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dc.contributor.authorDeegan, Shane
dc.contributor.authorSaveljeva, Svetlana
dc.contributor.authorLogue, Susan E
dc.contributor.authorPakos-Zebrucka, Karolina
dc.contributor.authorGupta, Sanjeev
dc.contributor.authorVandenabeele, Peter
dc.contributor.authorBertrand, Mathieu JM
dc.contributor.authorSamali, Afshin
dc.date.accessioned2018-09-20T16:05:34Z
dc.date.available2018-09-20T16:05:34Z
dc.date.issued2014-11-02
dc.identifier.citationDeegan, Shane; Saveljeva, Svetlana; Logue, Susan E; Pakos-Zebrucka, Karolina; Gupta, Sanjeev; Vandenabeele, Peter; Bertrand, Mathieu JM; Samali, Afshin (2014). Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under er stress conditions. Autophagy 10 (11), 1921-1936
dc.identifier.issn1554-8627,1554-8635
dc.identifier.urihttp://hdl.handle.net/10379/11121
dc.description.abstractEndoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells.
dc.publisherInforma UK Limited
dc.relation.ispartofAutophagy
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Ireland
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/3.0/ie/
dc.subjectapoptosis
dc.subjectautophagic cell death
dc.subjectautophagy
dc.subjectcaspase
dc.subjectendoplasmic reticulum stress
dc.subjectunfolded protein response
dc.subjectendoplasmic-reticulum stress
dc.subjectcell-death
dc.subjectcytochrome-c
dc.subjectbcl-2 family
dc.subjectcaspase-8
dc.subjectactivation
dc.subjectassays
dc.subjectroles
dc.subjectchain
dc.subjectfadd
dc.titleDeficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under er stress conditions
dc.typeArticle
dc.identifier.doi10.4161/15548627.2014.981790
dc.local.publishedsourcehttps://www.tandfonline.com/doi/pdf/10.4161/15548627.2014.981790?needAccess=true
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