title: ERK-mediated activation of Fas apoptotic inhibitory molecule 2 (Faim2) prevents apoptosis of 661W cells in a model of detachment-induced photoreceptor cell death.
abstract: In this study, we examined the role of Fas apoptotic inhibitory molecule 2 (Faim2), an inhibitor of the Fas signaling pathway, and its regulation by stress kinase signaling during Fas-mediated apoptosis of 661W cells, an immortalized photoreceptor-like cell line Treatment of 661W cells with a Fas-activating antibody led to increased levels of Faim2. Both ERK and JNK stress kinase pathways were activated in Fas-treated 661W cells, but only the inhibition of the ERK pathway reduced the levels of Faim2. Blocking the ERK pathway using a pharmacological inhibitor increased the susceptibility of 661W cells to Fas-induced caspase activation and apoptosis. When the levels of Faim2 were reduced in 661W cells by siRNA knockdown, Fas activating antibody treatment resulted in earlier and more robust caspase activation, and increased cell death. These results demonstrate that Faim2 acts as a neuroprotectant during Fas-mediated apoptosis of 661W cells. The expression of Faim2 is triggered, at least in part, by Fas-receptor activation and subsequent ERK signaling. Our findings identify a novel protective pathway that auto-regulates Fas-induced photoreceptor apoptosis in vitro. Modulation of this pathway to increase Faim2 expression may be a potential therapeutic option to prevent photoreceptor death.
authors.affiliation: Department of Ophthalmology and Visual Sciences, WK Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Cagri G
authors.initials: CG
authors.lastname: Besirli
authors.forename: Qiong-Duon
authors.initials: QD
authors.lastname: Zheng
authors.forename: David M
authors.initials: DM
authors.lastname: Reed
authors.forename: David N
authors.initials: DN
authors.lastname: Zacks
mesh_terms: D000818:Animals; D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D012163:Retinal Detachment / Q000378:metabolism / Q000473:pathology*; D055214:Retinal Photoreceptor Cell Outer Segment / Q000502:physiology*; D015533:Transcriptional Activation; D019014:fas Receptor / Q000378:metabolism
chemical_list: D002070:Butadienes; C491899:Fas protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009570:Nitriles; C113580:U 0126; D019014:fas Receptor; C523971:lifeguard protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; C505526:Casp8 protein, mouse; D053181:Caspase 8