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Article: Role of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response

TitleRole of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response
Authors
Issue Date2003
PublisherOxford University Press. The Journal's web site is located at http://toxsci.oxfordjournals.org/
Citation
Toxicological Sciences, 2003, v. 74 n. 2, p. 335-344 How to Cite?
AbstractTrichothecene mycotoxins and other protein synthesis inhibitors activate mitogen-activated protein kinase (MAPKs) via a mechanism that has been termed the "ribotoxic stress response." MAPKs are believed to mediate the leukocyte apoptosis that is observed following experimental exposure to these chemical agents in vitro and in vivo. The purpose of this research was to test the hypothesis that double-stranded, RNA-activated protein kinase R (PKR) is a critical upstream mediator of the ribotoxic stress response induced by the trichothecene deoxynivalenol (DON) and other translational inhibitors. DON was found to readily induce phosphorylation of JNK 1/2, ERK 1/2, and p38 in the murine macrophage RAW 264.7 cell line, within 5 min of culture addition, in a concentration-dependent fashion. Effects were maximal from 15 to 30 min and lasted up to 6 h. The translational inhibitors anisomycin and emetine also had similar effects when added to cultures at equipotent concentrations to DON. DON rapidly activated PKR within 1 to 5 min, as evidenced by autophosphorylation and by phosphorylation of eukaryotic initiation factor 2α (IF2α). Interestingly, the latter effect was associated with rapid degradation of eIF2α. Pretreatment of RAW 264.7 cells with two inhibitors of PKR, 2-aminopurine (2-AP) or adenine (Ad), markedly impaired MAPK phosphorylation in RAW 264.7 cells according to the following rank order JNK > p38 > ERK. The capacity of DON to induce MAPK phosphorylation was also markedly suppressed in a stable transformant of the human promonocytic U-937 cell line containing an antisense PKR expression vector. This suppression followed a rank order of JNK > p38 > ERK in this PKR-deficient cell line when compared to control cells transfected with vector only. Apoptosis induction by DON and two other translational inhibitors, anisomycin and emetine, was almost completely abrogated in PKR-deficient cells. Together, the results indicate that PKR plays a critical upstream role in the ribotoxic stress response inducible by translational inhibitors.
Persistent Identifierhttp://hdl.handle.net/10722/170329
ISSN
2015 Impact Factor: 3.88
2015 SCImago Journal Rankings: 1.686
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorZhou, HRen_US
dc.contributor.authorLau, ASen_US
dc.contributor.authorPestka, JJen_US
dc.date.accessioned2012-10-30T06:07:31Z-
dc.date.available2012-10-30T06:07:31Z-
dc.date.issued2003en_US
dc.identifier.citationToxicological Sciences, 2003, v. 74 n. 2, p. 335-344en_US
dc.identifier.issn1096-6080en_US
dc.identifier.urihttp://hdl.handle.net/10722/170329-
dc.description.abstractTrichothecene mycotoxins and other protein synthesis inhibitors activate mitogen-activated protein kinase (MAPKs) via a mechanism that has been termed the "ribotoxic stress response." MAPKs are believed to mediate the leukocyte apoptosis that is observed following experimental exposure to these chemical agents in vitro and in vivo. The purpose of this research was to test the hypothesis that double-stranded, RNA-activated protein kinase R (PKR) is a critical upstream mediator of the ribotoxic stress response induced by the trichothecene deoxynivalenol (DON) and other translational inhibitors. DON was found to readily induce phosphorylation of JNK 1/2, ERK 1/2, and p38 in the murine macrophage RAW 264.7 cell line, within 5 min of culture addition, in a concentration-dependent fashion. Effects were maximal from 15 to 30 min and lasted up to 6 h. The translational inhibitors anisomycin and emetine also had similar effects when added to cultures at equipotent concentrations to DON. DON rapidly activated PKR within 1 to 5 min, as evidenced by autophosphorylation and by phosphorylation of eukaryotic initiation factor 2α (IF2α). Interestingly, the latter effect was associated with rapid degradation of eIF2α. Pretreatment of RAW 264.7 cells with two inhibitors of PKR, 2-aminopurine (2-AP) or adenine (Ad), markedly impaired MAPK phosphorylation in RAW 264.7 cells according to the following rank order JNK > p38 > ERK. The capacity of DON to induce MAPK phosphorylation was also markedly suppressed in a stable transformant of the human promonocytic U-937 cell line containing an antisense PKR expression vector. This suppression followed a rank order of JNK > p38 > ERK in this PKR-deficient cell line when compared to control cells transfected with vector only. Apoptosis induction by DON and two other translational inhibitors, anisomycin and emetine, was almost completely abrogated in PKR-deficient cells. Together, the results indicate that PKR plays a critical upstream role in the ribotoxic stress response inducible by translational inhibitors.en_US
dc.languageengen_US
dc.publisherOxford University Press. The Journal's web site is located at http://toxsci.oxfordjournals.org/en_US
dc.relation.ispartofToxicological Sciencesen_US
dc.rightsToxicological Sciences. Copyright © Oxford University Press.-
dc.subject.meshAnimalsen_US
dc.subject.meshAnisomycin - Pharmacologyen_US
dc.subject.meshApoptosis - Drug Effects - Physiologyen_US
dc.subject.meshDose-Response Relationship, Drugen_US
dc.subject.meshEmetine - Pharmacologyen_US
dc.subject.meshEnzyme Activation - Drug Effectsen_US
dc.subject.meshHumansen_US
dc.subject.meshMacrophages - Drug Effects - Enzymology - Pathologyen_US
dc.subject.meshMiceen_US
dc.subject.meshMitogen-Activated Protein Kinase Kinases - Antagonists & Inhibitors - Biosynthesisen_US
dc.subject.meshMitogen-Activated Protein Kinases - Antagonists & Inhibitors - Biosynthesisen_US
dc.subject.meshMonocytes - Drug Effects - Enzymology - Pathologyen_US
dc.subject.meshProtein Biosynthesis - Drug Effectsen_US
dc.subject.meshProtein Synthesis Inhibitors - Pharmacologyen_US
dc.subject.meshRibosomes - Drug Effects - Enzymologyen_US
dc.subject.meshTrichothecenes - Toxicityen_US
dc.subject.meshU937 Cellsen_US
dc.subject.meshEif-2 Kinase - Antagonists & Inhibitors - Biosynthesisen_US
dc.titleRole of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress responseen_US
dc.typeArticleen_US
dc.identifier.emailLau, AS:asylau@hku.hken_US
dc.identifier.authorityLau, AS=rp00474en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1093/toxsci/kfg148en_US
dc.identifier.pmid12773753-
dc.identifier.scopuseid_2-s2.0-0041589432en_US
dc.identifier.hkuros79590-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0041589432&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume74en_US
dc.identifier.issue2en_US
dc.identifier.spage335en_US
dc.identifier.epage344en_US
dc.identifier.isiWOS:000184397200015-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridZhou, HR=36089494200en_US
dc.identifier.scopusauthoridLau, AS=7202626202en_US
dc.identifier.scopusauthoridPestka, JJ=7101824985en_US

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