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dc.contributor.authorHur, Kyu Yeon
dc.contributor.authorSo, Jae-Seon
dc.contributor.authorFrank-Kamenetsky, Maria
dc.contributor.authorFitzgerald, Kevin
dc.contributor.authorKotelianski, Victor E.
dc.contributor.authorIwawaki, Takao
dc.contributor.authorLee, Ann-Hwee
dc.contributor.authorRuda, Vera
dc.contributor.authorGlimcher, Laurie H
dc.date.accessioned2012-05-04T21:42:37Z
dc.date.available2012-05-04T21:42:37Z
dc.date.issued2012-01
dc.date.submitted2011-06
dc.identifier.issn0022-1007
dc.identifier.issn1540-9538
dc.identifier.urihttp://hdl.handle.net/1721.1/70518
dc.descriptionOnline supplemental material. Table S1 shows the expression of genes related to drug metabolism in XBP1-deficient liver. Online supplemental material is available at http://www.jem.org/cgi/content/full/jem.20111298/DC1.en_US
dc.description.abstractThe mammalian stress sensor IRE1α plays a central role in the unfolded protein, or endoplasmic reticulum (ER), stress response by activating its downstream transcription factor XBP1 via an unconventional splicing mechanism. IRE1α can also induce the degradation of a subset of mRNAs in a process termed regulated IRE1-dependent decay (RIDD). Although diverse mRNA species can be degraded by IRE1α in vitro, the pathophysiological functions of RIDD are only beginning to be explored. Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in young adults in the United States and is primarily caused by CYP1A2-, CYP2E1-, and CYP3A4-driven conversion of APAP into hepatotoxic metabolites. We demonstrate here that genetic ablation of XBP1 results in constitutive IRE1α activation in the liver, leading to RIDD of Cyp1a2 and Cyp2e1 mRNAs, reduced JNK activation, and protection of mice from APAP-induced hepatotoxicity. A pharmacological ER stress inducer that activated IRE1α suppressed the expression of Cyp1a2 and Cyp2e1 in WT, but not IRE1α-deficient mouse liver, indicating the essential role of IRE1α in the down-regulation of these mRNAs upon ER stress. Our study reveals an unexpected function of RIDD in drug metabolism.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant AI32412)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant DK082448)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant DK089211)en_US
dc.description.sponsorshipAmerican Heart Associationen_US
dc.language.isoen_US
dc.publisherRockefeller University Press, Theen_US
dc.relation.isversionofhttp://dx.doi.org/10.1084/jem.20111298en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alike 3.0 Unporteden_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/en_US
dc.sourceRockefeller UPen_US
dc.titleIRE1α activation protects mice against acetaminophen-induced hepatotoxicityen_US
dc.typeArticleen_US
dc.identifier.citationHur, K. Y. et al. “IRE1  Activation Protects Mice Against Acetaminophen-induced Hepatotoxicity.” Journal of Experimental Medicine 209.2 (2012): 307–318. Web. 4 May 2012.en_US
dc.contributor.departmentRagon Institute of MGH, MIT and Harvarden_US
dc.contributor.departmentKoch Institute for Integrative Cancer Research at MITen_US
dc.contributor.approverRuda, Vera
dc.contributor.mitauthorRuda, Vera
dc.contributor.mitauthorGlimcher, Laurie H.
dc.relation.journalJournal of Experimental Medicineen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsHur, K. Y.; So, J.-S.; Ruda, V.; Frank-Kamenetsky, M.; Fitzgerald, K.; Koteliansky, V.; Iwawaki, T.; Glimcher, L. H.; Lee, A.-H.en
mit.licensePUBLISHER_CCen_US
mit.metadata.statusComplete


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