An antiapoptotic protein, c-FLIP(L), 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-FLIP(L)) 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-FLIP(L) 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-FLIP(L) 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-FLIP(L) might block this positive feedback loop, thereby suppressing ROS accumulation.[1]References
- An antiapoptotic protein, c-FLIP(L), directly binds to MKK7 and inhibits the JNK pathway. Nakajima, A., Komazawa-Sakon, S., Takekawa, M., Sasazuki, T., Yeh, W.C., Yagita, H., Okumura, K., Nakano, H. EMBO J. (2006) [Pubmed]
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