Antioxidant c-FLIP inhibits Fas ligand-induced NF-kappaB activation in a phosphatidylinositol 3-kinase/Akt-dependent manner.
Antioxidant c-FLIP inhibits Fas ligand-induced NF-kappaB activation in a phosphatidylinositol 3-kinase/Akt-dependent manner.
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DOI：
10.4049/jimmunol.1002915
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发表时间：
2011-09-15
期刊：
影响因子：
--
通讯作者：
Rojanasakul Y
中科院分区：
文献类型：
--
作者：
Iyer AK;Azad N;Talbot S;Stehlik C;Lu B;Wang L;Rojanasakul Y
Fas配体（FasL）属于肿瘤坏死因子（TNF）家族的死亡配体，与Fas受体结合后可激活核因子-κ B（NF-κB B）和磷脂酰肌醇3-激酶（PI 3 K）/Akt等下游信号通路和蛋白。然而，目前尚不清楚在FasL信号传导的背景下NF-κB和PI 3 K/Akt之间是否存在串扰。我们使用人肾上皮293 T细胞和Jurkat T淋巴细胞证明，尽管FasL激活Akt和NF-κB，但Akt以ROS依赖的方式抑制FasL依赖的NF-κB活性。FLICE抑制蛋白（c-FLIP）是一种抗氧化剂，也是DISC的重要组成部分，在NF-κB信号通路中抑制调节性I κ B激酶-γ（IKKγ）蛋白亚基上游的NF-κB，并且在抑制FasL诱导的NF-κB活性的背景下，Akt和c-FLIP之间存在正向串扰。研究发现c-FLIP的两个死亡效应结构域（DED）的存在及其半胱氨酸蛋白酶样结构域的S-亚硝基化对于介导c-FLIP依赖性下调NF-κB活性非常重要。综上所述，我们的研究揭示了NF-κB和PI 3 K/Akt之间的新联系，并建立了c-FLIP作为FasL介导的细胞死亡的重要调节因子。
Fas ligand (FasL) belongs to the tumor necrosis factor (TNF) family of death ligands, and its binding to the Fas receptor leads to activation of several downstream signaling pathways and proteins, including nuclear factor-kappa B (NF-κB) and phosphatidylinositol 3-kinase (PI3K)/Akt. However, it is not known whether cross talk exists between NF-κB and PI3K/Akt in the context of FasL signaling. We demonstrate using both human renal epithelial 293T cells and Jurkat T-lymphocyte cells that although FasL activates both Akt and NF-κB, Akt inhibits FasL-dependent NF-κB activity in a ROS-dependent manner. FLICE-inhibitory protein (c-FLIP), an antioxidant and an important component of the DISC, also represses NF-κB upstream of the regulatory I kappa B kinase-gamma (IKKγ) protein sub-unit in the NF-κB signaling pathway, and positive cross talk exists between Akt and c-FLIP in the context of inhibition of FasL-induced NF-κB activity. The presence of two death effector domains (DED) of c-FLIP, and S-nitrosylation of its caspase-like domain were found to be important for mediating c-FLIP-dependent down-regulation NF-κB activity. Taken together, our study reveals a novel link between NF-κB and PI3K/Akt, and establishes c-FLIP as an important regulator of FasL-mediated cell death.
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影响因子：
4
作者：
Field, N;Low, W;Collins, M
通讯作者：
Collins, M
影响因子：
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作者：
Chang, DW;Xing, Z;Yang, XL
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DOI：
10.1073/pnas.94.21.11333
发表时间：
1997-10-14
影响因子：
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通讯作者：
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DOI：
10.1006/bbrc.2000.2626
发表时间：
2000-05-10
影响因子：
3.1
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通讯作者：
McLachlan, JA
影响因子：
8
作者：
Dumont, A;Hehner, SP;Schmitz, ML
通讯作者：
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