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- Publisher Website: 10.1093/toxsci/kfg148
- Scopus: eid_2-s2.0-0041589432
- PMID: 12773753
- WOS: WOS:000184397200015
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Article: Role of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response
Title | Role of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response |
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Authors | |
Keywords | Apoptosis Macrophage Mitogen-activated protein kinase Mycotoxin Trichothecene |
Issue Date | 2003 |
Publisher | Oxford 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? |
Abstract | Trichothecene 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 Identifier | http://hdl.handle.net/10722/170329 |
ISSN | 2023 Impact Factor: 3.4 2023 SCImago Journal Rankings: 0.911 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Zhou, HR | en_US |
dc.contributor.author | Lau, AS | en_US |
dc.contributor.author | Pestka, JJ | en_US |
dc.date.accessioned | 2012-10-30T06:07:31Z | - |
dc.date.available | 2012-10-30T06:07:31Z | - |
dc.date.issued | 2003 | en_US |
dc.identifier.citation | Toxicological Sciences, 2003, v. 74 n. 2, p. 335-344 | en_US |
dc.identifier.issn | 1096-6080 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/170329 | - |
dc.description.abstract | Trichothecene 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.language | eng | en_US |
dc.publisher | Oxford University Press. The Journal's web site is located at http://toxsci.oxfordjournals.org/ | en_US |
dc.relation.ispartof | Toxicological Sciences | en_US |
dc.rights | Toxicological Sciences. Copyright © Oxford University Press. | - |
dc.subject | Apoptosis | - |
dc.subject | Macrophage | - |
dc.subject | Mitogen-activated protein kinase | - |
dc.subject | Mycotoxin | - |
dc.subject | Trichothecene | - |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Anisomycin - Pharmacology | en_US |
dc.subject.mesh | Apoptosis - Drug Effects - Physiology | en_US |
dc.subject.mesh | Dose-Response Relationship, Drug | en_US |
dc.subject.mesh | Emetine - Pharmacology | en_US |
dc.subject.mesh | Enzyme Activation - Drug Effects | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Macrophages - Drug Effects - Enzymology - Pathology | en_US |
dc.subject.mesh | Mice | en_US |
dc.subject.mesh | Mitogen-Activated Protein Kinase Kinases - Antagonists & Inhibitors - Biosynthesis | en_US |
dc.subject.mesh | Mitogen-Activated Protein Kinases - Antagonists & Inhibitors - Biosynthesis | en_US |
dc.subject.mesh | Monocytes - Drug Effects - Enzymology - Pathology | en_US |
dc.subject.mesh | Protein Biosynthesis - Drug Effects | en_US |
dc.subject.mesh | Protein Synthesis Inhibitors - Pharmacology | en_US |
dc.subject.mesh | Ribosomes - Drug Effects - Enzymology | en_US |
dc.subject.mesh | Trichothecenes - Toxicity | en_US |
dc.subject.mesh | U937 Cells | en_US |
dc.subject.mesh | Eif-2 Kinase - Antagonists & Inhibitors - Biosynthesis | en_US |
dc.title | Role of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response | en_US |
dc.type | Article | en_US |
dc.identifier.email | Lau, AS:asylau@hku.hk | en_US |
dc.identifier.authority | Lau, AS=rp00474 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1093/toxsci/kfg148 | en_US |
dc.identifier.pmid | 12773753 | - |
dc.identifier.scopus | eid_2-s2.0-0041589432 | en_US |
dc.identifier.hkuros | 79590 | - |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-0041589432&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 74 | en_US |
dc.identifier.issue | 2 | en_US |
dc.identifier.spage | 335 | en_US |
dc.identifier.epage | 344 | en_US |
dc.identifier.isi | WOS:000184397200015 | - |
dc.publisher.place | United Kingdom | en_US |
dc.identifier.scopusauthorid | Zhou, HR=36089494200 | en_US |
dc.identifier.scopusauthorid | Lau, AS=7202626202 | en_US |
dc.identifier.scopusauthorid | Pestka, JJ=7101824985 | en_US |
dc.identifier.issnl | 1096-0929 | - |