An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway

Abstract

Inhibition of NF‐κB activation increases susceptibility to tumor necrosis factor (TNF)α‐induced cell death, concurrent with caspases and prolonged c‐Jun N‐terminal kinase (JNK) activation, and reactive oxygen species (ROS) accumulation. However, the detailed mechanisms are unclear. Here we show that cellular FLICE‐inhibitory protein (c‐FLIP) is rapidly lost in NF‐κB activation‐deficient, but not wild‐type fibroblasts upon TNFα stimulation, indicating that NF‐κB normally maintains the cellular levels of c‐FLIP. The ectopic expression of the long form of c‐FLIP (c‐FLIPL) inhibits TNFα‐induced prolonged JNK activation and ROS accumulation in NF‐κB activation‐deficient fibroblasts. Conversely, TNFα induces prolonged JNK activation and ROS accumulation in c‐Flip −/− fibroblasts. Moreover, c‐FLIPL directly interacts with a JNK activator, MAP kinase kinase (MKK)7, in a TNFα‐dependent manner and inhibits the interactions of MKK7 with MAP/ERK kinase kinase 1, apoptosis‐signal‐regulating kinase 1, and TGFβ‐activated kinase 1. This stimuli‐dependent interaction of c‐FLIPL with MKK7 might selectively suppress the prolonged phase of JNK activation. Taken that ROS promote JNK activation and activation of the JNK pathway may promote ROS accumulation, c‐FLIPL might block this positive feedback loop, thereby suppressing ROS accumulation.