Analysis of candidate antagonists of IAP-mediated caspase inhibition using yeast reconstituted with the mammalian Apaf-1-activated apoptosis mechanism |
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| Authors: | Hawkins C J Silke J Verhagen A M Foster R Ekert P G Ashley D M |
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| Affiliation: | (1) Department of Haematology and Oncology, Murdoch Children's Research Institute, Australia;(2) The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Parkville, 3050, Australia;(3) Department of Neonatology, Royal Children's Hospital, Flemington Road, Parkville, 3052, Australia;(4) Department of Paediatrics, University of Melbourne, Parkville, 3010, Australia;(5) Department of Paediatrics, University of Melbourne, Parkville, 3010, Australia |
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| Abstract: | We have reconstituted the Apaf-1-activated apoptosis mechanism in Sacchromyces cerevisiae such that the presence of a constitutively active form of Apaf-1 together with both Caspase-9 and Caspase-3 results in yeast death. This system is a good model of the Apaf-1-activated pathway in mammalian cells: MIHA (XIAP/hILP), and to a lesser degree MIHB (c-IAP1/HIAP2) and MIHC (c-IAP-2/HIAP1) can inhibit caspases in this system, and protection by IAPs (inhibitor of apoptosis) can be abrogated by coexpression of the Drosophila pro-apoptotic proteins HID and GRIM or the mammalian protein DIABLO/Smac. Using this system we demonstrate that unlike DIABLO/Smac, other proteins which interact with mammalian IAPs (TAB-1, Zap-1, Traf-1 and Traf-2) do not act to antagonise IAP- mediated caspase inhibition. |
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| Keywords: | caspase IAP apoptosis yeast Drosophila S. cerevisiae |
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