期刊
BIOLOGICAL CHEMISTRY
卷 394, 期 4, 页码 435-448出版社
WALTER DE GRUYTER GMBH
DOI: 10.1515/hsz-2012-0328
关键词
anemia; gene-modified mice; hypoxia; hypoxia-inducible factor; ischemia; prolyl 4-hydroxylase
资金
- Health Science Council [114344]
- Center of Excellence [251314]
- Biosciences and Environment Council from the Academy of Finland [120156, 218129, 140765]
- S. Juselius Foundation
- FibroGen, Inc.
Hypoxia-inducible transcription factor (HIF), an alpha beta dimer, is the key inducer of hypoxia-responsive genes that operate both during normal development and pathological processes in association with decreased oxygen availability. The products of HIF target genes function in, e. g., hematopoiesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumorigenesis and metastasis. HIF is accumulated in hypoxia, whereas it is rapidly degraded in normoxic cells. The oxygen-sensing mechanism behind this phenomenon is provided by HIF prolyl 4-hydroxylases (HIF-P4Hs, commonly known as PHDs and EglNs) that require oxygen in their reaction. In normoxia, two prolines in the oxygen-dependent degradation domain of the HIF alpha subunit become hydroxylated by the HIF-P4Hs. The 4-hydroxyproline residues formed serve as recognition sites for the von Hippel-Lindau E3 ubiquitin ligase complex and result in subsequent ubiquitination and instant proteasomal degradation of HIF alpha in normoxia. The HIF-P4H reaction is inhibited in hypoxia. HIF alpha evades degradation and forms a functional dimer with HIF beta, leading to activation of the HIF target genes. The central role of HIF-P4Hs in the regulation of the hypoxia response pathway has provided an attractive possibility as a drug candidate for treatment of, e. g., severe anemias and ischemic conditions, and several companies are currently carrying out clinical studies on the use of HIF-P4H inhibitors to treat anemia in patients with a kidney disease. Therefore, it is important to understand the effects of individual HIF-P4H isoenzymes on the hypoxia response and potential other pathways in vivo. The common and specific functions of the HIF-P4H isoenzymes are discussed in this review on the basis of available data from cell biological studies and gene-modified animals.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据