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

Inhibition of NF-kappaB activation increases susceptibility to tumor necrosis factor (TNF)alpha-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-kappaB activation-deficient, but ...
not wild-type fibroblasts upon TNFalpha stimulation, indicating that NF-kappaB normally maintains the cellular levels of c-FLIP. The ectopic expression of the long form of c-FLIP (c-FLIPL) inhibits TNFalpha-induced prolonged JNK activation and ROS accumulation in NF-kappaB activation-deficient fibroblasts. Conversely, TNFalpha 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 TNFalpha-dependent manner and inhibits the interactions of MKK7 with MAP/ERK kinase kinase 1, apoptosis-signal-regulating kinase 1, and TGFbeta-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.
Mesh Terms:
Animals, Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein, Caspases, Fibroblasts, Gene Expression Regulation, Enzymologic, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 1, MAP Kinase Kinase 7, MAP Kinase Kinase Kinase 1, MAP Kinase Kinase Kinase 5, MAP Kinase Kinase Kinases, NF-kappa B, Protein Interaction Mapping, Protein Structure, Tertiary, Reactive Oxygen Species, Superoxide Dismutase, Tumor Necrosis Factor-alpha
EMBO J.
Date: Nov. 29, 2006
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