The regulation of hypoxia-inducible factor (HIF-1) and the role of HIF-1 in C. elegans longevity

摘要

Oxygen is one of the most abundant elements on the earth. It is the final electron receptor of aerobic respiration, which is an essential energy generation process in living creatures. Oxygen homeostasis is crucial for the survival and function of cells (Semenza, 2000). In animals, the oxygen levels exposed to each individual cell are systemically controlled by the respiration system and circulatory system.Hypoxia-inducible factor (HIF) transcription factors play key roles in oxygen homeostasis from invertebrate C. elegans to human beings. HIF is a heterodimeric transcription factor, consisting of an alpha subunit that is regulated by oxygen and a beta subunit (also termed ARNT) that can partner with related DNA-binding transcription factor proteins. Vascular endothelial growth factor, one of the earliest identified HIF-1 transcriptional targets, plays a central role in angiogenesis in vertebrate. In addition to promoting the formation of blood vessels for oxygen delivery, HIF also regulates erythropoietin that controls red blood cell production. Besides these genes, more than one hundred others have been identified to be regulated by mammalian HIF during oxygen deprivation (Elvidge et al., 2006; Manalo et al., 2005). Insufficient expression of HIF is associated with cardiovascular diseases (Semenza, 2000). On the other hand, overexpression of HIF also promotes metastasis of many cancers by providing oxygen and nutrients for fast dividing tumor cells (Semenza, 2009).C. elegans has proven to be a good model system to study HIF (Epstein et al., 2001; Shao et al., 2009; Shen et al., 2005). C. elegans HIF-1 was first identified by Jiang et al. in our group in 2001 (Jiang et al., 2001b). It is regulated by evolutionarily conserved pathways (Epstein et al., 2001). Since then, we have focused on studying the regulation of HIF-1. In this thesis I describe collaborative research to understand the regulation and function of HIF-1 in C. elegans. First we found SKN-1/Nrf, the transcriptional regulatory phase II detoxification network regulator, negatively regulated HIF-1 protein stability. Later we demonstrated that SKN-1 activated egl-9 transcription, thereby attenuating HIF-1 protein levels and HIF-1 activity. EGL-9 is HIF-1 prolyl hydroxylase and can hyproxylate HIF-1 at a conserved proline residue. The hydroxylation of HIF-1 by EGL-9 is essential for HIF-1 degradation in normoxia. In my second study, I found that HIF-1 mediated the life span extension associated with clk-1 knockout. clk-1 is a mitochondrial gene and encodes an enzyme which is responsible for the final step of CoQ9 synthesis.