An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway
An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway
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DOI：
10.1038/sj.emboj.7601423
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发表时间：
2006-11-29
期刊：
影响因子：
11.4
通讯作者：
Nakano, Hiroyasu
中科院分区：
文献类型：
--
作者：
Nakajima, Akihito;Komazawa-Sakon, Sachiko;Nakano, Hiroyasu
抑制NF-κ B活化可增加对肿瘤坏死因子（TNF）α诱导的细胞死亡的易感性，同时伴有半胱天冬酶和延长的c-Jun N-末端激酶（JNK）活化以及活性氧（ROS）蓄积。然而，详细的机制尚不清楚。在此，我们发现，细胞FLICE抑制蛋白（c-FLIP）在NF-κ B激活缺陷的成纤维细胞中迅速丢失，但在TNF α刺激后野生型成纤维细胞中没有丢失，表明NF-κ B正常维持c-FLIP的细胞水平。长型c-FLIP（c-FLIPL）的异位表达抑制NF-κ B活化缺陷成纤维细胞中TNF α诱导的延长的JNK活化和ROS积累。相反，TNFa诱导c-Flip（-/-）成纤维细胞中JNK活化和ROS积累延长。此外，c-FLIPL以TNF α依赖性方式直接与JNK激活剂MAP激酶激酶（MKK）7相互作用，并抑制MKK 7与MAP/ERK激酶激酶1、凋亡信号调节激酶1和TGF β激活激酶1的相互作用。c-FLIPL与MKK 7的这种刺激依赖性相互作用可能选择性地抑制JNK激活的延长期。认为ROS促进JNK活化，JNK通路的活化可促进ROS积累，c-FLIPL可阻断该正反馈回路，从而抑制ROS积累。
Inhibition of NF-kappa B 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-kappa B activation-deficient, but not wild-type fibroblasts upon TNF alpha stimulation, indicating that NF-kappa B normally maintains the cellular levels of c-FLIP. The ectopic expression of the long form of c-FLIP (c-FLIPL) inhibits TNF alpha-induced prolonged JNK activation and ROS accumulation in NF-kappa B activation-deficient fibroblasts. Conversely, TNFa 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 TNF alpha-dependent manner and inhibits the interactions of MKK7 with MAP/ERK kinase kinase 1, apoptosis-signal-regulating kinase 1, and TGFb-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.