Redox regulation of inflammation and carcinogenesis mediated by NF-κB/IKKβ and dual-specificity phosphatase

炎症和钙生成取决于多个蜂窝信号系统，包括ilacp/NF-∩ B路径和MAP激酶级联之间的主要链接。特别是，肿瘤坏死因子（TNF·），通过IKKβ和JNK激活NF-μ B，发挥炎症和致癌作用两者的重要作用。为了揭示这些信号系统是如何调节消声器和carci nogenesis的，我们调查了突变细胞在NF-∩ B激活中受损的反应。TNF·诱导反应性氧物种（ROS）在这些突变细胞和导致细胞死亡中的生产。TNF--介导的细胞死亡是一个想法，是在血液中被直接地卷入了癌症发生。细胞死亡是由活跃站点的几种酪氨酸磷酸酶的不激活来治疗的，这些活性站点都是还原敏感的半胱氨酸保留地，包括MAP激酶磷酸酶。MKPs的激活导致可持续JNK激活和caspase激活。有趣的是，也是ROS氧化物PTEN，下游激酶Akt中的任何激活都可以促进细胞的存活被Caspases破坏。因此， TNF·诱导细胞死亡由MKP的激活引起，由Akt退化由氧化压力引起。

A major link between inflammation and carcinogenesis depends on several cellular signaling systems including the ilacp/NF-кB pathway and the MAP kinase cascade. Especially, tumor necrosis factor (TNF・), which activates NF-кB through IKKβ and JNK, plays an important role both inflammation and carcinogenesis. To reveal how these signaling systems regulate inf lammation and carci nogenesis, we investigated cellular responses of mutant cells deficlent in NF-кB activation. TNF・induced reactive oxygen species (ROS) production in these mutant cells and lead cell death. TNF・-mediated cell death is thought to be profoundly involved in carcinogenesis in liver. Cell death is medicated by inactivation of several tyrosine phosphatases of which active site is redox-sensitive cysteine residue including MAP kinase phosphatases. Inactivation of MKPs leads the sustained JNK activation and caspase activation. Interestingly, although ROS oxidize PTEN, the down stream kinase Akt of which activation can promote cell survival is degraded by caspases. Thus, TNF・induces cell death by inactivation of MKP and by Akt degradation mediated by oxidative stress.