title: A lactate-induced response to hypoxia.
abstract: Organisms must be able to respond to low oxygen in a number of homeostatic and pathological contexts. Regulation of hypoxic responses via the hypoxia-inducible factor (HIF) is well established, but evidence indicates that other, HIF-independent mechanisms are also involved. Here, we report a hypoxic response that depends on the accumulation of lactate, a metabolite whose production increases in hypoxic conditions. We find that the NDRG3 protein is degraded in a PHD2/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates under hypoxia. The stabilized NDRG3 protein binds c-Raf to mediate hypoxia-induced activation of Raf-ERK pathway, promoting angiogenesis and cell growth. Inhibiting cellular lactate production abolishes the NDRG3-mediated hypoxia responses. Our study, therefore, elucidates the molecular basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases.
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Dong Chul
authors.initials: DC
authors.lastname: Lee
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Hyun Ahm
authors.initials: HA
authors.lastname: Sohn
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors.forename: Zee-Yong
authors.initials: ZY
authors.lastname: Park
authors.affiliation: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Sangho
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Pathology, Inje University Seoul Paik Hospital, Seoul 100-032, Korea.
authors.forename: Yun Kyung
authors.initials: YK
authors.lastname: Kang
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors.forename: Kyoung-Min
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Kang
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Ye Jin
authors.initials: YJ
authors.lastname: Jang
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Suk-Jin
authors.initials: SJ
authors.lastname: Yang
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Young Ki
authors.initials: YK
authors.lastname: Hong
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea; Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Korea.
authors.forename: Hanmi
authors.initials: H
authors.lastname: Noh
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea; Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Korea.
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Research Center for Integrative Cellulomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea; Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Korea.
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Bae
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Dong Min
authors.initials: DM
authors.lastname: Kim
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Sang J
authors.initials: SJ
authors.lastname: Chung
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Hyang Sook
authors.initials: HS
authors.lastname: Yoo
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea. Electronic address: kpark@kribb.re.kr.
authors.forename: Kyung Chan
authors.initials: KC
authors.lastname: Park
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea; Ochang Branch Institute, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea; Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Korea. Electronic address: yeomyi@kribb.re.kr.
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yeom
mesh_terms: D015687:Cell Hypoxia; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / 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; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding; D048490:raf Kinases / Q000378:metabolism
chemical_list: 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; D048490:raf Kinases; D010100:Oxygen