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dc.contributor.authorSamali, Afshin
dc.date.accessioned2015-04-17T10:45:23Z
dc.date.available2015-04-17T10:45:23Z
dc.date.issued2013
dc.identifier.citationCawley, K,Logue, SE,Gorman, AM,Zeng, QP,Patterson, J,Gupta, S,Samali, A (2013) 'Disruption of microRNA Biogenesis Confers Resistance to ER Stress-Induced Cell Death Upstream of the Mitochondrion'. Plos One, 8 .en_US
dc.identifier.urihttp://hdl.handle.net/10379/4924
dc.description.abstractGlobal downregulation of microRNAs (miRNAs) is a common feature of human tumors and has been shown to enhance cancer progression. Several components of the miRNA biogenesis machinery (XPO5, DICER and TRBP) have been shown to act as haploinsufficient tumor suppressors. How the deregulation of miRNA biogenesis promotes tumor development is not clearly understood. Here we show that loss of miRNA biogenesis increased resistance to endoplasmic reticulum (ER) stress-induced cell death. We observed that HCT116 cells with a DICER hypomorphic mutation (Exn5/Exn5) or where DICER or DROSHA were knocked down were resistant to ER stress-induced cell death. Extensive analysis revealed little difference in the unfolded protein response (UPR) of WT compared to Exn5/Exn5 HCT116 cells upon ER stress treatment. However, analysis of the intrinsic apoptotic pathway showed that resistance occurred upstream of the mitochondria. In particular, BAX activation and dissipation of mitochondrial membrane potential was attenuated, and there was altered expression of BCL-2 family proteins. These observations demonstrate a key role for miRNAs as critical modulators of the ER stress response. In our model, downregulation of miRNA biogenesis delays ER stress-induced apoptosis. This suggests that disrupted miRNA biogenesis may contribute to cancer progression by inhibiting ER stress-induced cell death.en_US
dc.language.isoenen_US
dc.relation.ispartofPlos Oneen
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Ireland
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/3.0/ie/
dc.subjectENDOPLASMIC-RETICULUM STRESSen_US
dc.subjectUNFOLDED PROTEIN RESPONSEen_US
dc.subjectINDUCED APOPTOSISen_US
dc.subjectDOWN-REGULATIONen_US
dc.subjectBREAST-CANCERen_US
dc.subjectBCL-2 FAMILYen_US
dc.subjectDICER EXPRESSIONen_US
dc.subjectPOOR-PROGNOSISen_US
dc.subjectETOPOSIDEen_US
dc.subjectDROSHAen_US
dc.titleDisruption of microRNA Biogenesis Confers Resistance to ER Stress-Induced Cell Death Upstream of the Mitochondrionen_US
dc.typeArticleen_US
dc.date.updated2015-03-16T14:46:56Z
dc.identifier.doiARTN e73870
dc.description.peer-reviewedpeer-reviewed
dc.contributor.funder|~|
dc.internal.rssid5040789
dc.local.contactAfshin Samali, Bioscience Research Building, North Campus, Nui Galway. 2440 Email: afshin.samali@nuigalway.ie
dc.local.copyrightcheckedYes
dc.local.versionPUBLISHED
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Attribution-NonCommercial-NoDerivs 3.0 Ireland
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Ireland