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src heterodimerically activates Lyn or Fyn to serve as targets for the diagnosis and treatment of esophageal squamous cell carcinoma

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Science China(Life Sciences) 2023年第6期66卷 1245-1263页

作者： Jing Zhang Di Zhao Lingyuan Zhang Yuanfan Xiao Qingnan Wu Yan Wang Jie Chen Qimin Zhan Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&InstituteBeijing100142China Peking University International Cancer Institute Peking UniversityBeijing100191China Research Unit of Molecular Cancer Research Chinese Academy of Medical SciencesBeijing100142China Institute of Cancer Research Shenzhen Bay LaboratoryShenzhen518107China

Although src is one of the oldest and most investigated oncoproteins,its function in tumor malignancy remains to be defined *** this study,we demonstrated that the inhibition of src activity by ponatinib effectively suppressed several malignant phenotypes of esophageal squamous cell carcinoma(ESCC)both in vitro and in vivo,whereas it did not produce growthinhibitory effects on normal esophageal epithelial cells(NEECs).Importantly,we combined phosphoproteomics and several cellular and molecular biologic strategies to identify that src interacted with the members of src-family kinases(SFKs),such as Fyn or Lyn,to form *** interactions with Fyn and Lyn phosphorylated the tyrosine sites in SH2(Fyn Tyr^(185)or Lyn Tyr^(183))and kinase domains(Fyn Tyr^(420) or Lyn Tyr^(397)),which critically contributed to ESCC *** contrast,src could not form heterodimers with Fyn or Lyn in *** used RNA sequencing to comprehensively demonstrate that the inhibition of src activity effectively blocked several critical tumor-promoting pathways,such as JAK/STAT,mTOR,stemness-related,and metabolism-related *** of the real-time polymerase chain reaction(RT-PCR)assay confirmed that Lyn and Fyn were critical effectors for the src-mediated expression of tumor growth or metastasis-related ***,results of the clinical ESCC samples showed that the hyperactivation of psrc Tyr^(419),Fyn Tyr^(185) or Tyr^(420),and Lyn Tyr^(183)or Tyr^(397)could be biomarkers of ESCC *** study illustrates that src/Fyn and src/Lyn heterodimers serve as targets for the treatment of ESCC.

关键词： esophageal squamous cell carcinoma heterodimer src-family kinase src tyrosine phosphorylation

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Blockade of c-src Within the Paraventricular Nucleus Attenuates Inflammatory Cytokines and Oxidative Stress in the Mechanism of the TLR4 Signal Pathway in Salt-Induced Hypertension

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Neuroscience Bulletin 2020年第4期36卷 385-395页

作者： Qing Yang Xiao-Jing Yu Qing Su Qiu-Yue Yi Xin-Ai Song Xiao-Lian Shi Hong-Bao Li Jie Qi Guo-Qing Zhu Yu-Ming Kang Department of Physiology and Pathophysiology Xi'an Jiaotong University School of Basic Medical SciencesKey Laboratory of Environment and Genes Related to Diseases of the Ministry of EducationXi'an Jiaotong UniversityXi’an 710061China Department of Cardiovascular Surgery First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061China Department of Pharmacology School of Basic Medical SciencesXi’an Jiaotong University Health Science CenterXi’an 710061China Key Laboratory of Cardiovascular Disease and Molecular Intervention Department of PhysiologyNanjing Medical UniversityNanjing 210029China

Toll-like receptor 4 (TLR4) and cellular src (csrc) are closely associated with inflammatory cytokines and oxidative stress in hypertension, so we designed this study to explore the exact role of c-src in the mechanism of action of the TLR4 signaling pathway in salt-induced hypertension. Salt-sensitive rats were given a high salt diet for 10 weeks to induce hypertension. This resulted in higher levels of TLR4, activated c-src, pro-inflammatory cytokines, oxidative stress, and arterial pressure. Infusion of a TLR4 blocker into the hypothalamic paraventricular nucleus (PVN) decreased the activated c-src, while microinjection of a c-src inhibitor attenuated the PVN levels of nuclear factor-kappa B, pro-inflammatory cytokines, and oxidative stress. Our findings suggest that a longterm high-salt diet increases TLR4 expression in the PVN and this promotes the activation of c-src, which upregulates the expression of pro-inflammatory cytokines and results in the overproduction of reactive oxygen ***, inhibiting central c-src activity may be a new target for treating hypertension.

关键词： Toll-like receptor 4 Cellular src Inflammatory cytokines Oxidative stress Hypothalamic paraventricular nucleus Salt-induced hypertension

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Seismic cyclic loading test of src columns confined with 5-spirals

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Science China(Technological Sciences) 2008年第5期51卷 529-555页

作者： WENG ChengChiang YIN YenLiang WANG JuiChen LIANG ChingYu Department of Civil Engineering Chiao Tung UniversityHsinchu 30050China Ruentex Group Taibei 10492China

Presented herein is an experimental study on seismic resistance of rectangular steel reinforced concrete (src) columns confined with a new type of multi-spiral cage. The multi-spiral cage is a device of five interconnected spirals, named "5-spirals", with a large spiral at the center and four small ones at the corners. The innovation of applying the 5-spirals to src column is to take its superiority in concrete confinement and efficiency in automatic production for the precast construction industry. Four full-scale src columns were tested under horizontal cyclic loading. All of the tested columns were capable of sustaining a drift angle up to 6% radians. The hysteresis loops observed from the cyclic loading tests indicated that the spirally confined src columns demonstrated excellent performances in both strength and ductility. The test results suggested that with significant saving of the confinement steel, the newly innovated 5-spirals can be successfully applied to the precast rectangular src columns.

关键词： steel reinforced concrete rectangular src column precast construction 5-spirals concrete confinement cyclic loading test seismic resistance

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The expression of c-src gene in the carcinogenesis process of human cardia adenocarcinoma

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World Journal of Gastroenterology 1999年第6期5卷 488-491页

作者： WANG Xiu Jie, YUAN Shu Lan, XIAO Lin, WANG Xu Hua and WANG Chao Jun Institute of Cancer Research First University Hospital West China University of Medical Sciences Chengdu 610041 Sichuan Province China Department of Oncology China

AIM To investigate the activation, expression of c src gene and its role in the carcinogenetic process of human cardia adenocarcinoma (CA). METHODS Fifty six cases of CA, 34 cases of normal, 36 cases of protiferative epithelia adjacent to carcinoma, and 20 cases of lymph node metastases of CA were studied for PP60 c src , the expression product of c src gene immunohistochemically by using the specific monoclonal antibody, Mab327. RESULTS The positive rates of PP60 c src in the normal epithelia, protiferative epithelia, CA and lymph node metastases were 29 4% (10/*!34), 94 4% (34/*!36), 71 4% (40/*!56) and 60 0% (12/*!20) , respectively, among them, the differences of the positive rates were statistically significant ( P src in CA and proliferative epithelia were significantly higher than that in the normal epithelia ( P src positive rates in the papillary, tubular, poorly differentiated and mucous adenocarcinoma were 75 0% (6/*!8) , 81 8% (18/*!22) , 50 0% (10/*!20) and 100 0% (6/*!6) , respectively, whereas those of tubular and mucous adenocarcinomas were significantly higher than those of papillary and poorly differentiated adenocarcinomas ( P src expression levels of tubular and mucous adenocarcinomas were also significantly higher than those of papillary and poorly differentiated adenocarcinomas ( P src gene are associated with the initiation and development of human CA; the protein amount of PP60 c src increased during the process of carcinogenesis; and PP60 c src expression is also related to lymph node metastases.

关键词： c src gene expression product PP60 c src cardia adenocarcinoma carcinogenesis neoplasm metastasis immunohistochemistry

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Neuroprotective effects of Shaoyao Gancao decoction against excitatory damage in PC12 cells based on the src-NR2-nNOS pathway

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Journal of Traditional Chinese Medical Sciences 2024年第3期11卷 293-302页

作者： Xiaoxu Fan Hongyan Ma Tiantian Zhou Min Fu Zhiyuan Qiao Yingtong Feng Zhen Wang Yiwei Shen Jingxia Wang School of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing 102488China School of Traditional Chinese Medicine Xinjiang Medical UniversityUrumqi 830017China The Centre for Translational Biology Research Institute of McGill University Health CentreMontréal H4A 3J1Canada

Objective:To explore the neuroprotective effects of the Shaoyao Gancao decoction(SGD)against excitatory damage in PC12 cells and the role of the src-NR2-nNOS pathway mediation by SGD in regulatingγ-aminobutyric acid(GABA)-glutamate(Glu)***: N-Methyl-d-aspartic acid(NMDA)was used to establish a PC12 cell excitability injury *** investigate the neuroprotective effect of SGD,a cell counting kit-8(CCK-8)assay was used to determine PC12 cell viability,Annexin V/Propidium Iodide(Annexin V/PI)double staining was used to determine PC12 cell apoptosis,and Ca^(2+)concentration was observed using laser confocal *** receptor agonists and antagonists were used to analyze the neuroprotective interactions betweenγ-aminobutyric acid(GABA)and NMDA ***,molecular biology techniques were used to determine mRNA and protein expression in the src-NR2-nNOS *** analyzed the correlations between the regulatory sites of GABA and NMDA interactions,excitatory neurotoxicity,and brain damage at the molecular ***: NMDA excitotoxic injury manifested as a significant decrease in cell activity,increased apoptosis and caspase-3 protein expression,and a significant increase in intracellular Ca^(2+)*** of SGD,a GABAA receptor agonist(muscimol),or a GABAB receptor agonist(baclofen)decreased intracellular Ca^(2+)concentrations,attenuated apoptosis,and reversed NMDA-induced upregulation of caspase-3,src,NMDAR2A,NMDAR2B,and ***,a GABA_(A)receptor antagonist(bicuculline)and a GABA_(B)receptor antagonist(saclofen)failed to significantly increase excitatory ***: Taken together,these results not only provide an experimental basis for SGD administration in the clinical treatment of central nervous system injury diseases,but also suggest that the src-NR2A-nNOS pathway may be a valuable target in excitotoxicity treatment.

关键词： Shaoyao Gancao decoction PC12 N-Methyl-D-aspartic acid(NMDA) γ-aminobutyric acid(GABA) src nNOs

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Zeylenone promotes apoptosis of chronic myelogenous leukemia-derived K562 cells by a mechanism involving Jak2 and src kinase

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中国药理学与毒理学杂志 2016年第10期30卷 1069-1070页

作者： HUO Xiao-wei LIAO Yong-hong TIAN Yu GAO Li LIU Dong-yu LI Li-yong CAO Li Institute of Medicinal Plant Development Chinese Academy of Medical Sciences and Peking Union Medical College

OBJECTIVE The present study was designed to investigate anticancer effect of zeylenone(Zey)on K562 cells derived from chronic myelogenous leukemia(CML)both in vitro and in vivo,followed by exploring the underlying *** Initially,the effects of Zey on cel viability,proliferation,and apoptosis were measured in K562 cells by MTT,soft agar assay,AO/EB staining,hoechst 33258 staining and flow cytometric analysis after they were treated with Zey for indicated time,the involving signaling pathways were then investigated by JC-1,real-time quantitative polymerase chain reaction(RT-q PCR),Western blotting and immunofluorescence ***,the in vivo anti-tumoractivity of Zey was assessed with nude xenografts and the involving mechanism was confirmed by immunohistochemical(IHC)and histopathological *** We identified that Zey dose-dependently decreased cell viability,colony formation and expression of Proliferating Cell Nuclear Antigen(PCNA),and significantly induced K562 cell apoptosis via regulating Bcl-2 family members,decreasing mitochondrial transmembrane potential,and activating caspase-3,caspase-9,and caspase-8(Psrc and downregulated their downstream proteins,including stat3,PI3K/AKT/m TOR,and ERK1/2 signaling pathways(Psrc *** findings suggest the potential of Zey as an effective anticancer agent in CML treatment.

关键词： zeylenone apoptosis K562 cells Jak2 src

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The saponin DT-β attenuates tumor necrosis factor-α-induced vascular inflammation associated with src/NF-KB/MAPK pathway modulation

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中国药理学通报 2015年第B11期31卷 197-198页

This study aimed to explore the effect of DT-13 （25（R,S）-ruscogenin- 1-O- [ β-d-glucopyranosyl- （1→2） ] [ β-d-xylopyranosyl-（ 1→3） 1-β -d- fucopyranoside） on tumor necrosis factor （TNF）-α-induced vascular inflamma- tion and the potential molecular mechanisms. In vitro, DT-β suppressed TNF-α-induced adhesion and migration of human umbilical vein endothelial cells （HUVECs） by inhibiting the expression of intercellular adhesion molecule-1 （ ICAM-1 ） and vascular cell adhesion molecule-1 （VCAM-1）. DT-β markedly suppressed NF-KB p65 phosphoryl- ation, and when NF-KB p65 was over-expressed, the inhibitory effect of DT-β on adhesion molecular decreased. DT-β also suppressed TNF-α induced luciferase activities of ICAM-1 and VCAM-1 promoter containing NF-KB binding sites. Furthermore DT-β markedly suppressed p38 phosphorylation and src degradation induced by TNF-α DT-β at 4 mg·kg- 1 prevented vascular , whereas had no significant effect on ERK and JNK activation. In-vivo, inflammation and the expression of adhesion molecules induced by TNF-α in mice. These findings suggest that DT- β abrogates vascular inflammation by down-regulating adhesion molecules associated with modulating the NF-KB, p38MAPK, src signaling pathways, and NF-KB binding site is at least one of the targets of DT-β. This study pro- vides novel information regarding the mechanism by which DT-β exerts its effects on vascular inflammation, which is important for the onset and progression of various diseases.

关键词： DT-β Endothelial inflammation Adhesion molecule NF-KB src MAPKs

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Focal adhesion kinase and src phosphorylations in HGF-induced proliferation and invasion of human cholangiocarcinoma cell line, HuCCA-1

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World Journal of Gastroenterology 2005年第37期11卷 5845-5852页

作者： Urai Pongchairerk Jun-Lin Guan Vijittra Leardkamolkarn Department of Anatomy Faculty of science Mahidol University Bangkok 10400Thailand Department of Molecular Medicine College of Veterinary Medicine Cornell University Ithaca New York 14853 USA

AIM: To study the role of focal adhesion kinase (FAK) and its association with src in hepatocyte growth factor (HGF)-induced cell signaling in cholangiocarcinoma ***: Previously isolated HuCCA-1 cells were re-characterized by immunofluorescent staining and reverse transcriptase-polymerase chain reaction assay for the expression of cytokeratin 19, HGF and c-Met mRNA. Cultured HuCCA-1 cells were treated with HGF and determined for cell proliferation and invasion effects by MTT and invasion assays. Western blotting, immunoprecipitation, and co-immunoprecipitation were also performed to study the phosphorylation and interaction of FAK and src. A novel src inhibitor (AZM555130) was applied in cultures to investigate the effects on FAK phosphorylation inhibition and on cell proliferation and ***: HGF enhanced HuCCA-1 cell proliferation and invasion by mediating FAK and src ***-src interaction occurred in a time-dependent manner that src was proved to be an upstream signaling molecule to FAK. The inhibitor to src decreased FAK phosphorylation level in correlation with the reduction of cell proliferation and ***: FAK plays a significant role in signaling pathway of HGF-responsive cell line derived from cholangiocarcinoma. Autophosphorylated src, induced by HGF, mediates src kinase activation, which subsequently phosphorylates its substrate, FAK, and signals to cell proliferation and invasion.

关键词： Human cholangiocarcinoma Hepatocyte growth factor C-Met Focal adhesion kinase src

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NIH3T3细胞中PTPα基因高表达激活src的早期细胞表型变化

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生物化学与生物物理学报 2002年第2期34卷 193-198页

作者：杨劲松郑新民陈诗书上海第二医科大学生化教研室、分子生物学实验室、人类基因治疗研究中心美国康奈尔大学上海第二医科大学生化教研室、分子生物学实验室、人类基因治疗研究中心上海200025 纽约14850

利用蛋白质酪氨酸磷酸酶α(PTPα)基因转染NIH3T3细胞 ,研究PTPα诱导前后细胞生物学行为的变化 ,为肿瘤形成早期机制的研究提供细胞模型。用携带PTPα基因的四环素调控体系转染NIH3T3细胞并诱导 2 4h后 ,用RT PCR和蛋白质印迹法证实PT... 详细信息

利用蛋白质酪氨酸磷酸酶α(PTPα)基因转染NIH3T3细胞 ,研究PTPα诱导前后细胞生物学行为的变化 ,为肿瘤形成早期机制的研究提供细胞模型。用携带PTPα基因的四环素调控体系转染NIH3T3细胞并诱导 2 4h后 ,用RT PCR和蛋白质印迹法证实PTPα在诱导细胞中的表达高于未诱导细胞 ,用RT PCR及蛋白质印迹法发现内源性src的表达水平在诱导与未诱导细胞中没有变化 ,而src激酶的活性在诱导细胞中增高 ,并且在诱导细胞中src的酪氨酸磷酸化水平降低。再用透射式电子显微镜和流式细胞技术观察到诱导细胞的表型已发生变化 ,实验结果表明PTPα诱导 2 4h使细胞的表型开始发生转化 ,这种变化很可能与PTPα表达水平升高使srcC末端的pTyr52 7去磷酸化而激活src相关

关键词： PTPα src 转化

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src Is Dephosphorylated at Tyrosine 530 in Human Colon Carcinomas

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Chinese Journal of Cancer Research 2011年第3期23卷 229-231页

作者： Jeffrey D Bjorge Donald J Fujita Department of Biochemistry and Molecular Biology and Southern Alberta Cancer Research InstituteUniversity of Calgary

Objective：src is a protein tyrosine kinase that plays important roles in cancer development,and src kinase activity has been found to be elevated in several types of ***,the cause of the elevation of src kinase activity in the majority of human colon carcinomas is still largely *** aim at finding the cause of elevated src kinase activity in human colon ***：We employed normal colon epithelial FHC cells and examined src activation in human colon carcinoma specimens from 8 *** expression levels were determined by Western blotting,and the activity of src kinase by kinase ***：Actin levels were different between tumor and normal tissues,demonstrating the complexities and inhomogeneities of the tissue *** kinase activities were increased in the majority of the colon carcinomas as compared with normal colon epithelial cells （range 13-29）.src protein levels were reduced in the colon *** Y530 phosphorylation levels were reduced to a higher extent than protein levels in the ***：The results suggest that src specific activities were highly increased in human colon carcinomas;phosphorylation at src Y530 was reduced,contributing to the highly elevated src specific activity and src kinase activity.

关键词： src Kinase activation Dephosphorylation Colon carcinoma

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