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A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response

Ricin activates the proinflammatory ribotoxic stress response through the mitogen activated protein 3 kinase (MAP3K) ZAK, resulting in activation of mitogen activated protein kinases (MAPKs) p38 and JNK1/2. We had a novel zak−/− mouse generated to study the role of ZAK signaling in vivo during ricin...

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Autores principales: Jandhyala, Dakshina M., Wong, John, Mantis, Nicholas J., Magun, Bruce E., Leong, John M., Thorpe, Cheleste M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037485/
https://www.ncbi.nlm.nih.gov/pubmed/27598200
http://dx.doi.org/10.3390/toxins8090259
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author Jandhyala, Dakshina M.
Wong, John
Mantis, Nicholas J.
Magun, Bruce E.
Leong, John M.
Thorpe, Cheleste M.
author_facet Jandhyala, Dakshina M.
Wong, John
Mantis, Nicholas J.
Magun, Bruce E.
Leong, John M.
Thorpe, Cheleste M.
author_sort Jandhyala, Dakshina M.
collection PubMed
description Ricin activates the proinflammatory ribotoxic stress response through the mitogen activated protein 3 kinase (MAP3K) ZAK, resulting in activation of mitogen activated protein kinases (MAPKs) p38 and JNK1/2. We had a novel zak−/− mouse generated to study the role of ZAK signaling in vivo during ricin intoxication. To characterize this murine strain, we intoxicated zak−/− and zak+/+ bone marrow–derived murine macrophages with ricin, measured p38 and JNK1/2 activation by Western blot, and measured zak, c-jun, and cxcl-1 expression by qRT-PCR. To determine whether zak−/− mice differed from wild-type mice in their in vivo response to ricin, we performed oral ricin intoxication experiments with zak+/+ and zak−/− mice, using blinded histopathology scoring of duodenal tissue sections to determine differences in tissue damage. Unlike macrophages derived from zak+/+ mice, those derived from the novel zak−/− strain fail to activate p38 and JNK1/2 and have decreased c-jun and cxcl-1 expression following ricin intoxication. Furthermore, compared with zak+/+ mice, zak−/− mice have decreased duodenal damage following in vivo ricin challenge. zak−/− mice demonstrate a distinct ribotoxic stress–associated phenotype in response to ricin and therefore provide a new animal model for in vivo studies of ZAK signaling.
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spelling pubmed-50374852016-09-29 A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response Jandhyala, Dakshina M. Wong, John Mantis, Nicholas J. Magun, Bruce E. Leong, John M. Thorpe, Cheleste M. Toxins (Basel) Communication Ricin activates the proinflammatory ribotoxic stress response through the mitogen activated protein 3 kinase (MAP3K) ZAK, resulting in activation of mitogen activated protein kinases (MAPKs) p38 and JNK1/2. We had a novel zak−/− mouse generated to study the role of ZAK signaling in vivo during ricin intoxication. To characterize this murine strain, we intoxicated zak−/− and zak+/+ bone marrow–derived murine macrophages with ricin, measured p38 and JNK1/2 activation by Western blot, and measured zak, c-jun, and cxcl-1 expression by qRT-PCR. To determine whether zak−/− mice differed from wild-type mice in their in vivo response to ricin, we performed oral ricin intoxication experiments with zak+/+ and zak−/− mice, using blinded histopathology scoring of duodenal tissue sections to determine differences in tissue damage. Unlike macrophages derived from zak+/+ mice, those derived from the novel zak−/− strain fail to activate p38 and JNK1/2 and have decreased c-jun and cxcl-1 expression following ricin intoxication. Furthermore, compared with zak+/+ mice, zak−/− mice have decreased duodenal damage following in vivo ricin challenge. zak−/− mice demonstrate a distinct ribotoxic stress–associated phenotype in response to ricin and therefore provide a new animal model for in vivo studies of ZAK signaling. MDPI 2016-09-02 /pmc/articles/PMC5037485/ /pubmed/27598200 http://dx.doi.org/10.3390/toxins8090259 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Jandhyala, Dakshina M.
Wong, John
Mantis, Nicholas J.
Magun, Bruce E.
Leong, John M.
Thorpe, Cheleste M.
A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response
title A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response
title_full A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response
title_fullStr A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response
title_full_unstemmed A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response
title_short A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response
title_sort novel zak knockout mouse with a defective ribotoxic stress response
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037485/
https://www.ncbi.nlm.nih.gov/pubmed/27598200
http://dx.doi.org/10.3390/toxins8090259
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