title: 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-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 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-κB upstream of the regulatory IκB kinase-γ protein subunit 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 of c-FLIP and S-nitrosylation of its caspase-like domain were found to be important for mediating c-FLIP-dependent downregulation of 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.
authors.affiliation: Department of Pharmaceutical Sciences, Hampton University, Hampton, VA 23668, USA. anand.iyer@hamptonu.edu
authors.forename: Anand Krishnan V
authors.initials: AK
authors.lastname: Iyer
authors.forename: Neelam
authors.initials: N
authors.lastname: Azad
authors.forename: Siera
authors.initials: S
authors.lastname: Talbot
authors.forename: Christian
authors.initials: C
authors.lastname: Stehlik
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.forename: Liying
authors.initials: L
authors.lastname: Wang
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D053222:Fas Ligand Protein / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000975:Antioxidants; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053222:Fas Ligand Protein; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt