A lactate-induced response to hypoxia = 젖산 매개 저산소 반응

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Title
A lactate-induced response to hypoxia = 젖산 매개 저산소 반응
Author(s)
Dong Chul Lee; Hyun Ahm Sohn; Z Y Park; Sangho Oh; Y K Kang; K M Lee; Min Ho Kang; Ye Jin Jang; Suk Jin Yang; Young Ki Hong; Hanmi Noh; Jung Ae Kim; Dong Joon Kim; Kwang-Hee Bae; Dong Min Kim; Sang Jeon Chung; Hyang Sook Yoo; Dae Yeul Yu; Kyung Chan ParkYoung Il Yeom
Bibliographic Citation
Cell, vol. 161, no. 3, pp. 595-609
Publication Year
2015
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. Lactate, a common product of anaerobic metabolism, can promote a hypoxic response independent of HIF. It does so by binding as stabilizing the NDRG3 protein that, in turn, triggers signals for cell growth and angiogenesis.
ISSN
0092-8674
Publisher
Elsevier-Cell Press
DOI
http://dx.doi.org/10.1016/j.cell.2015.03.011
Type
Article
Appears in Collections:
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
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