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한국생명공학연구원

Cell, 161, 1-15, April 23, 2015 | http://dx.doi.org/10.1016/j.cell.2015.03.011 A Lactate-Induced Response to Hypoxia

Abstract

Dong Chul Lee,¹ Hyun Ahm Sohn,¹ Zee-Yong Park,⁵ Sangho Oh,³ Yun Kyung Kang,⁶ Kyoung-min Lee,⁵ Minho Kang,¹ Ye Jin Jang,¹ Suk-Jin Yang,¹ Young Ki Hong,¹ Hanmi Noh,^1,7 Jung-Ae Kim,^1,7 Dong Joon Kim,¹ Kwang-Hee Bae,^4,7 Dong Min Kim,¹ Sang J. Chung,¹ Hyang Sook Yoo,¹ Dae-Yeul Yu,¹ Kyung Chan Park,^1,* and Young Il Yeom^1,2,7,*

¹Medical Genomics Research Center
²Ochang Branch Institute
³Korean Bioinformation Center
⁴Research Center for Integrative Cellulomics
Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea
⁵Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea
⁶Department of Pathology, Inje University Seoul Paik Hospital, Seoul 100-032, Korea
⁷Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Korea

^*Correspondence: yung Chan Park, Young Il Yeom

Summary
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.

논문정보

형식Research article
게재일2015년 04월 (BRIC 등록일 2015-04-21)
연구진국내 연구진
분야
피인용횟수120회 이상 인용된 논문 (상위피인용논문 등록일 2020-05-22)

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