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Effect of c-jun nh2-terminal kinase-mediated p53 expression on neuron autophagy following traumatic brain injury in rats

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chinese Medical Journal 2012年第11期125卷 2019-2024页

作者： HONG Ming-yan GAO jun-ling cUI Jian-zhong WANG Kai-jie TIAN Yan-xia LI Ran WANG Hai-tao WANG Huan Department of Surgcry Hebei Medical University Shijiazhuang Hebei 050017 China School of Basic Medical Sciences Hebei United University Tangshan Hebei 063000 China Worker＇s Hospital Tangshan Hebei 063000 China

Background Activation of c-jun nh2-terminal kinase （JNK） has been implicated in neuron apoptosis as well as autophagy in response to various stressors after traumatic brain injury （TBI）. However, the underlying molecular pathway remains unclear. Our study assessed whether JNK-mediated p53 phosphorylation might be an important mechanism for enhancing neuron autophagy in response to TBI. Methods A total of 186 male Sprague-Dawley （SD） rats （300-350 g） were used in this study. By randomized block method rats were randomly divided into four groups： sham-operated （n=46）, TBI （n=60）, TBI ＋ dimethyl sulfoxide （DMSO）（n=40）, and TBI ＋ SP600125 （n=40）. JNK was treated with SP600125, a specific JNK inhibitor. JNK, p-P53, Beclin-1, damage-regulated autophagy modulator （DRAM） and p-bcl-2 were evaluated by Western blotting analysis. The cellular localization and expression of Beclin-1 and DRAM was observed by immunofluorescence and immunohistochemistry, and the expression of Beclin-l-Bcl-2/Bcl-xL complexes was evaluated by immunoprecipitation. Multiple-group comparisons were conducted using analysis of variance （ANOVA）. P values of less than 0.05 were considered statistically significant. Results It was observed that the expression of JNK, p-P53, Beclin-1, DRAM and p-bcl-2 was increasing after TBI, and the expression of Beclin-1 and DRAM was mainly located in the cytoplasm of neurons. But these were significantly inhibited in SP600125 group compared with sham group and TBI＋SP600125 group （P 〈0.05）. The expression of Beclin-l-Bcl-2/Bcl-xL complexes was reduced after TBI. conclusion JNK-mediated p53 phosphorylation might be an important mechanism for enhancing neuron autophagy in response to TBI.

关键词： brain injuries, autophagy c-jun nh2-terminal kinase p53 damage-regulated autophagy modulator

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Antinociceptive Effect of Najanalgesin from Naja Naja Atra in a Neuropathic Pain Model via Inhibition of c-jun nh2-terminal kinase

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chinese Medical Journal 2015年第17期128卷 2340-2345页

作者： Ying-Xia Liang Zhi-Yu Zhang Rui Zhang Department of Anesthesiology Weifang Medical University Weifang Shandong 261053 China Department of Microsurgery Shouguang People's Hospital Shouguang Shandong 262700 China

Background： Najanalgesin, a toxin isolated from the venom ofNaja nqja atra, has been shown to exert significant analgesic effects in a neuropathic pain model in rats. However, the molecular mechanism underlying this protective effect ofnajanalgesin is poorly understood. The present study sought to evaluate the intracellular signaling pathways that are involved in the antinociceptive effect of najanalgesin on neuropathic pain. Methods： The antinociceptive properties of najanalgesin were tested in hind paw withdrawal thresholds in response to mechanical stimulation. We analyzed the participation of the mitogen-activated protein kinase p38, extracellular-regulated kinase （ERK）, and c-jun N-terminal kinase （JNK） by western blot analysis. This inhibition of JNK was confirmed by immunohistochemistry. Results： The phosphorylation levels of INK （as well as its downstream molecule c-jun）, p38, and ERK were significantly increased after injury. Najanalgesin only inhibited JNK and c-jun phosphorylation but had no effect on either ERK or p38. This inhibition of JNK was confirmed by immunohistochemistry, which suggested that the antinociceptive effect of najanalgesin on spinal nerve ligation-induced neuropathic pain in rats is associated with JNK activation in the spinal cord. conclusion： The antinociceptive effect of najanalgesin thnctions by inhibiting the JNK in a neuropathic pain model.

关键词： c-jun c-jun nh2-terminal kinase L5 Spinal Nerve Ligation Najanalgesin

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Differential activation of mitogen-activated protein kinases by γ-irradi-ation in IEc-6 cells: Role of intracellular ca^(2+)

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Journal of Medical colleges of PLA(china) 2002年第3期17卷 181-187页

作者：周舟王小华 Igisu Hideki 林远楼淑芬 Matsuoka Masato 程天民余争平 Institute of combined Injury Third Military Medical University Chongqing 400038 China Institute of combined Injury Third Military Medical University Chongqing 400038 China Department of Environmental Toxicology University of Occupational and Environmental Health Kitakyushu 807-85555 Japan Institute of combined Injury Third Military Medical University Chongqing 400038 China

Objective: To explore the effects of γ-irradiation on mitogen-activated protein kinases (MAPKs) and role of intracellular calcium in this event in intestinal epithelial cell line 6 (IEc-6 cells). Methods: After cultured rat IIEc-6 cells with or without the pretreatment of intracellular ca2+ chelator were exposed to Y-ir-radiation of 6 Gy, the total and phosphorylated MAPKs in the cells were determined with Western blotting and apoptosis was examined with flow cytometry. Activities of Extracellular signal-regulated protein kinase (ERK) and p38 MAPK were determined by using immuoprecipitation followed by Western blotting. Results: In response to γ-irradiation, phosphorylation of ERK was not significantly observed, while the levels of phosphorylated c-jun nh2-terminal kinase (JNK) and p38 MAPK were increased in 30 min and reached the peak 2 h after exposure to 6 Gy γ-irradiation, though the cell viability was significantly lowered 12 h. On the other hand, no obvious changes were seen in the total protein levels of ERK, JNK and p38 MAPK. chelation of intracellular ca2+ almost completely suppressed the JNK and p38 MAPK phosphorylation induced by γ-irradia-tion, but removal of external ca2+ had no such effect. Activation of p38 MAPK, but not of ERK, was seen to have a correlation with γ-irradiation induced apoptosis. conclusion: The results suggest that γ-irradiation is a potent activator for JNK and p38 MAPK, and ca2+ mobilized from intracellular stores plays an important role in the activation of MAPKs and the induction of apoptosis in IEc-6 cells.

关键词： r-irradiation extracellular signal-regulated protein kinase c-jun nh2-terminal kinase mitogen- activated protein kinases p38 MAPK intracellular ca2+ intestinal epithelial cell line 6

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Paxillin serine 178 phosphorylation in control of cell migration and metastasis formation through regulation of EGFR expression in breast cancer

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Journal of cancer Metastasis and Treatment 2019年第6期4卷 71-86页

作者： Saertje Verkoeijen Ya-Feng Ma Wies van Roosmalen Reshma Lalai Martine H.A.M.van Miltenburg Marjo de Graauw Bob van de Water Sylvia E.Le Dévédec Institute for Life Sciences&chemistry Hogeschool Utrecht HUUtrecht 3501 AAthe Netherlands Division of Drug Discovery and Safety Leiden Academic Centre for Drug ResearchLeiden UniversityLeiden 2300 RAthe Netherlands

Aim:Paxillin is a well-known multidomain scaffold protein that is involved in the regulation of cell-matrix adhesion dynamics,a process required for the tumor cell migration and *** of the serine residue 178 requires c-jun nh2-terminal kinase(JNK)activation,which occurs downstream of epidermal growth factor receptor(EGFR)-mediated signaling and drives cell *** this study,we investigated the significance of paxillin Ser178 phosphorylation in breast cancer ***:We employed the rat mammary carcinoma MTLn3 cell line with which we established stabile variants of both wild type and mutant GFP-paxillin *** those,we next performed several in vitro assays including cell proliferation,migration and focal adhesion ***,we monitored the metastatic spread of both cell line variants in an othrotopic mouse model for breast ***:Here we show that expression of the phospho-defective mutant paxillinS178A in the metastatic mammary adenocarcinoma MTLn3 cell-line significantly decreased EGF-induced cell migration,which was correlated with impaired focal adhesion ***,paxillinS178A attenuated lung metastasis formation in an orthotopic in vivo mammary gland tumor/metastasis model,demonstrating the importance of JNK-mediated paxillin phosphorylation in breast cancer *** of paxillinS178A caused a decrease in EGFR expression, ;while re-expression of EGFR in MTLn3-paxillinS178A cells fully restored EGF-driven cell motility and focal adhesion ***,re-expression of EGFR in MTLn3-paxillinS178A rescued spontaneous metastasis from breast to ***:Overall our data show an important role for JNK-mediated paxillin Ser178 phosphorylation in the regulation of EGFR expression and thereby,in EGF-driven cell migration and metastasis formation.

关键词： Paxillin c-jun nh2-terminal kinase focal adhesion epidermal growth factor receptor cell migration metastasis breast cancer

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