Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling
Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling
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DOI：
10.1128/mcb.25.12.4853-4862.2005
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发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Chandel, NS
中科院分区：
文献类型：
--
作者：
Emerling, BM;Platanias, LC;Chandel, NS
哺乳动物细胞具有感知低氧水平（缺氧）的能力。对缺氧的适应性反应涉及转录因子缺氧诱导因子1（HIF-1）的诱导。在缺氧过程中调节HIF-1激活的细胞内信号通路仍然未知。在这里，我们证明了p38 α（-/-）细胞在缺氧条件下不能激活HIF-1。缺乏p38 α上游调节因子Mkk3和Mkk6的细胞在缺氧条件下也不能激活HIF-1。p38 α（-/-）细胞能够在常氧期间响应于缺氧或铁螯合剂而激活HIF-1。此外，p38 α和HIF-1的缺氧激活被取消的myxothiazol，线粒体复合物III抑制剂，和谷胱甘肽过氧化物酶1（GPX 1），过氧化氢的清除剂。因此，p38 α和HIF-1的活化依赖于线粒体活性氧的产生。这些结果为p38丝裂原活化蛋白激酶信号转导对HIF-1的活化至关重要提供了遗传学证据。
Mammalian cells have the ability to sense low oxygen levels (hypoxia). An adaptive response to hypoxia involves the induction of the transcription factor hypoxia-inducible factor 1 (HIF-1). The intracellular signaling pathways that regulate HIF-1 activation during hypoxia remain unknown. Here, we demonstrate that p38 alpha(-/-) cells fail to activate HIF-1 under hypoxic conditions. Cells deficient in Mkk3 and Mkk6, the upstream regulators of p38 alpha, also fail to activate HIF-1 under hypoxic conditions. The p38 alpha(-/-) cells are able to activate HIF-1 in response to anoxia or iron chelators during normoxia. Furthermore, the hypoxic activation of p38 alpha and HIF-1 was abolished by myxothiazol, a mitocbondrial complex III inhibitor, and glutathione peroxidase 1 (GPX1), a scavenger of hydrogen peroxide. Thus, the activation of p38 alpha and HIF-1 is dependent on the generation of mitochondrial reactive oxygen species. These results provide genetic evidence that p38 mitogen-activated protein kinase signaling is essential for HIF-1 activation.