PMID- 27598200
OWN - NLM
STAT- MEDLINE
DCOM- 20171108
LR  - 20181113
IS  - 2072-6651 (Electronic)
IS  - 2072-6651 (Linking)
VI  - 8
IP  - 9
DP  - 2016 Sep 2
TI  - A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response.
LID - 10.3390/toxins8090259 [doi]
LID - 259
AB  - 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.
FAU - Jandhyala, Dakshina M
AU  - Jandhyala DM
AD  - Department of Molecular Biology and Microbiology, Tufts University School of 
      Medicine, Boston, MA 02111, USA. dakshina.jandhyala@tufts.edu.
AD  - Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, 
      Boston, MA 02111, USA. dakshina.jandhyala@tufts.edu.
FAU - Wong, John
AU  - Wong J
AD  - School of Nursing, MGH Institute of Health Professions, Boston, MA 02129, USA. 
      jwong1@mghihp.edu.
FAU - Mantis, Nicholas J
AU  - Mantis NJ
AD  - Division of Infectious Disease, Wadsworth Center, New York State Department of 
      Health, Albany, NY 12208, USA. nicholas.mantis@health.ny.gov.
FAU - Magun, Bruce E
AU  - Magun BE
AD  - School of Nursing, MGH Institute of Health Professions, Boston, MA 02129, USA. 
      bmagun@mghihp.edu.
FAU - Leong, John M
AU  - Leong JM
AD  - Department of Molecular Biology and Microbiology, Tufts University School of 
      Medicine, Boston, MA 02111, USA. john.leong@tufts.edu.
FAU - Thorpe, Cheleste M
AU  - Thorpe CM
AD  - Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, 
      Boston, MA 02111, USA. cthorpe@tuftsmedicalcenter.org.
LA  - eng
GR  - R01 AI046454/AI/NIAID NIH HHS/United States
GR  - R21 AI088336/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160902
PL  - Switzerland
TA  - Toxins (Basel)
JT  - Toxins
JID - 101530765
RN  - 0 (Chemokine CXCL1)
RN  - 0 (Cxcl1 protein, mouse)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 9009-86-3 (Ricin)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (ZAK protein, mouse)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Chemokine CXCL1/metabolism
MH  - Duodenum/*drug effects/enzymology/pathology
MH  - Enzyme Activation
MH  - Genotype
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - MAP Kinase Kinase Kinases/*deficiency/genetics
MH  - Macrophages/*drug effects/enzymology/pathology
MH  - Mice, 129 Strain
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Phenotype
MH  - Proto-Oncogene Proteins c-jun/metabolism
MH  - Ricin/*toxicity
MH  - Signal Transduction/drug effects
MH  - Stress, Physiological/*drug effects
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC5037485
OTO - NOTNLM
OT  - JNK1/2
OT  - MAP3K
OT  - Ribotoxic Stress Response
OT  - Ricin
OT  - ZAK
OT  - inflammation
OT  - macrophage
OT  - murine
OT  - p38
OT  - protein synthesis inhibition
COIS- The authors declare no conflict of interest.
EDAT- 2016/09/07 06:00
MHDA- 2017/11/09 06:00
PMCR- 2016/09/01
CRDT- 2016/09/07 06:00
PHST- 2016/04/26 00:00 [received]
PHST- 2016/08/13 00:00 [revised]
PHST- 2016/08/19 00:00 [accepted]
PHST- 2016/09/07 06:00 [entrez]
PHST- 2016/09/07 06:00 [pubmed]
PHST- 2017/11/09 06:00 [medline]
PHST- 2016/09/01 00:00 [pmc-release]
AID - toxins8090259 [pii]
AID - toxins-08-00259 [pii]
AID - 10.3390/toxins8090259 [doi]
PST - epublish
SO  - Toxins (Basel). 2016 Sep 2;8(9):259. doi: 10.3390/toxins8090259.