧供应受损疾病的发病机制，尤其是缺血和肿瘤发生。尽管在阐明由铁（II）和2-氧代戊二酸依赖性双加氧酶对HIF进行氧依赖性调节的潜在机制方面已经取得了巨大进展，但在癌症等疾病中，HIF的诱导可能与这些调节模式脱钩。因此，人们对理解单个P(er)/ARNT/S(im)（PAS）结构域的结构/功能关系重新产生了兴趣，这些结构域对于维持转录活性HIF复合物很重要，而不管HIF是如何被诱导的。本综述重点介绍了对HIF两个亚基中发现的PAS结构域进行生物物理和生化表征的策略，并为未来在治疗环境中利用这些结构域的研究提供了一个平台。
