Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells
Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells
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DOI：
10.1128/mcb.21.10.3436-3444.2001
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发表时间：
2001-05-01
影响因子：
5.3
通讯作者：
Johnson, RS
中科院分区：
文献类型：
--
作者：
Seagroves, TN;Ryan, HE;Johnson, RS
对不同水平的氧气做出反应的能力对所有呼吸细胞都很重要。对缺氧或缺氧的反应有多种形式，从系统适应到细胞自主适应。也许最古老的细胞自主对低氧的适应是新陈代谢的：巴斯德效应，包括氧化磷酸化减少和厌氧发酵增加。由于厌氧发酵产生的ATP远低于每个葡萄糖分子的氧化磷酸化，因此增加糖酵解途径的活性对于维持低氧细胞中的游离ATP水平是必要的，我们提出了遗传和生化证据，证明在哺乳动物细胞中，这种代谢开关受转录因子HIF-1的调节。结果，缺乏HIF-1α的细胞在缺氧期间表现出生长速度下降，乳酸水平下降和酸中毒减轻。我们发现，这种糖酵解能力的下降导致HIF-1α高效低氧细胞的游离ATP水平显著降低。因此，HIF-1的激活是低氧过程中代谢状态的重要控制因素，这一要求对细胞发育、血管生成和血管损伤的调控具有重要意义。
The ability to respond to differential levels of oxygen is important to all respiring cells. The response to oxygen deficiency or hypoxia, takes many forms and ranges from systemic adaptations to those that are cell autonomous. Perhaps the most ancient of the cell-autonomous adaptations to hypoxia is a metabolic one: the Pasteur effect, which includes decreased oxidative phosphorylation and an increase in anaerobic fermentation. Because anaerobic fermentation produces far less ATP than oxidative phosphorylation per molecule of glucose, increased activity of the glycolytic pathway is necessary to maintain free ATP levels in the hypoxic cell, were, we present genetic and biochemical evidence that, in mammalian cells, this metabolic switch is regulated by the transcription factor HIF-1. As a result, cells lacking HIF-1 alpha exhibit decreased growth rates during hyposia, as well as decreased levels of lactic acid production and decreased acidosis. We show that this decrease in glycolytic capacity results in dramatically lowered free ATP levels in HIF-1 alpha -efficient hypoxic cells. Thus, HIF-1 activation is an essential control element of the metabolic state during hypoxia this requirement has important implications for the regulation of cell growth during development, angiogenesis, and vascular injury.