Hypoxic activation of nuclear factor-kappa B is mediated by a Ras and Raf signaling pathway and does not involve MAP kinase (ERK1 or ERK2).
Hypoxic activation of nuclear factor-kappa B is mediated by a Ras and Raf signaling pathway and does not involve MAP kinase (ERK1 or ERK2).
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发表时间：
1994-10
期刊：
影响因子：
11.2
通讯作者：
A. Koong;E. Chen;N. Mivechi;N. Denko;Peter J. Stambrook;A. Giaccia
中科院分区：
文献类型：
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作者：
A. Koong;E. Chen;N. Mivechi;N. Denko;Peter J. Stambrook;A. Giaccia
我们以前已经证明，缺氧导致核因子-kappa B(NF-kappa B)的激活，以及其抑制亚基I kappa Bα在酪氨酸残基上的磷酸化。利用Ha-Ras和Raf-1的显性负性突变体，我们研究了导致核因子-kappaB在低氧条件下激活的一些早期信号事件。Ha-Ras和Raf-1的显性负性等位基因均抑制低氧诱导的NF-kappaB，提示低氧诱导的NF-kappaB的诱导途径依赖于Ras和Raf-1的活性。此外，虽然低氧条件下也可以激活丝裂原活化蛋白激酶(ERK1和ERK2)，但这些蛋白激酶似乎不参与低氧条件下对核因子-kappaB的调节，因为丝裂原活化蛋白激酶的显性负突变体不抑制低氧条件下核因子-kappaB的激活。由于Ras和Raf-1先前已被证明在膜相关酪氨酸激酶(如Src)下游发挥作用，我们确定了膜相关蛋白Src是否也在低氧条件下被激活。我们检测到，在细胞暴露于缺氧的15-30分钟内，Src原癌基因的活性增加。我们推测，低氧激活Src可能是Ras激活信号通路中最早的事件之一，最终导致核因子-kappa B抑制亚基I-kappa Bα的磷酸化和解离。
We have previously shown that hypoxia causes the activation of nuclear factor-kappa B (NF-kappa B), and the phosphorylation of its inhibitory subunit, I kappa B alpha, on tyrosine residues. With the use of dominant negative mutants of Ha-Ras and Raf-1, we investigated some of the early signaling events leading to the activation of NF-kappa B by hypoxia. Both dominant negative alleles of Ha-Ras and Raf-1 inhibited NF-kappa B induction by hypoxia, suggesting that the hypoxia-induced pathway of NF-kappa B induction is dependent on Ras and Raf-1 kinase activity. Furthermore, although conditions of low oxygen can also activate mitogen-activated protein kinases (ERK1 and ERK2), these kinases do not appear to be involved in regulating NF-kappa B by low oxygen conditions, as dominant negative mutants of mitogen-activated protein kinase do not inhibit NF-kappa B activation by hypoxia. Since Ras and Raf-1 have been previously shown to work downstream from membrane-associated tyrosine kinases such as Src, we determined if the Src membrane-associated kinase was also activated by low oxygen conditions. We detected an increase in Src proto-oncogene activity within 15-30 min of cellular exposure to hypoxia. We postulate that Src activation by hypoxia may be one of the earliest events that precedes Ras activation in the signaling cascade which ultimately leads to the phosphorylation and dissociation of the inhibitory subunit of NF-kappa B, I kappa B alpha.