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.
Nakajima
Akihito
A
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Komazawa-Sakon
Sachiko
S
Takekawa
Mutsuhiro
M
Sasazuki
Tomonari
T
Yeh
Wen-Chen
WC
Yagita
Hideo
H
Okumura
Ko
K
Nakano
Hiroyasu
H
D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B / Q000819:agonists / Q000378:metabolism; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D020169:Caspases; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048688:MAP Kinase Kinase 7; D048728:MAP Kinase Kinase Kinase 1; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7