PMID- 29684334
OWN - NLM
STAT- MEDLINE
DCOM- 20190506
LR  - 20190506
IS  - 1872-6240 (Electronic)
IS  - 0006-8993 (Linking)
VI  - 1691
DP  - 2018 Jul 15
TI  - The MKK7 inhibitor peptide GADD45beta-I attenuates ER stress-induced mitochondrial 
      dysfunction in HT22 cells: Involvement of JNK-Wnt pathway.
PG  - 1-8
LID - S0006-8993(18)30200-2 [pii]
LID - 10.1016/j.brainres.2018.04.012 [doi]
AB  - JNK, a member of the mitogen activated protein kinases (MAPKs) superfamily, plays 
      a key role in cell death in many neurological disorders, but systemic inhibition 
      of JNK has detrimental side effects. JNK can be regulated by two direct upstream 
      kinases: MAPK kinase 4 (MKK4) and MAPK kinase 7 (MKK7). Here, we investigated the 
      effect of GADD45beta-I, a recently designed cell-permeable inhibitor peptide for 
      MKK7, on endoplasmic reticulum (ER) stress-induced cytotoxicity in neuronal HT22 
      cells. We found that treatment with the ER stress inducer tunicamycin (TM) 
      increased the phosphorylation of JNK and MKK7 in HT22 cells, which was nullified 
      by GADD45beta-I. GADD45beta-I significantly attenuated TM-induced toxicity via 
      inhibiting apoptotic cell death, as evidenced by decreased number of 
      TUNEL-positive cells and reduced caspase-3 activity. GADD45beta-I treatment also 
      decreased expression of ER stress associated pro-apoptotic proteins and prevented 
      morphological changes of the ER after TM exposure. In addition, inhibition of 
      mitochondrial oxidative stress and preservation of intracellular ATP levels were 
      observed in GADD45beta-I-treated cells. The experiments using siRNA transfection and 
      Topflash reporter assay revealed a possible involvement of Wnt/beta-catenin pathway 
      in GADD45beta-I-induced protection in HT22 cells. In summary, our results 
      demonstrated that GADD45beta-I exerted protective effects against TM-induced 
      cytotoxicity via regulating JNK-Wnt pathway. Targeting MKK7 could represent a new 
      therapeutic strategy for the treatment of neurological diseases where ER stress 
      associated neuronal injury are involved.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Xu, Quan-Hua
AU  - Xu QH
AD  - Department of Neurosurgery, Bijie First People's Hospital, Bijie, Guizhou 551700, 
      China.
FAU - Song, Bing-Jun
AU  - Song BJ
AD  - Basic Medical Sciences Research Center, Shaanxi Fourth People's Hospital, Xi'an, 
      Shaanxi 710043, China.
FAU - Liu, Dan
AU  - Liu D
AD  - Key Laboratory of Carcinogenesis and Translational Research (Ministry of 
      Education), Department of Anesthesiology, Peking University Cancer Hospital & 
      Institute, Beijing 100142, China.
FAU - Chen, Yu-Hua
AU  - Chen YH
AD  - Basic Medical Sciences Research Center, Shaanxi Fourth People's Hospital, Xi'an, 
      Shaanxi 710043, China.
FAU - Zhou, Yuan
AU  - Zhou Y
AD  - Basic Medical Sciences Research Center, Shaanxi Fourth People's Hospital, Xi'an, 
      Shaanxi 710043, China.
FAU - Liu, Wen-Bo
AU  - Liu WB
AD  - Basic Medical Sciences Research Center, Shaanxi Fourth People's Hospital, Xi'an, 
      Shaanxi 710043, China.
FAU - Li, Hua
AU  - Li H
AD  - Basic Medical Sciences Research Center, Shaanxi Fourth People's Hospital, Xi'an, 
      Shaanxi 710043, China.
FAU - Long, Tian-Lin
AU  - Long TL
AD  - Department of Neurosurgery, Bijie First People's Hospital, Bijie, Guizhou 551700, 
      China.
FAU - Zhang, Rui
AU  - Zhang R
AD  - Department of Neurosurgery, Bijie First People's Hospital, Bijie, Guizhou 551700, 
      China.
FAU - Liu, Wei
AU  - Liu W
AD  - Basic Medical Sciences Research Center, Shaanxi Fourth People's Hospital, Xi'an, 
      Shaanxi 710043, China. Electronic address: liuwei_sx4y@126.com.
LA  - eng
PT  - Journal Article
DEP - 20180421
PL  - Netherlands
TA  - Brain Res
JT  - Brain research
JID - 0045503
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (GADD45beta-I)
RN  - 0 (Peptides)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Wnt Proteins)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Caspase 3/metabolism
MH  - Cell Line, Transformed
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Enzyme Inhibitors/*pharmacology
MH  - Hippocampus/cytology
MH  - In Situ Nick-End Labeling
MH  - L-Lactate Dehydrogenase/metabolism
MH  - MAP Kinase Kinase 4/genetics/metabolism
MH  - Mice
MH  - Mitochondrial Diseases/*drug therapy/etiology
MH  - Neurons/drug effects
MH  - Peptides/*pharmacology
MH  - Phosphorylation/drug effects
MH  - RNA, Messenger/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/*drug effects
MH  - Wnt Proteins/genetics/metabolism
OTO - NOTNLM
OT  - ER stress
OT  - JNK
OT  - MKK7
OT  - Mitochondrial dysfunction
OT  - Wnt
EDAT- 2018/04/24 06:00
MHDA- 2019/05/07 06:00
CRDT- 2018/04/24 06:00
PHST- 2017/08/13 00:00 [received]
PHST- 2018/03/29 00:00 [revised]
PHST- 2018/04/12 00:00 [accepted]
PHST- 2018/04/24 06:00 [pubmed]
PHST- 2019/05/07 06:00 [medline]
PHST- 2018/04/24 06:00 [entrez]
AID - S0006-8993(18)30200-2 [pii]
AID - 10.1016/j.brainres.2018.04.012 [doi]
PST - ppublish
SO  - Brain Res. 2018 Jul 15;1691:1-8. doi: 10.1016/j.brainres.2018.04.012. Epub 2018 
      Apr 21.