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2008年中国病理生理学会第十一届肿瘤和第十二届免疫专...

作者： Lili Li Lili Guo Zijian Li Xue Chen Xiangjian Luo Xiaoqian Ma Lanbo Xiao Ya Cao Cancer Research Institute,Xiangya School of Medicine,Central South University,110 Xiangya Road,Changsha,Hunan,PR China Cancer Research Institute,Xiangya School of Medicine,Central South University,110 Xiangya Road,Changsha,Hunan,P.R.China,

＜正＞The Epstein-Barr virus （EBV） encoded latent membrane protein 1 （LMP 1）,an oncogenic protein, plays an important role in the carcinogenesis of nasopharyngeal carcinoma （NPC）.Phosphorylation of p53 protein is likely to play the key role in regulating its activity,p53 protein accumulates but mutation of p53 gene is not common in NPC.The molecular mechanisms of p53 augmentation have not been completely elucidated.Here,the role of map kinases in the phosphorylation of p53 modulated by LMP1 was determined,p53 could be activated and phosphorylated clearly at Serl5, Ser20,Ser392 and Thr81 modulated by LMP1.Furthermore,LMPl-induced phosphorylation of p53 at Serl5 was directly by ERKs;at Ser20 and Thr81 by JNK,at Ser 15 and Ser392 by p38 kinase.The phosphorylation of p53 was associated with its transcriptional activity and stability modulated by LMP1.These results strongly suggest that map kinases have a direct role in LMPl-induced phosphorylation of p53 at multiple sites,which provide a novel view for us to tmderstand the mechanism of the activation of p53 in the carcinogenesis of nasopharyngeal carcinoma.

关键词： Epstein-Barr virus Latent membrane protein 1 p53 map kinases phosphorylation

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Molecular determinants of the antitumor effects of trichostatin A in pancreatic cancer cells

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World Journal of Gastroenterology 2010年第16期16卷 1970-1978页

作者： Elisabeth Emonds Brit Fitzner Robert Jaster Department of Medicine II Division of GastroenterologyMedical FacultyUniversity of Rostock

AIM:To gain molecular insights into the action of the histone deacetylase inhibitor(HDACI) trichostatin-A(TSA) in pancreatic cancer(PC) cells.METHODS:Three PC cell lines,BxPC-3,AsPC-1 and CAPAN-1,were treated with various concentrations of TSA for def ined periods of time.DNA synthesis was assessed by measuring the incorporation of 5-bromo-2'deoxyuridine.Gene expression at the level of mRNA was quantif ied by real-time polymerase chain reaction.Expression and phosphorylation of proteins was monitored by immunoblotting,applying an infrared imaging technology.To study the role of p38 map kinase,the specif ic enzyme inhibitor SB202190 and an inactive control substance,SB202474,were employed.RESULTS:TSA most eff iciently inhibited BrdU incorporation in BxPC-3 cells,while CAPAN-1 cells displayed the lowest and AsPC-1 cells an intermediate sensitivity.The biological response of the cell lines correlated with the increase of histone H3 acetylation after TSA application.In BxPC-3 cells(which are wild-type for KRAS),TSA strongly inhibited phosphorylation of ERK 1/2 and AKT.In contrast,activities of ERK and AKT in AsPC-1 and CAPAN-1 cells(both expressing oncogenic KRAS) were not or were only modestly affected by TSA treatment.In all three cell lines,but most pronounced in BxPC-3 cells,TSA exposure induced an activation of the map kinase p38.Inhibition of p38 by SB202190 slightly but signif icantly diminished the antiproliferative effect of TSA in BxPC-3 cells.Interestingly,only BxPC-3 cells responded to TSA treatment by a signif icant increase of the mRNA levels of bax,a pro-apoptotic member of the BCL gene family.Finally,in BxPC-3 and AsPC-1 cells,but not in the cell line CAPAN-1,signif icantly higher levels of the cell cycle inhibitor protein p21Waf1 were observed after TSA application.CONCLUSION:The biological effect of TSA in PC cells correlates with the increase of acetyl-H3,p21Waf1,phospho-p38 and bax levels,and the decrease of phosphoERK 1/2 and phospho-AKT.

关键词： Pancreatic cancer Histone deacetylase inhibitor Trichostatin-A KRAS map kinases p21Waf1 AKT

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Cross-talk between MEK1/2-ERK1/2 signaling and G protein-couple signaling in synoviocytes of collagen-induced arthritis rats

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Chinese Medical Journal 2008年第22期121卷 2278-2283页

作者： ZHANG Ling-ling WEI Wei WANG Qing-tong CHEN Jing-yu CHEN Yin Institute of Clinical Pharmacology Anhui Medical University Key Laboratory of Anti-inflammatory and Immuno-pharmacology in Anhui Province Key Laboratory of Research & Development of Chinese Medicine in Anhui Province Hefei Anhui 230032 China

Background Signaling pathways that regulate the production of cytokines and destructive enzymes have been implicated in rheumatoid arthritis （RA） pathogenesis. There are co-relations between signaling pathways. The aim of this study was to investigate interactions and cross-talks between MEK1/2-extracellular signal-related kinase （ERK1/2） signaling and G protein-couple signaling in synoviocytes of collagen-induced arthritis （CIA） rats by the stimulation of interleukin-1 （IL-1）, U0126, isoprenaline hydrochloride and aminophyline respectively. Methods Twenty Sprague-Dawley （SD） rats were induced by chicken type II collagen. Synoviocytes of CIA rats were isolated and cultured. The expressions of Gi, phosphorylated MEK1/2 （p-MEK1/2） and phosphorylated ERK1/2 （p-ERK1/2） were detected by Western blotting, cAMP level and protein kinase A （PKA） activity were measured by radioimmunoassay and kinase-glo luminescent kinase assay respectively. Results There was remarkable inflammation in CIA rats accompanied by swelling paws, hyperplastic synovium, pannus and cartilage erosion, cAMP level and PKA activity of synoviocytes decreased. Gi, p-ERK1/2 and p-MEK1/2 increased, rlL-la improved the expression of Gi, p-ERK1/2 and p-MEK1/2, cAMP and PKA increased with stimulation of rlL-1α. U0126 inhibited Gi, cAMP and PKA of synoviocytes stimulated by rlL-la. Isoprenaline hydrochloride enhanced Gi, cAMP and PKA, but had no effects on p-MEK1/2 and p-ERK1/2. Aminophyline increased cAMP and PKA, but inhibited p-MEK1/2 and p-ERK1/2. Conclusions Mitogen-activated protein kinases （mapKs） and G protein-couple signaling are associated with synovitis. There are cross talks between mapKs and G protein-couple signaling. The two signaling pathways represent potential therapeutic targets for RA.

关键词： arthritis signaling cross-talk G protein map kinases

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