Fong G-H, Takeda K
Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030-3501, USA.
Cell Death Differ. 2008 Apr;15(4):635-41. doi: 10.1038/cdd.2008.10. Epub 2008 Feb 15.
Oxygen-dependent hydroxylation of hypoxia-inducible factor (HIF)-alpha subunits by prolyl hydroxylase domain (PHD) proteins signals their polyubiquitination and proteasomal degradation, and plays a critical role in regulating HIF abundance and oxygen homeostasis. While oxygen concentration plays a major role in determining the efficiency of PHD-catalyzed hydroxylation reactions, many other environmental and intracellular factors also significantly modulate PHD activities. In addition, PHDs may also employ hydroxylase-independent mechanisms to modify HIF activity. Interestingly, while PHDs regulate HIF-alpha protein stability, PHD2 and PHD3 themselves are subject to feedback upregulation by HIFs. Functionally, different PHD isoforms may differentially contribute to specific pathophysiological processes, including angiogenesis, erythropoiesis, tumorigenesis, and cell growth, differentiation and survival. Because of diverse roles of PHDs in many different processes, loss of PHD expression or function triggers multi-faceted pathophysiological changes as has been shown in mice lacking different PHD isoforms. Future investigations are needed to explore in vivo specificity of PHDs over different HIF-alpha subunits and differential roles of PHD isoforms in different biological processes.
脯氨酰羟化酶结构域（PHD）蛋白对缺氧诱导因子（HIF）-α亚基进行的氧依赖性羟基化作用，标志着它们的多聚泛素化和蛋白酶体降解，并且在调节HIF丰度和氧稳态中发挥关键作用。虽然氧浓度在决定PHD催化的羟基化反应效率方面起主要作用，但许多其他环境和细胞内因素也能显著调节PHD的活性。此外，PHD也可能采用不依赖羟化酶的机制来改变HIF活性。有趣的是，虽然PHD调节HIF-α蛋白的稳定性，但PHD2和PHD3自身会受到HIF的反馈上调。在功能上，不同的PHD亚型可能对特定的病理生理过程有不同的贡献，包括血管生成、红细胞生成、肿瘤发生以及细胞生长、分化和存活。由于PHD在许多不同过程中具有多种作用，正如在缺乏不同PHD亚型的小鼠中所显示的那样，PHD表达或功能的丧失会引发多方面的病理生理变化。未来需要进行研究，以探索PHD对不同HIF-α亚基的体内特异性，以及PHD亚型在不同生物学过程中的不同作用。
