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dc.contributor.authorKavanagh, E
dc.contributor.authorRodhe, J
dc.contributor.authorBurguillos, MA
dc.contributor.authorVenero, JL
dc.contributor.authorJoseph, B
dc.date.accessioned2015-02-23T13:13:42Z
dc.date.available2015-02-23T13:13:42Z
dc.date.issued2014
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/6682
dc.description.abstractThe activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders.
dc.format.extente1565 - ?
dc.languageENG
dc.relation.isreplacedby123456789/9292
dc.relation.isreplacedbyhttp://qmro.qmul.ac.uk/xmlui/handle/123456789/9292
dc.titleRegulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia.
dc.identifier.doi10.1038/cddis.2014.514
dc.relation.isPartOfCell Death Dis
pubs.author-urlhttp://www.ncbi.nlm.nih.gov/pubmed/25501826
pubs.author-urlhttp://www.ncbi.nlm.nih.gov/pubmed/25501826
pubs.volume5


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