NDRG3-mediated lactate signaling in hypoxia.
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.
Genome Structure Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, Korea.
Kyung Chan
KC
Park
Genome Structure Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, Korea.
Dong Chul
DC
Lee
Genome Structure Research Center; Ochang Branch Institute, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, Korea.
Young Il
YI
Yeom
D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D019344:Lactic Acid / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; C431706:NDRG3 protein, human; D009419:Nerve Tissue Proteins; D019344:Lactic Acid; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen