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

Full text not available from this repository. (Request a copy)

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

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:

07 Dec 2013 13:36

Publisher DOI:

10.1038/nature08229

PubMed ID:

19626005

Web of Science ID:

000269085500039

URI:

https://boris.unibe.ch/id/eprint/30679 (FactScience: 194944)

Actions (login required)

Edit item Edit item
Provide Feedback