A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response
AbstractRicin 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
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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.
Jandhyala DM, Wong J, Mantis NJ, Magun BE, Leong JM, Thorpe CM. A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response. Toxins. 2016; 8(9):259.Chicago/Turabian Style
Jandhyala, Dakshina M.; Wong, John; Mantis, Nicholas J.; Magun, Bruce E.; Leong, John M.; Thorpe, Cheleste M. 2016. "A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response." Toxins 8, no. 9: 259.
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