Publication Date:
2009-07-25
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956120/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956120/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- CA 43540/CA/NCI NIH HHS/ -- CA 80188/CA/NCI NIH HHS/ -- R01 CA043540/CA/NCI NIH HHS/ -- R01 CA043540-09/CA/NCI NIH HHS/ -- R01 CA043540-22/CA/NCI NIH HHS/ -- R01 CA080188-01/CA/NCI NIH HHS/ -- R01 CA080188-08/CA/NCI NIH HHS/ -- England -- Nature. 2009 Aug 20;460(7258):1035-9. doi: 10.1038/nature08229. Epub 2009 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19626005" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, CD95/antagonists & inhibitors/immunology/*metabolism
;
*Apoptosis
;
BH3 Interacting Domain Death Agonist Protein/deficiency/genetics
;
Biomimetic Materials/pharmacology
;
Caspase Inhibitors
;
Enzyme Activation
;
Fas Ligand Protein/metabolism
;
Female
;
Hepatitis/metabolism/pathology
;
Hepatocytes/cytology/drug effects/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Signal Transduction
;
Thymus Gland/cytology/drug effects
;
X-Linked Inhibitor of Apoptosis Protein/antagonists &
;
inhibitors/deficiency/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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