Park Kyung Chan, Lee Dong Chul, Yeom Young Il
Genome Structure Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, Korea.
Genome Structure Research Center; Ochang Branch Institute, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, Korea.
BMB Rep. 2015 Jun;48(6):301-2. doi: 10.5483/bmbrep.2015.48.6.080.
Hypoxia is associated with many pathological conditions as well as the normal physiology of metazoans. We identified a lactate-dependent signaling pathway in hypoxia, mediated by the oxygen- and lactate-regulated protein NDRG family member 3 (NDRG3). Oxygen negatively regulates NDRG3 expression at the protein level via the PHD2/VHL system, whereas lactate, produced in excess under prolonged hypoxia, blocks its proteasomal degradation by binding to NDRG3. We also found that the stabilized NDRG3 protein promotes angiogenesis and cell growth under hypoxia by activating the Raf-ERK pathway. Inhibiting cellular lactate production abolishes NDRG3-mediated hypoxia responses. The NDRG3-Raf-ERK axis therefore provides the genetic basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases in addition to advancing our understanding of the normal physiology of hypoxia responses.
缺氧与许多病理状况以及后生动物的正常生理过程相关。我们在缺氧状态下鉴定出了一条依赖乳酸的信号通路，该通路由氧和乳酸调节蛋白NDRG家族成员3（NDRG3）介导。氧气通过PHD2/VHL系统在蛋白质水平上负向调节NDRG3的表达，而在长时间缺氧条件下过量产生的乳酸通过与NDRG3结合来阻断其蛋白酶体降解。我们还发现，稳定的NDRG3蛋白在缺氧条件下通过激活Raf-ERK通路促进血管生成和细胞生长。抑制细胞乳酸生成可消除NDRG3介导的缺氧反应。因此，NDRG3-Raf-ERK轴为乳酸诱导的缺氧信号提供了遗传基础，这不仅有助于我们深入了解缺氧反应的正常生理过程，还可用于开发针对缺氧诱导疾病的治疗方法。
