연사 : 염영일 박사(한국생명공학연구원)
연제 : Lactate-induced metabolic signaling in hypoxia
일시 : 2015년 11월 6일 (금) 오후 4시
장소 : 하나과학관 A동 109호
초청교수 : 최의주 교수
Abstract
Hypoxia is associated with many pathological conditions (cancer, wound healing, inflammation, cardiovascular disorders, etc) as well as the normal physiology (differentiation and development, exercise physiology, etc) of metazoans. Cells respond to low oxygen conditions in diverse ways to adapt to and survive the harsh environment. HIFα (hypoxia inducible factor α) proteins are induced in the early stage of hypoxia and play key roles in the regulation of hypoxia responses by inducing the expression of an array of genes, including those functioning in metabolic adaptation. While the HIF-mediated regulation of hypoxia responses is well studied, many observations indicate that HIF-independent processes are also important. However, mechanisms for the latter aspects of hypoxia response regulation remained poorly understood. We found a lactate-dependent signaling pathway in hypoxia, mediated by an oxygen- and lactate-regulated protein, NDRG family member 3 (NDRG3). Oxygen negatively regulates NDRG3 expression at the protein level by the PHD2/VHL system, whereas lactate, produced in excess under prolonged hypoxia, blocks its proteasomal degradation by inhibiting VHL-mediated ubiquitination of NDRG3 protein. The stabilized NDRG3 protein then promotes angiogenesis and cell growth under hypoxia by activating Raf-ERK pathway. Inhibiting cellular lactate production abolishes the NDRG3-mediated hypoxia responses. Our study indicates that HIF-1α and NDRG3 form an oxygen-dependent regulatory chain for hypoxia responses, divided into two chronological phases that are functionally coupled with each other using NDRG3 as the critical link. Thus, while both HIF-1α and NDRG3 are negatively regulated by oxygen in normoxia, lactate produced in excess by the HIF-1α-mediated activation of glycolysis during the early phase of hypoxia functions as a metabolic signal to induce NDRG3-mediated kinase signals at the later phase. The NDRG3-Raf-ERK axis therefore provides the genetic basis for the lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases as well as advance our understandings in the normal physiology of hypoxia responses.