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Cell. 2015 Apr 23;161(3):595-609. doi: 10.1016/j.cell.2015.03.011. Epub 2015 Apr 16.

A lactate-induced response to hypoxia.

Author information

1
Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
2
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
3
Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
4
Department of Pathology, Inje University Seoul Paik Hospital, Seoul 100-032, Korea.
5
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.
6
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.
7
Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea. Electronic address: kpark@kribb.re.kr.
8
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.

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.

PMID:
25892225
DOI:
10.1016/j.cell.2015.03.011
[Indexed for MEDLINE]
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