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- Title
XIAP discriminates between type I and type II FAS-induced apoptosis.
- Authors
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
- 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 β-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 β-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.
- Subjects
APOPTOSIS; RECEPTOR-ligand complexes; DNA-ligand interactions; AUTOIMMUNITY; LIVER cells; AUTOANTIBODIES; CARRIER proteins; CANCER patients; MOUSE diseases; LABORATORY mice
- Publication
Nature, 2009, Vol 460, Issue 7258, p1035
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature08229