XIAP discriminates between type I and type II FAS-induced apoptosis

Jost, Philipp J; Grabow, Stephanie; Gray, Daniel; McKenzie, Mark D; Nachbur, Ueli; Huang, David C S; Bouillet, Philippe; Thomas, Helen E; Borner, Christoph; Silke, John; Strasser, Andreas; Kaufmann, Thomas (2009). XIAP discriminates between type I and type II FAS-induced apoptosis. Nature, 460(7258), pp. 1035-1039. London: Macmillan Journals Ltd. 10.1038/nature08229

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
UniBE Contributor:	Kaufmann, Thomas (B)
Subjects:	600 Technology > 610 Medicine & health
ISSN:	0028-0836
Publisher:	Macmillan Journals Ltd.
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:10
Last Modified:	29 Mar 2023 23:33
Publisher DOI:	10.1038/nature08229
PubMed ID:	19626005
Web of Science ID:	000269085500039
URI:	https://boris.unibe.ch/id/eprint/30679 (FactScience: 194944)