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Antioxidant c-FLIP inhibits Fas ligand-induced NF-kappaB activation in a phosphatidylinositol 3-kinase/Akt-dependent manner.


ABSTRACT: Fas ligand (FasL) belongs to the TNF family of death ligands, and its binding to the FasR leads to activation of several downstream signaling pathways and proteins, including NF-?B and PI3K/Akt. However, it is not known whether cross-talk exists between NF-?B 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-?B, Akt inhibits FasL-dependent NF-?B activity in a reactive oxygen species-dependent manner. Cellular FLICE-inhibitory protein (c-FLIP), an antioxidant and an important component of the death-inducing signaling complex, also represses NF-?B upstream of the regulatory I?B kinase-? protein subunit in the NF-?B signaling pathway, and positive cross-talk exists between Akt and c-FLIP in the context of inhibition of FasL-induced NF-?B activity. The presence of two death effector domains of c-FLIP and S-nitrosylation of its caspase-like domain were found to be important for mediating c-FLIP-dependent downregulation of NF-?B activity. Taken together, our study reveals a novel link between NF-?B and PI3K/Akt and establishes c-FLIP as an important regulator of FasL-mediated cell death.

SUBMITTER: Iyer AK 

PROVIDER: S-EPMC3169770 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Antioxidant c-FLIP inhibits Fas ligand-induced NF-kappaB activation in a phosphatidylinositol 3-kinase/Akt-dependent manner.

Iyer Anand Krishnan V AK   Azad Neelam N   Talbot Siera S   Stehlik Christian C   Lu Bin B   Wang Liying L   Rojanasakul Yon Y  

Journal of immunology (Baltimore, Md. : 1950) 20110819 6


Fas ligand (FasL) belongs to the TNF family of death ligands, and its binding to the FasR leads to activation of several downstream signaling pathways and proteins, including NF-κB and 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 reacti  ...[more]

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