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

A major link between inflammation and carcinogenesis depends on several cellular signaling systemsincluding the ilacp/NF- zero B pathway and the MAP kinase cascade. Especiallytumor necrosis factor (TNF), which activates n - zero B through IKKβ and JNK，plays an important role both inflammation and carcinogenesis. To reveal how these signaling systems To reveal how these signaling systemsregulate inf lammation and carci nogenesiswe investigated cellular responses of mutant cells deficlent in NF- zero B activation. TNF inducedreactive oxygen species (ROS) production in these mutant cells and lead cell death. TNF -mediatedcell death is to be profoundly involved in carcinogenesis in liver. cell death is medicatedby inactivation of several tyrosine phosphatases of which active site is redox-sensitive cysteineincluding MAP kinase phosphatases. Inactivation of MKPs leads the sustained JNK activationand caspase activation. Interestingly, althos oxidize PTEN，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。

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.