BMB Rep. 2015; 48(6): 301-302  
NDRG3-mediated lactate signaling in hypoxia
Kyung Chan Park1,#, Dong Chul Lee1,# & Young Il Yeom1,2,*
1Genome Structure Research Center, 2Ochang Branch Institute, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, Korea
Correspondence to: E-mail: yeomyi@kribb.re.kr
Received: April 27, 2015; Published online: June 30, 2015.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

Abstract
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.
Keywords: Hypoxia, Lactate signaling, NDRG3, HIF-independent hypoxia responses, PHD2/VHL pathway


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