title: XIAP discriminates between type I and type II FAS-induced apoptosis.
abstract: FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of 'effector caspases' by FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia.
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Jost
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grabow
authors.forename: Daniel
authors.initials: D
authors.lastname: Gray
authors.forename: Mark D
authors.initials: MD
authors.lastname: McKenzie
authors.forename: Ueli
authors.initials: U
authors.lastname: Nachbur
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.forename: Christoph
authors.initials: C
authors.lastname: Borner
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000172:deficiency / Q000235:genetics; D040761:Biomimetic Materials / Q000494:pharmacology; D061945:Caspase Inhibitors; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D061945:Caspase Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor