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Toxins 2016, 8(9), 259; doi:10.3390/toxins8090259

A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response

Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA
Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA 02111, USA
School of Nursing, MGH Institute of Health Professions, Boston, MA 02129, USA
Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, NY 12208, USA
Author to whom correspondence should be addressed.
Academic Editor: Daniel Gillet
Received: 26 April 2016 / Revised: 13 August 2016 / Accepted: 19 August 2016 / Published: 2 September 2016
(This article belongs to the Section Plant Toxins)
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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. View Full-Text
Keywords: ZAK; MAP3K; Ricin; Ribotoxic Stress Response; protein synthesis inhibition; p38; JNK1/2; inflammation; murine; macrophage ZAK; MAP3K; Ricin; Ribotoxic Stress Response; protein synthesis inhibition; p38; JNK1/2; inflammation; murine; macrophage

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Jandhyala, D.M.; Wong, J.; Mantis, N.J.; Magun, B.E.; Leong, J.M.; Thorpe, C.M. A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response. Toxins 2016, 8, 259.

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