Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Jost, PJ; Grabow, S; Gray, D; McKenzie, MD; Nachbur, U; Huang, DC; Bouillet, P; Thomas, HE; Borner, C; Silke, J; Strasser, A; Kaufmann, T.
XIAP discriminates between type I and type II FAS-induced apoptosis.
Nature. 2009; 460(7258):1035-1039
Doi: 10.1038/nature08229
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- Führende Autor*innen der Med Uni Graz
- Jost Philipp
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Apoptosis -
- BH3 Interacting Domain Death Agonist Protein - deficiency
- BH3 Interacting Domain Death Agonist Protein - genetics
- Biomimetic Materials - pharmacology
- Caspase Inhibitors -
- Enzyme Activation -
- Fas Ligand Protein - metabolism
- Female -
- Hepatitis - metabolism
- Hepatitis - pathology
- Hepatocytes - cytology
- Hepatocytes - drug effects
- Hepatocytes - metabolism
- Male -
- Mice -
- Mice, Inbred C57BL -
- Signal Transduction -
- Thymus Gland - cytology
- Thymus Gland - drug effects
- X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors
- X-Linked Inhibitor of Apoptosis Protein - deficiency
- X-Linked Inhibitor of Apoptosis Protein - genetics
- X-Linked Inhibitor of Apoptosis Protein - metabolism
- fas Receptor - antagonists & inhibitors
- fas Receptor - immunology
- fas Receptor - metabolism