乳酸诱导的反应对缺氧.
Dong Chul Lee1, Hyun Ahm Sohn1, Zee-Yong Park2
1Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
Cell
|April 21, 2015
概括
这项研究揭示了一种新的缺氧独立途径,其中乳酸稳定了NDRG3蛋白,激活了Raf-ERK途径. 这种乳酸驱动的信号促进了血管生成和细胞生长,为与低氧相关的疾病提供了新的治疗点.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 身体生理学 身体生理学
背景情况:
- 有机体需要对低氧 (低氧) 的反应来实现稳态和疾病.
- 缺氧诱导因子 (HIF) 是一个已知的调节者,但也有独立于HIF的途径.
研究的目的:
- 阐明一种新的低氧信号的依赖乳酸的机制.
- 确定NDRG3蛋白在这种途径中的作用.
主要方法:
- 在不同氧气条件下研究了乳酸和NDRG3蛋白之间的相互作用.
- 使用了PHD2/VHL-依赖的降解试验.
- 研究了Raf-ERK通路的激活以及血管新生和细胞生长等下游效应.
- 评估了抑制细胞乳酸盐产生的影响.
主要成果:
- 在normxia中,NDRG3蛋白被降解,但在hypoxia中通过乳酸积累稳定.
- 稳定的NDRG3与c-Raf结合,从而激活了Raf-ERK通路.
- 这一途径促进血管生成和细胞生长.
- 抑制乳酸生产取消了NDRG3介导的缺氧反应.
结论:
- 乳酸积累直接通过稳定NDRG3.3,驱动HIF独立的低氧反应.
- NDRG3-乳酸盐-Raf-ERK轴是缺氧诱导的血管生成和细胞生长的关键调解器.
- 这一途径为低氧相关疾病提供了潜在的治疗点.
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