Place Trenton L, Domann Frederick E
Molecular and Cellular Biology Program, The University of Iowa, Iowa City, Iowa, USA.
Molecular and Cellular Biology Program, The University of Iowa, Iowa City, Iowa, USA ; Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa, USA.
Hypoxia (Auckl). 2013 Oct 1;2013(1):13-17. doi: 10.2147/HP.S50091.
The ability of cells to sense oxygen is a highly evolved process that facilitates adaptations to the local oxygen environment and is critical to energy homeostasis. In vertebrates, this process is largely controlled by three intracellular prolyl-4-hydroxylases (PHD 1-3). These related enzymes share the ability to hydroxylate the hypoxia-inducible transcription factor (HIF), and therefore control the transcription of genes involved in metabolism and vascular recruitment. However, it is becoming increasingly apparent that proline-4-hydroxylation controls much more than HIF signaling, with PHD3 emerging as an exceptionally unique and functionally diverse PHD isoform. In fact, PHD3-mediated hydroxylation has recently been purported to function in such diverse roles as sympathetic neuronal and muscle development, sepsis, glycolytic metabolism, and cell fate. PHD3 expression is also highly distinct from that of the other PHD enzymes, and varies considerably between different cell types and oxygen concentrations. This review will examine the evolution of oxygen sensing by the HIF-family of PHD enzymes, with a specific focus on complex nature of PHD3 expression and function in mammalian cells.
细胞感知氧气的能力是一个高度进化的过程，它有助于适应局部氧气环境，对能量稳态至关重要。在脊椎动物中，这一过程主要由三种细胞内脯氨酰-4-羟化酶（PHD 1-3）控制。这些相关酶具有共同的能力，即羟基化缺氧诱导转录因子（HIF），因此控制参与代谢和血管生成的基因的转录。然而，越来越明显的是，脯氨酸-4-羟基化所控制的远不止HIF信号传导，PHD3已成为一种极其独特且功能多样的PHD亚型。事实上，最近有观点认为PHD3介导的羟基化在交感神经元和肌肉发育、败血症、糖酵解代谢及细胞命运等多种不同作用中发挥功能。PHD3的表达也与其他PHD酶截然不同，在不同细胞类型和氧气浓度之间有很大差异。本综述将探讨PHD酶的HIF家族对氧气感知的进化过程，特别关注PHD3在哺乳动物细胞中表达和功能的复杂性。
