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Title 

A lactate-induced response to hypoxia

 

젖산 매개 저산소 반응

Authors 

Dong Chul LeeHyun Ahm SohnZ Y ParkSangho OhY K KangK M LeeMinho KangYe Jin JangSuk Jin YangYoung Ki HongHanmi NohJung Ae KimDong Joon KimKwang-Hee BaeDong Min KimSang Jeon ChungHyang Sook YooDae Yeul YuKyung Chan ParkYoung Il Yeom

Publisher 

Elsevier (Cell Press)

Issue Date 

2015

Citation 

Cell, vol. 161, no. 3, pp. 595-609

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

Link 

http://dx.doi.org/10.1016/j.cell.2015.03.011

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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