Shortcut to death

✍ Scribed by Jörn M. Schattenberg; Marcus Schuchmann

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 396 KB
• Volume: 50
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.23400

✦ Synopsis

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 ␤-cells, caspase cascade amplification through caspase-8-mediated activation of the proapoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (Xchromosome linked inhibitor of apoptosis protein) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAPbinding protein with low pI) mimetic drug in mice rendered hepatocytes and ␤-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.