乙型肝炎病毒X基因转染诱导大鼠肾小球系膜细胞增殖及上调促炎因子表达的机制
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摘要
第一部分乙型肝炎病毒X基因真核表达载体的构建
目的：构建乙型肝炎病毒(HBV)X基因与pCI-neo相融合的高效真核表达载体，为进一步研究HBV X基因的功能奠定基础。方法：设计并合成HBV X基因的引物，以HBV DNA阳性血清PCR扩增得到HBV X基因全序列，将X基因连接到真核表达载体pCI-neo，构成pCI-neo-X质粒，然后用酶切图谱分析、PCR检测和扩增产物序列分析等方法，鉴定所构建的真核表达载体。结果：以重组载体为模板扩增得到的片段大小与已知HBV X基因大小相同，酶切也得到目的基因片段，测序结果也显示与已知X基因序列相同。结论：成功构建了HBV X基因的真核表达载体，为进一步研究HBVX基因的功能奠定了基础。
第二部分乙型肝炎病毒X基因转染对大鼠肾小球系膜细胞增殖以及肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6表达的影响
目的探讨HBV X基因表达的蛋白(HBx)对体外培养的大鼠系膜细胞表达肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β、IL-6及细胞增殖的影响。方法将前面构成的pCI-neo-X真核表达载体，采用脂质体法将pCI-neo-X转染给体外培养的大鼠系膜细胞，Westem blot测定HBx的表达；以半定量反转录(RT)-PCR测定体外培养大鼠系膜细胞TNF-αmRNA、IL-1βmRNA、IL-6 mRNA表达；酶联免疫吸附试验(ELISA)测定培养上清液中TNF-α、IL-1β、IL-6。甲基噻唑基四唑(MTT)法测定细胞增殖。结果转染pCI-neo-X的系膜细胞，HBx在36和48小时表达明显。同时半定量反转录PCR测定显示TNF-αmRNA、IL-1βmRNA、IL-6 mRNA表达量较未转染和转染空载体组明显增高。培养36和48小时后上清液中TNF-α水平在转染pCI-neo-X组、未转染和转染空载体组分别为(185．3±70．7)pg／ml，(41．7±10．3)pg／ml，(44．0±10．1)pg／ml，(140．3±42．1)pg／ml，(43．7±10．6)pg／ml，(33．3±8．6)pg／ml；IL-1β水平分别为(402±60)pg／ml，(182±23)pg／ml，(170±18)pg／ml，(432±58)pg／ml，(181±20)pg／ml，(165±19)pg／ml；IL-6水平分别为(177．0±18．2)pg／ml，(85．7±16．9)pg／ml，(69．7±22．2)pg／ml，(179．7±26．3)pg／ml，(70．0±18．3)pg／ml，(73．0±14．0)pg／ml，pCI-neo-X组与未转染和转染空载体组比较，均有显著性差异(p＜0．05)；细胞增殖在36和48小时pCI-neo-X组最明显，吸光度分别为1．56±0．36，1．69±0．32，与未转染组0．70±0．08，0．74±0．18和转染空载体组0．68±0．18，0．80±0．19比较，有显著差异(p＜0．05)。
结论HBx可诱导大鼠系膜细胞高表达TNF-α、IL-1β和IL-6，促进系膜细胞增殖。HBx对系膜细胞的增殖作用可能与TNF-α、IL-1β、IL-6的高表达有关。
第三部分乙型肝炎病毒X蛋白通过激活核因子-κB和细胞外调节蛋白激酶上调大鼠系膜细胞表达肿瘤坏死因子-α
目的探讨HBV X基因转染大鼠系膜细胞导致细胞增殖及肿瘤坏死因子-α(TNF-α)高表达的细胞外蛋白调节激酶(ERK)信号转导机制。方法将含有HBVX基因的质粒pCI-neo-X转染入体外培养的大鼠系膜细胞，MTT法检测系膜细胞增殖，半定量RT-PCR检测TNF-αmRNA表达，ELISA检测培养上清液中TNF-α表达。Western blot检测HBx、ERK_(1/2)及p-ERK_(1／2)表达。分别采用特异性抑制剂U0126阻断ERK_(1/2)通路，Lactacystin阻断NF-κB通路和SB203580阻断p38MAPK通路，观察培养细胞增殖、TNF-α及其mRNA表达，以不加抑制剂作为对照。结果转染pCI-neo-X后，系膜细胞增殖明显，细胞TNF-αmRNA及上清液TNF-α表达均增高，通过阻断ERK_(1／2)或NF-κB通路，系膜细胞增殖减弱，细胞TNF-αmRNA及上清液TNF-α表达均下降。而阻断p38MAPK通路对系膜细胞增殖，细胞TNF-αmRNA及上清液TNF-α表达无明显影响。结论转染HBV X基因可促使系膜细胞增殖，细胞TNF-αmRNA及上清液TNF-α表达均增高，这一作用可能部分是HBV X基因表达的蛋白通过激活ERK_(1／2)以及NF-κB通路信号而实现。而与p38MAPK通路无关。
PARTⅠConstruction of hepatitis B virus X gene eukaryoticexpression vector
Objective:To construct a highly effective eukaryotic expression vector pCI-neo withHBV X gene(pCI-neo-X).Methods:HBV DNA was extracted from the HBV DNApositive serum.HBV X gene was amplified by PCR,and identified by geloseelectrophoresis analysis.The PCR products and the eukaryotic expression vectors pCI-neowere digested by restriction endonucleases,then the digested X gene was inserted into thedigested eukaryotic expression vector.After screening,the positive recombinants werepicked out.PCR analysis and sequencing were made.Results Both vector DNA directsequence and restriction pattern confirmed that the HBV X gene was seccessfully insertedinto pCI-neo vector.Conclusion:The eukaryotic expression vextor pCI-neo has beensuccessfully constructed.
PartⅡHBV X gene transfection induces glomerular mesangialcell proliferation and upregulates TNF-α,IL-1βand IL-6 expression
Objectives The aim of this study is to approach the effect of HBx on expression oftumor necrosis factor-α(TNF-α),interluekin(IL)-1β,and IL-6 in,and proliferation of ratmesangial cell of rat in vitro.Methods Liposome bearing pCI-neo-X was transfected intocultured rat mesangial cell line of the rat in vitro through liposome method.X geneexpression in the cells was assessed by Western blot.The mRNA expression of TNF-α,IL-1βand IL-6 in expression of cultured mesangial cells line was assessed bysemiquantitative RT-PCR.Mesangial cell proliferation was assessed by MTT.Results HBxobviously expressed in cultured mesangial cells line at 36~(th) and at 48~(th) hour aftertransfection.The mRNA of TNF-α,IL-1βand IL-6 expression simutanously increased.Thesupernatent TNF-αlevels in supernatents in MC group,MC plus pCI-neo and MC pluspCI-neo-X at 36~(th) hours after transfection were (41.7±10.3) pg/ml,(44.0±10.1) pg/ml,(185.3±70.7)pg/ml,respectively,and at 48~(th) hours were(43.7±10.6)pg/ml,(33.3±8.6)pg/ml,(140.3±42.1) pg/ml,respectively;The supernatent IL-1βlevels in MC group,MC plus pCI-neo and MC plus pCI-neo-X were (182±23) pg/ml,(170±18) pg/ml,(402±60) pg/ml,respectively,at 36~(th),and (181±20)pg/ml,(165±19)pg/ml,(432±58)pg/ml,respectively,at 48~(th);The supematent IL-6 levels in MC group,MC plus pCI-neoand MC plus pCI-neo-X were (85.7±16.9) pg/ml,(69.7±22.2) pg/ml,(177.0±18.2)pg/ml,respectively at 36~(th) and (70.0±18.3) pg/ml,(73.0±14.0) pg/ml,(179.7±26.3)pg/ml,respectively at 48~(th),The expression of TNF-α,IL- 1βand IL-6 in pCI-neo-X groupwere all markedly higher than those in other two groups(all p＜0.05).The cell proliferationwas also obvious at the same time.Absorbance in transfcted pCI-neo-X cells were1.56±0.36 at 36~(th) and 1.69±0.32 at 48~(th) in hour after transfection,which was markedlyhigher than in untrasfected group 0.70±0.08 at 36~(th),0.74±0.18 at 48~(th) in hour or than intransfcted pCI-neo cells 0.68±0.18 at 36~(th),0.80±0.19 at 48~(th) in hour,respectively,all p＜0.05).Conclussion Therefore,we can conclude that HBx can induce expression ofmRNA of TNF-α,IL-1βand IL-6.HBx may play a critical role in the cell proliferationthrough TNF-α,IL-1βand IL-6 high expression.
PartⅢHepatitis B virus X protein upregulates tumor necrosisfactor-αexpression of rat mesangial cell line via NF-κB and ERKspathway
Objectives HBx,a 17-kd protein encoded by X gene of HBV,has been shown tofunction as a transcriptional trans-activator of a variety of viral and cellularpromoter/enhancer elements.The aim of the study is to investigate the signal transductionpathway of HBx in glomerular mesangial cell proliferation and TNF-αexpression.Methods PCI-neo-X was transfected into cultured glomerular mesangial cells.Bothmesangial cell proliferation and supematant TNF-αexpression were compared betweentreated or untreated with ERK inhibitor U0126,NF-κB inhibitor lactacystin and p38inhibitor SB203580 respectively.HBx,ERK_(1/2) and p-ERK_(1/2) expression in glomerularmesangial cells was assessed by Western-blot.TNF-αmRNA expression was assessed bysemi-quantitative RT-PCR.TNF-αlevels in supernatants were measured by ELISA.Mesangial cell proliferation was assessed by MTT.Results HBx expression was found intransfected glomerular mesangial cells,and became prominent at 36 and 48 hours aftertransfection whatever with or without U0126 in culture media.TNF-αmRNA expressionwas significantly decreased in U0126 group compared with U0126-free group.TNF-αlevels in supernatants in pCI-neo-X transfection without U0126 group were (189.0±18.1)pg/ml at 36 hours and (172.3±24.3) pg/ml at 48 hours after transfection,(41.7±10.3) pg/ml.In contract,TNF-αlevels in supernatants with U0126 were (65.6±11.6) pg/ml and (84.0±24.6) pg/ml.The TNF-αlevels in the latter groups showed significantly lower thanthe formers (P＜0.05).Glomerular mesangial cell proliferation was also partially inhibitedwhen treated with ERKs inhibitor U0126 or NF-κB inhibitor lactacystin,but no effect wasobserved in p38 inhibitor SB203580 treated group at 36 and 48 hours after transfection.Conclussion HBx can induce glomerular mesangial cell proliferation and increaseTNF-αmRNA expression and its protein production.HBx upregulated TNF-αexpressionand induced cell proliferation of glomerular mesangial cell line partly through ERK_(1/2)signal transduction pathway.
目的：构建乙型肝炎病毒(HBV)X基因与pCI-neo相融合的高效真核表达载体，为进一步研究HBV X基因的功能奠定基础。方法：设计并合成HBV X基因的引物，以HBV DNA阳性血清PCR扩增得到HBV X基因全序列，将X基因连接到真核表达载体pCI-neo，构成pCI-neo-X质粒，然后用酶切图谱分析、PCR检测和扩增产物序列分析等方法，鉴定所构建的真核表达载体。结果：以重组载体为模板扩增得到的片段大小与已知HBV X基因大小相同，酶切也得到目的基因片段，测序结果也显示与已知X基因序列相同。结论：成功构建了HBV X基因的真核表达载体，为进一步研究HBVX基因的功能奠定了基础。
第二部分乙型肝炎病毒X基因转染对大鼠肾小球系膜细胞增殖以及肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6表达的影响
目的探讨HBV X基因表达的蛋白(HBx)对体外培养的大鼠系膜细胞表达肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β、IL-6及细胞增殖的影响。方法将前面构成的pCI-neo-X真核表达载体，采用脂质体法将pCI-neo-X转染给体外培养的大鼠系膜细胞，Westem blot测定HBx的表达；以半定量反转录(RT)-PCR测定体外培养大鼠系膜细胞TNF-αmRNA、IL-1βmRNA、IL-6 mRNA表达；酶联免疫吸附试验(ELISA)测定培养上清液中TNF-α、IL-1β、IL-6。甲基噻唑基四唑(MTT)法测定细胞增殖。结果转染pCI-neo-X的系膜细胞，HBx在36和48小时表达明显。同时半定量反转录PCR测定显示TNF-αmRNA、IL-1βmRNA、IL-6 mRNA表达量较未转染和转染空载体组明显增高。培养36和48小时后上清液中TNF-α水平在转染pCI-neo-X组、未转染和转染空载体组分别为(185．3±70．7)pg／ml，(41．7±10．3)pg／ml，(44．0±10．1)pg／ml，(140．3±42．1)pg／ml，(43．7±10．6)pg／ml，(33．3±8．6)pg／ml；IL-1β水平分别为(402±60)pg／ml，(182±23)pg／ml，(170±18)pg／ml，(432±58)pg／ml，(181±20)pg／ml，(165±19)pg／ml；IL-6水平分别为(177．0±18．2)pg／ml，(85．7±16．9)pg／ml，(69．7±22．2)pg／ml，(179．7±26．3)pg／ml，(70．0±18．3)pg／ml，(73．0±14．0)pg／ml，pCI-neo-X组与未转染和转染空载体组比较，均有显著性差异(p＜0．05)；细胞增殖在36和48小时pCI-neo-X组最明显，吸光度分别为1．56±0．36，1．69±0．32，与未转染组0．70±0．08，0．74±0．18和转染空载体组0．68±0．18，0．80±0．19比较，有显著差异(p＜0．05)。
结论HBx可诱导大鼠系膜细胞高表达TNF-α、IL-1β和IL-6，促进系膜细胞增殖。HBx对系膜细胞的增殖作用可能与TNF-α、IL-1β、IL-6的高表达有关。
第三部分乙型肝炎病毒X蛋白通过激活核因子-κB和细胞外调节蛋白激酶上调大鼠系膜细胞表达肿瘤坏死因子-α
目的探讨HBV X基因转染大鼠系膜细胞导致细胞增殖及肿瘤坏死因子-α(TNF-α)高表达的细胞外蛋白调节激酶(ERK)信号转导机制。方法将含有HBVX基因的质粒pCI-neo-X转染入体外培养的大鼠系膜细胞，MTT法检测系膜细胞增殖，半定量RT-PCR检测TNF-αmRNA表达，ELISA检测培养上清液中TNF-α表达。Western blot检测HBx、ERK_(1/2)及p-ERK_(1／2)表达。分别采用特异性抑制剂U0126阻断ERK_(1/2)通路，Lactacystin阻断NF-κB通路和SB203580阻断p38MAPK通路，观察培养细胞增殖、TNF-α及其mRNA表达，以不加抑制剂作为对照。结果转染pCI-neo-X后，系膜细胞增殖明显，细胞TNF-αmRNA及上清液TNF-α表达均增高，通过阻断ERK_(1／2)或NF-κB通路，系膜细胞增殖减弱，细胞TNF-αmRNA及上清液TNF-α表达均下降。而阻断p38MAPK通路对系膜细胞增殖，细胞TNF-αmRNA及上清液TNF-α表达无明显影响。结论转染HBV X基因可促使系膜细胞增殖，细胞TNF-αmRNA及上清液TNF-α表达均增高，这一作用可能部分是HBV X基因表达的蛋白通过激活ERK_(1／2)以及NF-κB通路信号而实现。而与p38MAPK通路无关。
PARTⅠConstruction of hepatitis B virus X gene eukaryoticexpression vector
Objective:To construct a highly effective eukaryotic expression vector pCI-neo withHBV X gene(pCI-neo-X).Methods:HBV DNA was extracted from the HBV DNApositive serum.HBV X gene was amplified by PCR,and identified by geloseelectrophoresis analysis.The PCR products and the eukaryotic expression vectors pCI-neowere digested by restriction endonucleases,then the digested X gene was inserted into thedigested eukaryotic expression vector.After screening,the positive recombinants werepicked out.PCR analysis and sequencing were made.Results Both vector DNA directsequence and restriction pattern confirmed that the HBV X gene was seccessfully insertedinto pCI-neo vector.Conclusion:The eukaryotic expression vextor pCI-neo has beensuccessfully constructed.
PartⅡHBV X gene transfection induces glomerular mesangialcell proliferation and upregulates TNF-α,IL-1βand IL-6 expression
Objectives The aim of this study is to approach the effect of HBx on expression oftumor necrosis factor-α(TNF-α),interluekin(IL)-1β,and IL-6 in,and proliferation of ratmesangial cell of rat in vitro.Methods Liposome bearing pCI-neo-X was transfected intocultured rat mesangial cell line of the rat in vitro through liposome method.X geneexpression in the cells was assessed by Western blot.The mRNA expression of TNF-α,IL-1βand IL-6 in expression of cultured mesangial cells line was assessed bysemiquantitative RT-PCR.Mesangial cell proliferation was assessed by MTT.Results HBxobviously expressed in cultured mesangial cells line at 36~(th) and at 48~(th) hour aftertransfection.The mRNA of TNF-α,IL-1βand IL-6 expression simutanously increased.Thesupernatent TNF-αlevels in supernatents in MC group,MC plus pCI-neo and MC pluspCI-neo-X at 36~(th) hours after transfection were (41.7±10.3) pg/ml,(44.0±10.1) pg/ml,(185.3±70.7)pg/ml,respectively,and at 48~(th) hours were(43.7±10.6)pg/ml,(33.3±8.6)pg/ml,(140.3±42.1) pg/ml,respectively;The supernatent IL-1βlevels in MC group,MC plus pCI-neo and MC plus pCI-neo-X were (182±23) pg/ml,(170±18) pg/ml,(402±60) pg/ml,respectively,at 36~(th),and (181±20)pg/ml,(165±19)pg/ml,(432±58)pg/ml,respectively,at 48~(th);The supematent IL-6 levels in MC group,MC plus pCI-neoand MC plus pCI-neo-X were (85.7±16.9) pg/ml,(69.7±22.2) pg/ml,(177.0±18.2)pg/ml,respectively at 36~(th) and (70.0±18.3) pg/ml,(73.0±14.0) pg/ml,(179.7±26.3)pg/ml,respectively at 48~(th),The expression of TNF-α,IL- 1βand IL-6 in pCI-neo-X groupwere all markedly higher than those in other two groups(all p＜0.05).The cell proliferationwas also obvious at the same time.Absorbance in transfcted pCI-neo-X cells were1.56±0.36 at 36~(th) and 1.69±0.32 at 48~(th) in hour after transfection,which was markedlyhigher than in untrasfected group 0.70±0.08 at 36~(th),0.74±0.18 at 48~(th) in hour or than intransfcted pCI-neo cells 0.68±0.18 at 36~(th),0.80±0.19 at 48~(th) in hour,respectively,all p＜0.05).Conclussion Therefore,we can conclude that HBx can induce expression ofmRNA of TNF-α,IL-1βand IL-6.HBx may play a critical role in the cell proliferationthrough TNF-α,IL-1βand IL-6 high expression.
PartⅢHepatitis B virus X protein upregulates tumor necrosisfactor-αexpression of rat mesangial cell line via NF-κB and ERKspathway
Objectives HBx,a 17-kd protein encoded by X gene of HBV,has been shown tofunction as a transcriptional trans-activator of a variety of viral and cellularpromoter/enhancer elements.The aim of the study is to investigate the signal transductionpathway of HBx in glomerular mesangial cell proliferation and TNF-αexpression.Methods PCI-neo-X was transfected into cultured glomerular mesangial cells.Bothmesangial cell proliferation and supematant TNF-αexpression were compared betweentreated or untreated with ERK inhibitor U0126,NF-κB inhibitor lactacystin and p38inhibitor SB203580 respectively.HBx,ERK_(1/2) and p-ERK_(1/2) expression in glomerularmesangial cells was assessed by Western-blot.TNF-αmRNA expression was assessed bysemi-quantitative RT-PCR.TNF-αlevels in supernatants were measured by ELISA.Mesangial cell proliferation was assessed by MTT.Results HBx expression was found intransfected glomerular mesangial cells,and became prominent at 36 and 48 hours aftertransfection whatever with or without U0126 in culture media.TNF-αmRNA expressionwas significantly decreased in U0126 group compared with U0126-free group.TNF-αlevels in supernatants in pCI-neo-X transfection without U0126 group were (189.0±18.1)pg/ml at 36 hours and (172.3±24.3) pg/ml at 48 hours after transfection,(41.7±10.3) pg/ml.In contract,TNF-αlevels in supernatants with U0126 were (65.6±11.6) pg/ml and (84.0±24.6) pg/ml.The TNF-αlevels in the latter groups showed significantly lower thanthe formers (P＜0.05).Glomerular mesangial cell proliferation was also partially inhibitedwhen treated with ERKs inhibitor U0126 or NF-κB inhibitor lactacystin,but no effect wasobserved in p38 inhibitor SB203580 treated group at 36 and 48 hours after transfection.Conclussion HBx can induce glomerular mesangial cell proliferation and increaseTNF-αmRNA expression and its protein production.HBx upregulated TNF-αexpressionand induced cell proliferation of glomerular mesangial cell line partly through ERK_(1/2)signal transduction pathway.
引文
1．徐虹．儿童乙型肝炎病毒相关性肾炎的流行病学[J]．实用儿科临床杂志，2008，23(5)：323-325
2．陈佳，李秋．儿童乙型肝炎病毒相关性肾炎30例临床病理分析[J]．重庆医学，2005，34(10)：1453-1455
3.Wang NS,Wu ZL,Zhang YE,et al.Existense and significance of hepatitis B virusDNA in kidneys of IgA nephropathy[J].World J Gastroenterol,2005,11(5):712-716
4.Vaughan RW,Zurowska A,Moszkowska G,et al.HLA-DRB and-DQB1 alleles in Polish patients with hepatitis B associated membranous nephropathy[J].Tissue Antigens,1998,52(2):130-134
5.Han SH.Extrahepatic manifestations of chronic hepatitis B[J].Clin Liver Dis,2004,8(2):03-418
6.Wang NS,Wu ZL,Zhang YE,et al.Role of hepatitis B virus infection in pathogenesis of IgA nephropathy[J].World J Gastroenterol,2003,9(9):2004-2008
7． 王素霞，邹万忠，王盛兰，等．乙型肝炎病毒相关性肾炎的超微结构及免疫电镜观察[J]．中华病理学杂志，2001，30(4)：289
8.Lin CY.Hepatitis B virus deoxyribonucleic acid in kidney cells probably leading to viral pathogenesis among hepatitis B virus associated membranous nephropathy patients[J].Nephron.1993,63(1):58-64
9.Cross JC,Wen P,Rutter W J.Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen-activated cellular serine/threonine kinases[J].Proc.Natl.Acad.Sci.USA,1993,90(17):8078-8082
10.Kekule AS,Lauer U,WeissL,et al.Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway[J].Nature(London)1993,361(6414):742-745.
11.Doria M,Klein N,Lucito R,et al.The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors[J].EMBO J,1995,14(19):4747-4757.
12.Benn J,Su F,Doria M.et al.Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases[J].J Virol,1996,70(8):4978-4985.
13.Wang HD,Yuh CH.,Dang C V,et al.The hepatitis B virus X protein increases the cellular level of TATA-binding protein,which mediates transactivation of RNA polymerase Ⅲ genes[J].Mol.Cell.Biol,1995,15(12),:6720-6728
14.Maguire H F,Hoeffler J P,Siddiqui,A.HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions[J].Science,1991,252(5007):842-844.
15.Haviv I.,Vaizel D,Shaul Y.1:pX,the HBV-encoded coactivator,interacts with components of the transcription machinery and stimulates transcription in a TAF-independent manner[J].EMBO J,1996,15(20):3413-3420.
16.Murakami S.Hepatitis B Virus X protein:a multifunctional regulatory protein[J].J Gastroenterol, 2001, 36(10): 651-660
17.Klein NP ,Schneider RJ . Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras[J]. Mol Cell Biol ,1997, 17(11): 6427-6436
18.Benn J ,Su F ,Doria M,et al. Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases[J]. J Virol ,1996 ,70 (8) :4978-4985
19.Henkler F ,Lopes AR ,Jones M,et al . Erk-independent partial activation ofAP-1 sites by the hepatitis B virus HBx protein[J]. J Gen Virol, 1998 , 79(11): 2737-2742
20.Henkler FF , Koshy R. Hepatitis B virus transcriptional activators mechanisms and possible role in oncogenesis[J]. J Viral Hepat ,1996, 3 (3) :109-121
1.Murakami S.Hepatitis B virus X protein:Structure,Function and Biology[J].Intervirology,1999,42(1):81-99
2.Han SHB.Extrahepatic manifedtations of chronic heptitis B[J].Clin Liver Dis,2004,8(2):403-418
3.Lin N,Chen HY,Li D,et al.Apoptosis and its pathway in X gene-transfected HepG2 cells[J].World J Gastroenterol,2005,11(28):4326-4331
4.Nijharaa R,Janaa SS,Goswamib SK,et al.An internal segment(residues 58-119)of the hepatitis B virus X protein is sufficient to activate MAP kinase pathways in mouse liver[J].FEBS Letters,2001,504(1):59-64
5.Madden CR,Slagle BL.Stimulation of cellular proliferation by hepatitis B virus X protein[J].Dis Markers,2001,17(3):153-157
6.Chen YB,Yan ML,Gong JP,et al.Establishment of hepatocellular carcinoma multidrug resistant monoclone cell line HepG2/mdrl[J].Chin Med J,2007,120(8):703-707
7.Li H,Cao HF,Wan J,et al.Growth inhibitory effect of wild-type Kras2 gene on a colonic adenocarcinoma cell line[J].World J Gastroenterol,2007,13(6):934-938
8.Bouchard M J,Schneider R J.The enigmatic X gene of hepatitis B virus[J].J Virol,2004,78(12):12725-12734
9.[9]Park SG,Chung C,Kang H,et al.Up-regulation of cyclin D1 by HBx is mediated by NF-κB2/BCL3 complex throughκB site of cyclin D1 promoter[J].J Biol Chem,2006,281(42):31770-31777
10．何於娟，欧一衡，张彦，等．未知基因KH的真核表达载体构建及其对细胞增殖的影响[J]．中华肿瘤杂志，2005，27(3)：129-133
11．李建民，陈薇，贾秀杰，等．用定点整合系统表达抗基孔肯亚病毒人-鼠嵌合抗体的研究[J]．细胞与分子免疫学杂志，2005，21(3)：312-315
12.Murakami S. Hepatitis B virus X protein, a multifunctional viral regulator[J]. J Gastroenterol, 2001, 36(10):651-660
13.Thio CL, Thomas DL, Karacki P, et al. Comprehensive analysis of classⅠand classⅡHLA antigens and chronic hepatitis B virus infection[J]. J Virol, 2003,77(22):12083-12087
14.Lee YZ, Kang-Park S, Do SI, et al. The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinese-dependent surviral signaling cascade[J]. J Biol Chem,2001, 276(20): 16969-16977
15.Su F, Theodosis CN, Schneider RJ. Rle of NF-κB and myc proteins in apoptosis induced by hepatitis B virus HBX protein[J]. J Virol, 2001, 75(1):215-225
16.Diao J, Khine AA, Sarangi F, et al. X protein of hepatitis B virus inhibits Fas-mediated apoptosis and is associated with up-regulation of the SAPK/JNK pathway[J]. J Biol Chem, 2001, 276(11):8324-8340
17.Arbuthnot P, Capovilla A, Kew M. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effect on apoptosis, DNA repair, mitogen-activated protein kinese and JAK/STAT pathway[J]. J Gastroenterol Hepatol, 2000, 15(4):357-368
18.Schmidt EV, Christoph G, Zeller R, et al. The cytomegalovirus enhancer: A pan-active control element in transgenic mice[J]. Mol Cell Biol, 1990, 10(8):4406-4411
19.Gluzman Y. SV40-transformedsimian dells support the replication of early SV40 mutations[J]. Cell, 1981,23(1): 175-182
20.Brondyk B. pCI and pSI mammalian expression vectors[J]. Promega Notes, 1994,
1.Combes B,Shorey J,Barrera A,et al.Glomerulonephritis with deposition of Australia antigen-antibody complex in glomerular basement membrane[J].Lancet,1971,2(7718):234-237
2．方利君，盛芳芸，郭怡清，等．成人与小儿乙型肝炎病毒相关性肾炎的比较[J]．中华传染病杂志，1996，14(2)：92-96
3．王朝晖，陈楠，任红，等．肾组织中检测乙型肝炎病毒DNA和RNA的意义[J]．上海医学，2001，24(10)：633-634
4.Han SH.Extrahepatic manifestation of chronic hepatitis B[J].Clin Liver Dis,2004,8(2):403-418
5.Sakallioglu O,Gok F,Kalman S,et al.Hepatitis B complicated focal segmental glomerulosclerosis[J].J Nephrol,2005;18(4):433-435
6.Hsu HC,Wu CY,Lin CY,et al.Membrane nephropathy in 52 hepatitis B surface antigen(HBsAg)carrier children in Taiwan[J].Kidney Int,1989,36(3):1103-1107
7.Venkataseshan VS,Lieberman K,Kim UD,et al.Hepatitis B-associated glomerulonephritis:pathology,pathogenesis,and clinical course[J].Medicine(Baltimore),1990,69(4):200-216
8.Lai KN,Li PK,Lui SF,et al.Membrane nephropathy related to hepatitis B virus in adults[J].N Engl J Med,1991,324:1457-1463
9.Johnson R J,Couser WG.Hepatitis B infection and renal diseases:clinical,immunopathogenetic and therapeutic considerations[J].Kidney Int,1990,37(2):663-676
10.Lin CY.Hepatitis B virus DNA in kidney cells probably leading to viral pathogenesis amony hepatitis B virus associated membranous nephropathy patients[J].Nephron,1993,63(1):58-64
11．陈楠，王朝晖，任红，等．肾组织中乙型肝炎病毒DNA和RNA的存在及其意义[J]．中华医学杂志，2001，81(21)：1309-1312
12．张爱平，张训，侯凡凡．原位杂交和原位聚合酶链反应检测肾脏HBV DNA的存在[J]．中华肾脏病杂志，1996，12(5)：273-275
13.Wang SN,Wu ZL,Zhang YE,et al.Existence and significance of hepatitis B virus DNA in kidneys of IgA nephropathy[J].World J Gastroenterol,2005;11(5):712-716
14.Egido J,Gomez-Chiarri M,Ortiz A,et al.Role of tumor necrosis factor-α in the pathogenesis of glomerilar diseases[J].Kidney Int,1993,43(Suppl 39):S59-S64
15.Makino T,Ito M,Kiuchiu F,et al.Inhibitory effect of decoction of Perilla frutescens on cultured murine mesangial cell proliferation and quantitative analysis of its active constituents[J].Planta Med,2001,67(1):24-28
16.Jimi N,Segawa K,Minami K,et al.Inhibitory effect of the intravenous anesthetic,ketamine,on rat mesangial cell proliferation[J].Anesth Analg,1997,84(1):190-195
17.Oda H,Yorioka N,Ito T,et al.Nicardipine hydrochloride suppresses DNA synthesis in human mesangial cells stimulated with recombinant human(rh)platelet-derived growth factor AA,rh interleukin-1 alpha,or rh tumor necrosis factor-alpha[J].Nephron,1996,73(1):16-22
18.Wu SH,Lu C,Dong L,et al.Lipoxin A4 inhibits TNF-α-induced production of interleukins and proliferation of rat mesangial cells[J].Kidney Int,2005,68(1):35-46
19.Noiri E,Kuwata S,Nosaka K,et al.Tumor necrosis factor-α mRNA expression in lipopolysaccharide-stimulated rat kindey[J].Am J Pathol,1994,144(6):1159-1166
20.Hrvacevic R,Dimitrijevic D,Spasic P,et al.Interleukin-1 beta in patients with primary immunocomplex glomerulonephritis[J].Vojnosanit Pregl,2001,58(1):33-38
21.Colenman DL,Ruef C.Interleukin-6:An autocrine regulator of mesangial cell growth[J].Kidney Int,1992,41(3):604-606
22.Zhang JL,Zhao WG,Wu KL,et al.Human hepatitis B virus X protein promotes cell proliferation and inhibits cell apoptosis through interacting with a serine protease Hepsin[J].Arch Virol,2005,150(4):721-741
23.Bouchard M J,Puro R J,Schneider RJ,et al.Activation and inhibition of cellular calcium and tyrosine kinase signaling pathways identify targets of the HBx protein involved in hepatitis B virus replication[J].J Virol,2003,77(14):7713-7719
24.Zhang Z,Protzer U,Liang J,et al.Inhibition of cellular proteasome activities enhances hepadnavirus replication in an HBX-dependent manner[J].J Virol,2004,78(9):4566-4572
25.Chan DW,Ngi O.Knock-down of hepatitis B virus X protein reduces the tumorigenicity of hepatocellular carcinoma cells[J].J Pathol,2006,208(3):372-380
26.Zhang JL,Zhao WG,Wu KL,et al.Human hepatitis B virus X protein promotes cell proliferation and inhibits cell apoptosis through interacting with a serine protease Hepsin[J].Arch Virol,2005,150(4):721-741
27.Baud L,Oudinet JP,Bens M,et al.Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide[J].Kidney Int,1989,35(5):1111-1118
28.Hruby ZW,Shirota K,Jothy S,et al.Antiserum against tumor necrosis factor-alpha and a protease inhibitor reduce immune glomerular injury[J].Kidney Int,1991，40(1):43-51
29．贾力，姜新猷，费莉．细胞因子对肾小球系膜细胞增殖的影响[J]．中国免疫学杂志，1997，13(1)：49-51
30.Takemura T,Yoshioka K,Murakami K,et al.Cellular localization of inflammatory cytokines in human glomerulonephritis[J].Virchows Arch,1994,424(5):459-464
31.Waldherr R,Noronha IL,Niemir Z,et al.Expression of cytokines and growth factors in human glomerulonephritis[J].Pediatr Nephrol,1993,7(4):471-478
32.Neale T J,Ruger BM,Macaulay H,et al.Tumor necrosis factor-alpha is expressed by glomerular visceral epithelial cells in human membranous nephropathy[J].Am J Pathol,1995,146(6):1444-1454
33.Bertani T,Abbate M,Zoja C,et al.Tumor necresis factor induces glomerular damage in the rabbit[J].Am J Pathol,1989,134(2):419-430
34.Tomosugi NI, Cashman SJ, Hay H, et al. Modulation of antibody-mediated glomerular injury in vivo by bacterial lipopolysaccharide, tumor necrosis factor, and IL-1 [J]. J Immunol, 1989,142(9):3083-3090
35.Le Hir M, Haas C, Marino M, et al. Prevention of crescentic glomerulonephritis induced by anti-glomerular menbrane antibody in tumor necrosis factor-deficient mice[J]. Lab Invest, 1998,78(12): 1625-1631
36.Timoshanko JR, Sedgwick JD, Holdsworth SR, et al. Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis[J]. J Am Soc Nephrol, 2003, 14(7): 1785-1793
37.Karkar AM, Koshino Y, Cashman SJ, et al. Passive immunization against tumor necrosis factor-alpha (TNF-alpha) and IL-1 beta protects LPS enhancing glomerular injury in nephrotoxic nephritis in rats[J]. Clin Exp Immunol, 1992,90(2):312-318
38.Karkar Am, Smith J, Pusey CD. Prevention and treatment of experimental crescentic glomerulonephritis by blocking tumor necrosis factor-alpha[J]. Nephrol Dial Transplant, 2001,16(3):518-524
39.Karkar Am, Tarn FW, Steinkasserer A, et al. Modulation of antibody-mediated glomerular injury in vivo by IL-lra, soluble IL-lreceptor, and soluble TNF receptor[J].Kidney Int, 1995,48(6):1738-1746
40.Khan SB, Cook HT, Bhangal G, et al. Antibody blockade of TNF-alpha reduces inflammation and scarring in experimental crescentic glomerulonephritis[J]. Kidney Int, 2005,67(5): 1812-1820
41.Little MA, Bhangal G, Smyth CL, et al. Therapeutic effect of anti-TNF-alpha antibodies in an experimental model of anti-neutrophil cytoplasm antibody-associated systemic vasculitis[J]. J Am Soc Nephrol, 2006, 17(1): 160-139
42.Ortiz A, Bustos C, Alonso J, et al. Involvement of tumor necrosis factor-alpha in the pathogenesis of tumor necrosis factor-alpha in the pathogenesis of experimental and human glomerulonephritis[J]. Adv Nephrol Necker Hosp, 1995, 24:53-77
43.Booth A, Harper L, Hammad T, et al. Prospective study of TNFalpha blokade with infiiximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis[J]. J Am Soc Nephrol, 2004,15(3):717-721
44.Dinarello CA. Interleukin-1 and interleukin-1 antagonism[J]. Blood, 1991, 77(8):1627-1652
45.Tomosugi NI, Cashman SJ, Hay H, et al. Modulation of antibody- mediated glomerular injury in vivo by bacterial lipopolysaccharide, tumor necrosis factor, and IL-1[J]. J Immunol, 1989, 142(9):3083-3090
46.Karkar AM, Tarn FW, Steinkasserer A, et al. Modulation of antibody-mediated glomerular injury in vivo by IL-lra, soluble IL-1 receptor, and soluble TNF receptor[J]. Kidney Int, 1995,48(6): 1738-1746
47.Lan HY, Nikolic-Paterson DJ, Mu W, et al. Interleukin-1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat[J]. Kidney Int, 1995,47(5):1303-1309
48.Tesch GH, Yang N, Yu H, et al. Intrinsic renal cells are the major source of interleukin-1 beta synthesis in normal and diseased rat kidney[J]. Nephrol Dial Transplant, 1997,12(6): 1109-1115
49.Werber HI, Emancipator SN, Tykocinski ML, et al. The interleukin 1 gene is expressed by rat glomerular mesangial cells and is augmented in immune complex glomerulonephritis[J]. J Immunol, 1987, 138(10):3207-3212
50.Richardson CA, Gordon KL, Couser WG, et al. IL-1 beta increases laminin B2 chain mRNA levels and activates NF-kappa B in rat glomerular epithelial cells[J]. Am J Physiol,1995, 268(2): F273-F278,
51.Massy ZM, Guijarro C, Micheal P, et al. The central role of nuclear factor-??????????????B in mesangial cell activation[J]. Kidney Int, 1999, Suppl, 71:S76-S79
52.Dinarello CA. Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist[J]. Int Rev Immunol, 1998,16(5-6):457-499
53.Niemir ZI, Stein H, Dworacki G, et al. Podocytes are the major source of IL-1 alpha and IL-1 beta in human glomerulonephritides[J]. Kidney Int, 1997,52(2):393-403
54.Lonnemann G, Engler-Blum G, Mullar GA, et al. Cytokines in humanrenal interstitial fibrosis. Ⅱ. Intrinsic interleukin(IL)-l synthesis and IL-1-dependent production of IL-6 and IL-8 by cultured kidney fibroblasts[J]. Kidney Int, 1995, 47(3):845-854
55.Sims JE, Gayle MA, Slack JL, et al. Interleukin-1 signaling occurs exclusively via the type I receptor[J]. Proc Natl Acad Sci USA,1993,90(13):6155-6159
56.Sims JE, Giri JG, Dower SK. The two interleukin-1 recepts play different roles in IL-1 actions[J]. Clin Immunol Immunopathol,1994,72(l):9-14
57.Noronha IL, Kruger C, Andrassy K, et al. In situ productionof TNF-alpha, IL-1 beta and IL-2R in ANCA-positive glomerulonephritis[J]. Kidney Int, 1993, 43(3):682-692
58.Matsumoto K, Dowling J, Atkins RC. Production of interleukin 1 in glomerular cell cultured from patients with rapidly progressive crescentic glomerulonephritis[J]. Am J Nephrol, 1988,8(6):463-470
59.Tesch GH, Yang N, Yu H, et al. Intrinsic renal cells are the major source of interleukin-1 beta synthesis in normal and diseasedrat kidney [J]. Nephrol Dial Transplant, 1997,12(6): 1109-1115
60.Tipping PG, Lowe MG, Holdsworth SR. Glomerular interleukin 1 production is dependent on macrophage infiltration in anti-GBM glomerulonephritisfJ]. Kidney Int,1991,39(1):103-110
61.Timoshanko JR, Kitching AR, Iwakura Y, et al. Contributions of IL-1beta and IL-1 alpha to crescentic glomerulonephritis in mice[J]. J Am Soc Nephrol,2004,15(4):910-918
62.Lan HY, Nikolic-Paterson DJ, Zarama M, et al. Supression of ecperimental crescentic glomerulonephritis by the interleukin-1 receptor antagonist[J]. Kidney Int,1993,43(2):479-485
63.Nikolic-Paterson DJ, Lan HY, Hill PA, et al. Suppression of experimental glomerulonephritis by the interleukin-1 receptor antagonist: inhibition of intercellular adhesion molecule-1 expression[J]. J Am Soc Nephrol, 1994, 4(9): 1695-1700
64.Tang WW, Feng L, Vannice JI, et al. Interleukin-1 receptor antagonist ameliorates experimental anti-glomerular basement membrane antibody-associated glomerulonephritis[J]. J Clin Invest, 1994, 93(1):273-279
65.Yu XQ, Fan JM, Nikolic-Peterson DJ, et al. IL-1 up-regulates osteopontin expression in experimental crescentic glomerulonephritis in the rat[J]. Am J Pathol,1999,154(3):833-841
66.Lan HY, Nikolic-Paterson DJ, Mu W, et al. Interleukin-1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat[J]. Kidney Int,1995,47(5):1303-1309
67.Yokoo T, Kitamura M. Gene trandfer of interleukin-1 receptor antagonist into the renal glomerulus via a mesangial cell vector[J]. Biochem Biophys Res Commun,1996,226(3):883-888
68.Yokoo T, Ohashi T, Utsunomiya Y, et al. Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppressed renal injury in mouse Goodpasture syndrome[J]. Blood, 2001,98(l):57-64
69.Timoshanko JR, Kitching AR, Iwakura Y, et al. Lekocyte-derived interleukin-1 beta interacts with renal interleukin-1 receptor I to promote renal tumor necrosis factor and glomerular injury in murine crescentic glomerulonephritis[J]. Am J Pathol,2004,164(6):1967-1977
70.Horii Y, Muraguchi Z, Iwano M, et al. Involement of IL-6 in mesangial proliferative glomerulonephritis[J]. J Immunol,1989, 143(12):3949-3955
71.Zoja C, Betton S, Morigi M, et al. Interluekin-1 regulates cytokine gene expression in human mesangial cells through the interluekin-1 receptor type Ⅰ[J]. J Am Soc Nephrol,1992,2(12): 1709-1715
72.Abbott F, Ryan JJ, Ceska M, et al. Interluekin-1βstimulates human mesangial cells to synthesize and release Interluekins-6 and -8[J]. Kidney Int, 1991,40(4):597-605
73.Coleman DL, Rufe C. Interleukin-6: An autocrine regulator of mesangial cell growth[J].Kidney Int, 1992,41(3):604-606
74.Fukatsu A, Matsuo S, Tamai H, et al. Distribution of interleukin-6 in normal and diseased human kidney[J]. Lab Invest, 1991, 65(l):61-66
75.Murakami S. Hepatitis B virus X protein: structure, function and biology[J].Intervirology,1999, 42(2-3):81-99
76.Lara-Pezzi E, Majano PL, Gomez-Gonzalo M, et al. The hepatitis B virus X protein up-regulates tumor necrosis factor a gene expression in hepatocytes[J]. Hepatology,1998,28(4):1013-1021
77.Doria M, Klein N, Lucito R, et al. The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors[J].EMBPJ,1995,14(19):4747-4757
78.Tsai EY, Jain J, Pesavento PA, et al. Tumor necrosis factor alpha gene regulation in activited T cells involves ATF-2/Jun and NFATp[J]. Mol Cell Biol, 1996,16(2):459-467
79.Tsai EY, Yie J, Thanos D, et al. Cell-type-specific regulation of the human tumor necrosis factor-alpha gene in B cell and T cell by NFATp and ATF-2/Jun [J]. Mol Cell Biol, 1996,16(10):5232-5244
80.Koike K, Moriya K, Yotsuyanagi H, et al. Induction of cell cycle progression in quiescent mouse fibroblasts[J]. J Clin Invest, 1994, 94(1):44-49
81.Cooker LA, Peterson D, Rambow J, et al. TNF-alpha, but not IFN-gamma, regulates CCN2 (CTGF), collagen type I, and proliferation in mesangial cells: possible roles in the progression of renal fibrosis[J]. Am J Physiol Renal Physiol, 2007,293(1):F157-F165
82.Hideki Ohno, Shuichi Kaneko,Yong Lin. Human Hepatitis B Virus X Protein Augments the DNA binding of nuclear factor for IL-6 through its basic-leucine zipper domain[J]. J Med Virol, 1999, 58(1):11-18
83. Kim JS , Rho BY , Lee TH, et al. The interaction of hepatitis B virus X protein and protein phosphatase type 2 Ca and its effect on IL-6[J]. Bioch Biophys Res Commun,2006, 351(1):253-258
1.Han SH. Extrahepatic manifestation of chronic hepatitis B[J].Clin Liver Dis, 2004,8(2):403-418
2.Wang SN, Wu ZL, Zhang YE, et al. Existence and significance of hepatitis B virus DNA in kidneys of IgA nephropathy[J]. World J Gastroenterol, 2005, 11(5):712-716
3.Venkataseshan VS, Lieberman K, Kim UD, et al. Hepatitis B-associated glomerulonephritis: pathology, pathogenesis, and clinical course[J]. Medicine(Baltimore), 1990, 69(4): 200-216
4.Ren J, Wang L, Chen Z, et al. Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus associated nephropathy[J]. J Med Virol,2006,78(5):551-560
5.Colgrove R, Simon G, Ganem D. Transcriptional activation of homologous and heterologous genes by the hepatitis B virus X gene product in cells permissive for virol replication[J]. J Virol, 1989,63(9):4019-4026
6.Kekule A, Lauer U, Weiss L, et al. Hepatitis B virus transactivator HBx uses a tumor promoter signalling pathway[J]. Nature, 1993, 361(6414):742-745
7.Maguire HF, Hoeffler JP, Siddiqui A. HBV X protein alters the DNA bingding specificity of CREB and ATF-2 by protein-protein interactional[J]. Science, 1991,252():842-844
8.Yoo Y, Ueda H, Park K, et al. Regulation of transforming growth factor-b1 expression by the hepatitis B virus(HBV) X transactivator[J]. J Clin Invest, 1996, 97(2):388-395
9.Benn J, Schneider RJ. Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade[J]. Proc Natl Acad Sci USA,1994, 91(22):10350-10354
10.Bouchard MJ, Wang L, Schneider RJ. Activation of focal adhesion kinase by hepatitis B virus HBx protein: multiple functions in viral replication[J]. J Virol, 2006,80(9):4406-4414
11.Benn J, Su F, Doria M, et al. Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signaling-regulated and c-Jun N-terminal mitogen-activated protein linases[J]. J Virol, 1996, 70(8):4978-4985
12.Klein NP, Schneider RJ. Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras[J]. Mol Cell Biol, 1997, 17(11):6427-6436
13.Lee YI, Kang-Park S, Do S, et al. The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent xurvival signaling cascade[J]. J Biol Chem,2001, 276(20): 16969-16977
14.Lee YH, Yun Y. HBx protein of hepatitis B virus activates Jak1-STAT signaling[J]. J Biol Chem, 1998, 273(39):25510-25515
15.Egido J, Gomez-Chiarri M, Ortiz A, et al. Role of tumor necrosis factor-a in the pathogenesis of glomerilar diseases[J]. Kidney Int, 1993, 43(Suppl 39): S59-S64
16.Makino T, Ito M, Kiuchiu F, et al. Inhibitory effect of decoction of Perilla frutescens on cultured murine mesangial cell proliferation and quantitative analysis of its active constituents[J]. Planta Med, 2001, 67(1):24-28
17.Ho AW, Wong CK, Lam CW, et al. Tumor necrosis factor-alpha up-regulates the expression of CCL2 and adhesion molecules of human proximal tubular epithelial cells through MAPK signaling pathways[J]. Immunobiology, 2008, 213(7):533-544
18.Makino T, Ito M, Kiuchiu F, et al. Inhibitory effect of decoction of Perilla frutescens on cultured murine mesangial cell proliferation and quantitative analysis of its active constituents[J]. Planta Med, 2001, 67(1):24-28
19.Noiri E, Kuwata S, Nosaka K, et al. Tumor necrosis factor-a mRNA expression in lipopolysaccharide-stimulated rat kindey[J]. Am J Pathol, 1994, 144(6):1159- 1166
20.Delgado M, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibite expression of Fas ligand in activated T lymphocytes by regulating c-Myc, NF-kappa B, NF-AT, and early growth factors2/3[J].J Immulo, 2001, 166(2): 1028-1040
21.Gilmore TD. The Rel/NF-kappa B/I kappa B signal transduction pathway and cancer[J]. Cancer Treat Res, 2003, 115:241-265
22.Amit S, Ben-Neriah Y. NF-kappa B activation in cancer: a challenge for ubiquitination-and proteasome-based therapeutic approach[J]. Semin CancerBiol, 2003,13(1): 15-28
23.Nakshatri H, Goulet RJ Jr. NF-kappa B and breast cancer[J]. Curr Probl Cancer,2002,26(5):282-309
24.Bell S, Degitz K, Quirling M, et al. Involvement of NF-kappa B signaling in skin physiology and disease[J]. Cell Signal, 2003,15(1):1-7
25.Li Q, Verma IM. NF-kappa B regulation in the immune system[J]. Nat Rev Immunol,2002,2(10):725-734
26.Bharti AC, Aggarwal BB. Nuclear factor-kappa B and cancer:its role in prevenrion and therapy[J]. Biochem Pharmacol,2002,64(5-6):883-888
27.Sun Z, Andersson R. NF-kappa B activation and inhibition: a review[J]. Shock, 2002,18(2):99-106
28.Yamamoto Y, Gaynor RB. Role of the NF-kappa B pathway in the pathogenesis of human disease states[J]. Curr Mol Med, 2001, 1(3):287-296
29.Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathwayby protein interactions[J]. Biochem J, 2000,351(pt2):289-305
30.Guan J; Chen XP; Zhu H, et al. Involvement of extracellular signal-regulated kinase/mitogen-activated protein kinase pathway in multidrug resistance induced by HBx in hepatoma cell line[J]. World J Gastroenterol. 2004,10(23):3522-3527
31.Chung TW, Lee YC, Kim CH. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential[J]. FASEB J. 2004, 18(10): 1123-1125
32.Matsumoto K; Nagahara T; Okano J, et al. The growth inhibition of hepatocellular and cholangiocellular carcinoma cells by gemcitabine and the roles of extracellular signal-regulated and checkpoint kinases[J]. Oncol Rep. 2008, 20(4):863-872
33．郭晓，潘崚．ERK阻滞剂U0126对白血病细胞K562细胞周期的作用及机制[J]．第三军医大学学报，2008，30(5)：393-395
34.Wolf I,Rubinfeld H,Yoon S,et al.Involvement of the activation loop of ERK in the detachment from cytosolic anchoring[J].J Biol Chem,2001,276(27):24490-24497
35.Kumar S,Boehm J,Lee JC.p38 MAPK kinases inhibitors:key signaling molecules as therapeutic targets for inflammatory diseases[J].Nat Rev Drug Discov,2003,2(9):717-726
36.Kothapalli D,Zhao L,Hawthorne EA,et al.Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells[J].J Cell Biol,2007,176(4):535-544.
1.Murakami S,Cheong J,Kaneko S,et al.Transactivation of human hepatitis B virus X protein,HBx operates through a mechanism distinct from protein kinase C and okadaic acid activation pathways[J].J Virol,1994;199(1):243-246
2.Murakami S,Cheong J,Kaneko S,et al.Autoregulation of human hepatitis B virus X gene.In:Nishioka,K,Suzuki,H,Mishiro,S,Oda,T,eds.Viral Hepatitis and Liver Diseases.Tokyo:Springer Verlauf,1994;743-747
3.Cheong JH,Yi MK,Murakami S,et al.Human RPB5,a subunit shared eukaryotic nuclear polymerases,binds human hepatitis B virus X protein and may play a role in X transactivation[J].EMBO J,1995;14(1):143-150
4.Murakami S.Hepatitis B Virus X protein:a multifunctional regulatory protein[J].J Gastroenterol, 2001, 36(10): 651-660
5.Doitsh G, Shaul Y. HBV transcription repression in response to genotoxic stress is p53-dependent and abrogated by pX[J]. Oncogene, 1999; 18(52): 7506-7513
6.Dewantoro O, Gani RA, Akbar N. Hepatocarcinogenesis in viral Hepatitis B infection:the role of HBx and p53[J]. Acta Med Indones, 2006,38(3):154-159
7.Ahn JY, Chung EY, Jang KL, et al. Transcriptional repression of p21 (wafl) promoter by hepatitis B virus X protein via a p53-independent pathway[J]. Gene, 2001,275 (1):163-168
8.Zhang Z, Torii N, Liang TJ, et al. Structural and functional characterization of interaction between hepatitis B virus X protein and the proteasome complex[J]. J Biol Chem, 2000, 275 (20): 15157-15165
9.Lee TH, Elledge SJ, Butel JS. Hepatitis B virus X protein interacts with a probable cellular DNA repair protein[J]. J Virol, 1995, 69(2): 1107-1114
10.Bouchard MJ, Wang LH, Schneider RJ, et al. Calcium signaling by HBx protein in hepatitis B virus DNA replication[J]. Science, 2001; 294 (5550): 2376-2378.
11.Bouchard MJ, Wang LH, Schneider RJ. Activation of focal adhesion kinase by hepatitis B virus HBx protein: Multiple functions in viral replication[J]. J Virol, 2006;80 (9): 4406-4414
12.Jia L, Wang XW, Harris CC. Hepatitis B virus X protein inhibits nucleotideexcision repair[J]. Int J Cancer, 1999, 80(6): 875-79.
13.Klein NP, Schneider RJ. Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras[J]. Mol Cell Biol, 1997, 17(11): 6427-6436
14.Huh KW, Siddiqui A. Characterization of the mitochondrial association of hepatitis B virus X protein, HBx[J]. Mitochondrion, 2002; 1 (4): 349-359
15.Tanaka Y, Kanai F, Omata M, et al. Interaction of the hepatitis B virus X protein (HBx) with heat shock protein 60 enhances HBx-mediated apoptosis[J]. Biochem Biophys Res Commun, 2004,318 (2): 461-69
16.Zhang SM, Sun DC, Wang SQ, et al. HBx protein of hepatitis B virus (HBV) can form complex with mitochondrial HSP60 and HSP70[J]. Arch Virol, 2005, 150(8):1579-1590
17.Takada S, Shirakata Y, Koike K et al. Association of hepatitis B virus X protein with mitochondria causes mitochondrial aggregation at the nuclear periphery, leading to cell death[J]. Oncogene, 1999, 18(50): 6965-6973.
18.Tanaka Y, Kanai F, Omata M, et al. Interaction of the hepatitis B virus X protein (HBx)with heat shock protein 60 enhances HBx-mediated apoptosis[J]. Biochem Biophys Res Commun, 2004, 318(2): 461-469.
19.Pang R, Lee TK, Poon RT, et al. Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis[J]. Gastroenterology, 2007, 1323(3): 1180-1183
20.Chen J, Siddiqui A. Hepatitis B virus X protein stimulates the mitochondrial translocation of Raf-1 via oxidative stress[J]. J Viro,. 2007,81(12):6757-6760
21.Blum HE, Zhang ZS, Galun E, et al. Hepatitis B virus X protein is not central to the viral life cycle in vitro[J]. J Virol, 1992, 66(2): 1223-1227
22.Chen HS, Kaneko S, Miller RH, et al. The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks[J]. J Virol, 1993, 67(3):1218-1226
23.Reifenberg K, Nusser P, Lohler J, et al.Virus replication and virion export in X-deficient hepatitis B virus transgenic mice[J]. J Gen Virol, 2002, 83(5):991-996
24.Zhang Z, Torii N, Hu Z, et al. X-deficient woodchuck hepatitis virus mutations behave like attenuated viruses and induce protective immunity in vivo[J]. J Clin Investig, 2001,108(10):1523-1531
25.Zoulim F, Saputelli J, Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo[J]. J Virol, 1994, 68(3): 2026-2030
26.Xu Z, Yen TS, Ou JH, et al. Enhancement of hepatitis B virus replication by its X protein in transgenic mice[J]. J Virol, 2002, 76(5): 2579-2584
27.Bouchard MJ, Puro RJ, Schneider RJ, et al. Activation and inhibition of cellular calcium and tyrosine kinase signaling pathways identify targets of the HBx protein involved in hepatitis B virus replication[J]. J Virol, 2003, 77(14): 7713-7719
28.Melegari M, Wolf SK, Schneider RJ. Hepatitis B virus DNA replication is coordinated by core protein serine phosphorylation and HBx expression[J]. J Virol, 2005, 79 (15):9810-9820
29.Tang H, Delgermaa L, Huang F, et al. The transcriptional transactivation function of HBx protein is important for its augmentation role in hepatitis B virus replication[J]. J Virol, 2005,79(9):5548-5556
30.Zheng Y, Johnson DL, Ou JH. Regulation of hepatitis B virus replication by the ras-mitogen-activated protein kinase signaling pathway[J]. J Viro,l 2003, 77 (14):7707-7712
31.Xu Z, Yen TS, Ou JH et al. Enhancement of hepatitis B virus replication by its X protein in transgenic mice[J]. J Viro,l 2002, 76 (5): 2579-2584
32.Bouchard MJ, Puro RJ, Schneider RJ, et al. Activation and inhibition of cellular calcium and tyrosine kinase signaling pathways identify targets of the HBx protein involved in hepatitis B virus replication[J]. J Virol, 2003,77 (14): 7713- 7719
33.Zhang Z, Protzer U, Liang J, et al. Inhibition of cellular proteasome activities enhances hepadnavirus replication in an HBX-dependent manner[J]. J Virol, 2004, 78 (9):4566-4572
34.Leupin O, Bontron S, Strubin M, et al. Hepatitis B virus X protein stimulates viral genome replication via a DDB1-dependent pathway distinct from that leading to cell death[J]. J Virol, 2005, 79 (7): 4238-4245
35.Hu Z, Zhang Z, Liang TJ, et al. Altered proteolysis and global gene expression in hepatitis B virus X transgenic mouse liver[J]. J Virol, 2006,80 (3):1405-1413
36.Kim CM, Koike I, Miyamura T, et al. HBx gene of hepatitis B virus induces liver cancer in transgenic mice[J]. Nature ,1991 , 353(6324):317-320
37.Klein A, Guhl E, Tzeng YJ, et al. HBx cause cyclin D1 over expression and development of breast cancer in transgenic animals that are heterozygous for p53[J].Oncogene, 2003, 22(19):2910-2919
38.Koike K, Moriya K, Yotsuyanagi H, et al. Compensatory apoptosis in preneoplastic liver of a transgenic mouse model for viral hepatocarcinogenesis[J]. Cancer Letter,1998, 134(2): 181-186
39.Schuster R, Gerlich WH, Schaefer S. Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts[J]. Oncogene, 2000, 19(9):1173-1180
40.Schuster R, Hildt E, Chang SF, et al. Conserved transactivating and proapoptotic functions of hepadnaviral X protein in ortho- and avihepadnaviruses[J]. Oncogene,2002, 21(43): 6606-6613.
41.Artandi SE, DePinho RA. Mice without telomerase: what can they teach us about human cancer[J]? Nat Med, 2000, 6(8): 852-855.
42.Sharpless NE, DePinho RA. Cancer: crime and punishment[J]. Nature, 2005,436(7051): 636-637.
43.Braig M, Lee S, Loddenkemper C, et al. Oncogene-induced senescence as an initial barrier in lymphoma development[J]. Nature, 2005, 436(7051): 660-665
44.Tang H, Oishi N, Kaneko S, et al. Molecular functions and biologecal roles of hepatitis B virus X protein[J]. Cancer Sci, 2006,97(10):977-983
45.Klein NP ,Schneider RJ . Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras[J]. Mol Cell Biol ,1997, 17(11): 6427-6436
46.Benn J ,Su F ,Doria M,et al. Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases[J]. J Virol ,1996 ,70 (8) :4978-4985
47.Henkler F ,Lopes AR Jones M, et al . Erk-independent partial activation of AP-1 sites by the hepatitis B virus HBx protein[J]. J Gen Virol, 1998 , 79(11): 2737-2742
48.Henkler FF , Koshy R. Hepatitis B virus transcriptional activators :mechanisms and possible role in oncogenesis[J]. J Viral Hepat ,1996, 3 (3) :109-121
49.Chan DW, Ng IO. Knock-down of hepatitis B virus X protein reduces the tumorigenicity of hepatocellular carcinoma cells[J]. J Pathol, 2006, 208 (3): 372- 380
1.Bhimma R,Coovadia HM.Hepatitis B virus-associated nephropathy[J].Am J Nephrol,2004,24(2):205-206
2.Ozdamar SO,Gucer S,Tinaztepe K.HepatitisB virus associated nephropathies:a clinicopathological study in 14 children[J].Pediatr Nephrol,2003,18(1):23-28
3． 陈楠，王朝晖，任红，等．肾组织中乙型肝炎病毒DNA和RNA的存在及其意义[J]．中华医学杂志，2001，81(21)：1309-1312
4.He XY,Fang L J,Zhang YF,et al.In situ hybridization of hepatitis B DNA in hepatitis B-associated glomerulonephritis[J].Pediatr Nephrol,1998,12(2):117-120
5.Wang NS,Wu ZL,Zhang YE,et al.Role of hepatitis B virus infection in pathogenesis of IgA nephropathy[J].World J Gastroenterol,2003,9(9):2004-2008
6.Wang NS,Wu ZL,Zhang YE,et al.Existense and significance of hepatitis B virusDNA in kidneys of IgA nephropathy[J].World J Gastroenterol,2005,11(5):712-716
7．王素霞，邹万忠，王盛兰，等．乙型肝炎病毒相关性肾炎的超微结构及免疫电镜观察[J]．中华病理学杂志．2001，30(4)：289
8.Lin CY.Hepatitis B virus deoxyribonucleic acid in kidney cells probably leading to viral pathogenesis among hepatitis B virus associated membranous nephropathy patients[J].Nephron.1993,63(1):58-64
9.Kim SE,Park YH,Chung WY.Study on hepatitis B virus pre-S/S gene mutations of renal tissues in children with hepatitis B virus-associated memberanous nephropathy[J].Pediatr Nephrol,2006,21(8):1097-1103
10.Kusakabe A,Tanaka Y,Kurbanov F,et al.Virological features of hepatitis B virus-associated nephropathy in Japan[J].J Med Virol,2007,79(9):1305-1311.
11．李少稚，冯江敏．乙肝病毒相关性肾炎与人白细胞抗原相关性的探讨[J]．中国医科大学学报，2001，30(4)：290-292
12.Vaughan RW,Zurowska A,Moszkowska G,et al.HLA-DRB and-DQB1 alleles in Polish patients with hepatitis B associated membranous nephropathy[J].Tissue Antigens,1998,52(2):130-134
13.Bhimma R,HammondMG,Coovadia HM,et al.HLA class Ⅰ and Ⅱ in black children with hepatitis B virus-associated membranousnephropathy[J].Kidney Int,2002,61(4):1510-1515
14.Park MH,Song EY,Ahn C,et al.Two subtypes of hepatitisB virus-associated glomerulonephritis are associated with different HLA-DR2 alleles in Koreans[J].Tissue Antigens,2003,62(6):505-511
15.Lin CY,Lin CC,Chang G J J,et al.Defect of cell-mediated immune response against hepatitisB virus:An indication of pathogenesis of hepatitis B virus-associated membranous nephropathy[J].Nephron,1997,76(2):176-185
16．张国娟，冯江敏，周希静．乙肝病毒感染者T细胞亚群状态与肾脏损害的关系[J]．中国医科大学学报，1999，28(5)：357-358
17．陈佳，李秋．儿童乙型肝炎病毒相关性肾炎30例临床病理分析[J]．重庆医学，2005，34(10)：1453-1455
18.Ren J,Wang L,Chen Z,et al.Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus associated nephropathy[J].J Med Virol,2006,78(4):551-560
19.Han SH.Extrahepatic manifestations of chronic hepatitis B[J].Clin Liver Dis,2004,8(2):03-418
20.Lai FM,To KF,Wang AY,et al.Hepatitis B virus-related nephropathy and lupus nephritis:morphologic similarities of two clinical entities[J].Mod Pathol,2000,13(2):166-172
21.Bhimma R,Coovadia HM.Characterization of proteinuria in asymptomatic family members and household contacts of children with hepatitis B virus-associated membranous nephropathy[J].Am J Kidney Dis,2001,37(1):125-126
22.Bhimma R,Coovadia HM,Hammond MG,et al.HLA associations with HBV carriage and proteinuria[J].Pediatr Nephrol,2002,17(9):724-729
2．陈佳，李秋．儿童乙型肝炎病毒相关性肾炎30例临床病理分析[J]．重庆医学，2005，34(10)：1453-1455
3.Wang NS,Wu ZL,Zhang YE,et al.Existense and significance of hepatitis B virusDNA in kidneys of IgA nephropathy[J].World J Gastroenterol,2005,11(5):712-716
4.Vaughan RW,Zurowska A,Moszkowska G,et al.HLA-DRB and-DQB1 alleles in Polish patients with hepatitis B associated membranous nephropathy[J].Tissue Antigens,1998,52(2):130-134
5.Han SH.Extrahepatic manifestations of chronic hepatitis B[J].Clin Liver Dis,2004,8(2):03-418
6.Wang NS,Wu ZL,Zhang YE,et al.Role of hepatitis B virus infection in pathogenesis of IgA nephropathy[J].World J Gastroenterol,2003,9(9):2004-2008
7． 王素霞，邹万忠，王盛兰，等．乙型肝炎病毒相关性肾炎的超微结构及免疫电镜观察[J]．中华病理学杂志，2001，30(4)：289
8.Lin CY.Hepatitis B virus deoxyribonucleic acid in kidney cells probably leading to viral pathogenesis among hepatitis B virus associated membranous nephropathy patients[J].Nephron.1993,63(1):58-64
9.Cross JC,Wen P,Rutter W J.Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen-activated cellular serine/threonine kinases[J].Proc.Natl.Acad.Sci.USA,1993,90(17):8078-8082
10.Kekule AS,Lauer U,WeissL,et al.Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway[J].Nature(London)1993,361(6414):742-745.
11.Doria M,Klein N,Lucito R,et al.The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors[J].EMBO J,1995,14(19):4747-4757.
12.Benn J,Su F,Doria M.et al.Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases[J].J Virol,1996,70(8):4978-4985.
13.Wang HD,Yuh CH.,Dang C V,et al.The hepatitis B virus X protein increases the cellular level of TATA-binding protein,which mediates transactivation of RNA polymerase Ⅲ genes[J].Mol.Cell.Biol,1995,15(12),:6720-6728
14.Maguire H F,Hoeffler J P,Siddiqui,A.HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions[J].Science,1991,252(5007):842-844.
15.Haviv I.,Vaizel D,Shaul Y.1:pX,the HBV-encoded coactivator,interacts with components of the transcription machinery and stimulates transcription in a TAF-independent manner[J].EMBO J,1996,15(20):3413-3420.
16.Murakami S.Hepatitis B Virus X protein:a multifunctional regulatory protein[J].J Gastroenterol, 2001, 36(10): 651-660
17.Klein NP ,Schneider RJ . Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras[J]. Mol Cell Biol ,1997, 17(11): 6427-6436
18.Benn J ,Su F ,Doria M,et al. Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases[J]. J Virol ,1996 ,70 (8) :4978-4985
19.Henkler F ,Lopes AR ,Jones M,et al . Erk-independent partial activation ofAP-1 sites by the hepatitis B virus HBx protein[J]. J Gen Virol, 1998 , 79(11): 2737-2742
20.Henkler FF , Koshy R. Hepatitis B virus transcriptional activators mechanisms and possible role in oncogenesis[J]. J Viral Hepat ,1996, 3 (3) :109-121
1.Murakami S.Hepatitis B virus X protein:Structure,Function and Biology[J].Intervirology,1999,42(1):81-99
2.Han SHB.Extrahepatic manifedtations of chronic heptitis B[J].Clin Liver Dis,2004,8(2):403-418
3.Lin N,Chen HY,Li D,et al.Apoptosis and its pathway in X gene-transfected HepG2 cells[J].World J Gastroenterol,2005,11(28):4326-4331
4.Nijharaa R,Janaa SS,Goswamib SK,et al.An internal segment(residues 58-119)of the hepatitis B virus X protein is sufficient to activate MAP kinase pathways in mouse liver[J].FEBS Letters,2001,504(1):59-64
5.Madden CR,Slagle BL.Stimulation of cellular proliferation by hepatitis B virus X protein[J].Dis Markers,2001,17(3):153-157
6.Chen YB,Yan ML,Gong JP,et al.Establishment of hepatocellular carcinoma multidrug resistant monoclone cell line HepG2/mdrl[J].Chin Med J,2007,120(8):703-707
7.Li H,Cao HF,Wan J,et al.Growth inhibitory effect of wild-type Kras2 gene on a colonic adenocarcinoma cell line[J].World J Gastroenterol,2007,13(6):934-938
8.Bouchard M J,Schneider R J.The enigmatic X gene of hepatitis B virus[J].J Virol,2004,78(12):12725-12734
9.[9]Park SG,Chung C,Kang H,et al.Up-regulation of cyclin D1 by HBx is mediated by NF-κB2/BCL3 complex throughκB site of cyclin D1 promoter[J].J Biol Chem,2006,281(42):31770-31777
10．何於娟，欧一衡，张彦，等．未知基因KH的真核表达载体构建及其对细胞增殖的影响[J]．中华肿瘤杂志，2005，27(3)：129-133
11．李建民，陈薇，贾秀杰，等．用定点整合系统表达抗基孔肯亚病毒人-鼠嵌合抗体的研究[J]．细胞与分子免疫学杂志，2005，21(3)：312-315
12.Murakami S. Hepatitis B virus X protein, a multifunctional viral regulator[J]. J Gastroenterol, 2001, 36(10):651-660
13.Thio CL, Thomas DL, Karacki P, et al. Comprehensive analysis of classⅠand classⅡHLA antigens and chronic hepatitis B virus infection[J]. J Virol, 2003,77(22):12083-12087
14.Lee YZ, Kang-Park S, Do SI, et al. The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinese-dependent surviral signaling cascade[J]. J Biol Chem,2001, 276(20): 16969-16977
15.Su F, Theodosis CN, Schneider RJ. Rle of NF-κB and myc proteins in apoptosis induced by hepatitis B virus HBX protein[J]. J Virol, 2001, 75(1):215-225
16.Diao J, Khine AA, Sarangi F, et al. X protein of hepatitis B virus inhibits Fas-mediated apoptosis and is associated with up-regulation of the SAPK/JNK pathway[J]. J Biol Chem, 2001, 276(11):8324-8340
17.Arbuthnot P, Capovilla A, Kew M. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effect on apoptosis, DNA repair, mitogen-activated protein kinese and JAK/STAT pathway[J]. J Gastroenterol Hepatol, 2000, 15(4):357-368
18.Schmidt EV, Christoph G, Zeller R, et al. The cytomegalovirus enhancer: A pan-active control element in transgenic mice[J]. Mol Cell Biol, 1990, 10(8):4406-4411
19.Gluzman Y. SV40-transformedsimian dells support the replication of early SV40 mutations[J]. Cell, 1981,23(1): 175-182
20.Brondyk B. pCI and pSI mammalian expression vectors[J]. Promega Notes, 1994,
1.Combes B,Shorey J,Barrera A,et al.Glomerulonephritis with deposition of Australia antigen-antibody complex in glomerular basement membrane[J].Lancet,1971,2(7718):234-237
2．方利君，盛芳芸，郭怡清，等．成人与小儿乙型肝炎病毒相关性肾炎的比较[J]．中华传染病杂志，1996，14(2)：92-96
3．王朝晖，陈楠，任红，等．肾组织中检测乙型肝炎病毒DNA和RNA的意义[J]．上海医学，2001，24(10)：633-634
4.Han SH.Extrahepatic manifestation of chronic hepatitis B[J].Clin Liver Dis,2004,8(2):403-418
5.Sakallioglu O,Gok F,Kalman S,et al.Hepatitis B complicated focal segmental glomerulosclerosis[J].J Nephrol,2005;18(4):433-435
6.Hsu HC,Wu CY,Lin CY,et al.Membrane nephropathy in 52 hepatitis B surface antigen(HBsAg)carrier children in Taiwan[J].Kidney Int,1989,36(3):1103-1107
7.Venkataseshan VS,Lieberman K,Kim UD,et al.Hepatitis B-associated glomerulonephritis:pathology,pathogenesis,and clinical course[J].Medicine(Baltimore),1990,69(4):200-216
8.Lai KN,Li PK,Lui SF,et al.Membrane nephropathy related to hepatitis B virus in adults[J].N Engl J Med,1991,324:1457-1463
9.Johnson R J,Couser WG.Hepatitis B infection and renal diseases:clinical,immunopathogenetic and therapeutic considerations[J].Kidney Int,1990,37(2):663-676
10.Lin CY.Hepatitis B virus DNA in kidney cells probably leading to viral pathogenesis amony hepatitis B virus associated membranous nephropathy patients[J].Nephron,1993,63(1):58-64
11．陈楠，王朝晖，任红，等．肾组织中乙型肝炎病毒DNA和RNA的存在及其意义[J]．中华医学杂志，2001，81(21)：1309-1312
12．张爱平，张训，侯凡凡．原位杂交和原位聚合酶链反应检测肾脏HBV DNA的存在[J]．中华肾脏病杂志，1996，12(5)：273-275
13.Wang SN,Wu ZL,Zhang YE,et al.Existence and significance of hepatitis B virus DNA in kidneys of IgA nephropathy[J].World J Gastroenterol,2005;11(5):712-716
14.Egido J,Gomez-Chiarri M,Ortiz A,et al.Role of tumor necrosis factor-α in the pathogenesis of glomerilar diseases[J].Kidney Int,1993,43(Suppl 39):S59-S64
15.Makino T,Ito M,Kiuchiu F,et al.Inhibitory effect of decoction of Perilla frutescens on cultured murine mesangial cell proliferation and quantitative analysis of its active constituents[J].Planta Med,2001,67(1):24-28
16.Jimi N,Segawa K,Minami K,et al.Inhibitory effect of the intravenous anesthetic,ketamine,on rat mesangial cell proliferation[J].Anesth Analg,1997,84(1):190-195
17.Oda H,Yorioka N,Ito T,et al.Nicardipine hydrochloride suppresses DNA synthesis in human mesangial cells stimulated with recombinant human(rh)platelet-derived growth factor AA,rh interleukin-1 alpha,or rh tumor necrosis factor-alpha[J].Nephron,1996,73(1):16-22
18.Wu SH,Lu C,Dong L,et al.Lipoxin A4 inhibits TNF-α-induced production of interleukins and proliferation of rat mesangial cells[J].Kidney Int,2005,68(1):35-46
19.Noiri E,Kuwata S,Nosaka K,et al.Tumor necrosis factor-α mRNA expression in lipopolysaccharide-stimulated rat kindey[J].Am J Pathol,1994,144(6):1159-1166
20.Hrvacevic R,Dimitrijevic D,Spasic P,et al.Interleukin-1 beta in patients with primary immunocomplex glomerulonephritis[J].Vojnosanit Pregl,2001,58(1):33-38
21.Colenman DL,Ruef C.Interleukin-6:An autocrine regulator of mesangial cell growth[J].Kidney Int,1992,41(3):604-606
22.Zhang JL,Zhao WG,Wu KL,et al.Human hepatitis B virus X protein promotes cell proliferation and inhibits cell apoptosis through interacting with a serine protease Hepsin[J].Arch Virol,2005,150(4):721-741
23.Bouchard M J,Puro R J,Schneider RJ,et al.Activation and inhibition of cellular calcium and tyrosine kinase signaling pathways identify targets of the HBx protein involved in hepatitis B virus replication[J].J Virol,2003,77(14):7713-7719
24.Zhang Z,Protzer U,Liang J,et al.Inhibition of cellular proteasome activities enhances hepadnavirus replication in an HBX-dependent manner[J].J Virol,2004,78(9):4566-4572
25.Chan DW,Ngi O.Knock-down of hepatitis B virus X protein reduces the tumorigenicity of hepatocellular carcinoma cells[J].J Pathol,2006,208(3):372-380
26.Zhang JL,Zhao WG,Wu KL,et al.Human hepatitis B virus X protein promotes cell proliferation and inhibits cell apoptosis through interacting with a serine protease Hepsin[J].Arch Virol,2005,150(4):721-741
27.Baud L,Oudinet JP,Bens M,et al.Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide[J].Kidney Int,1989,35(5):1111-1118
28.Hruby ZW,Shirota K,Jothy S,et al.Antiserum against tumor necrosis factor-alpha and a protease inhibitor reduce immune glomerular injury[J].Kidney Int,1991，40(1):43-51
29．贾力，姜新猷，费莉．细胞因子对肾小球系膜细胞增殖的影响[J]．中国免疫学杂志，1997，13(1)：49-51
30.Takemura T,Yoshioka K,Murakami K,et al.Cellular localization of inflammatory cytokines in human glomerulonephritis[J].Virchows Arch,1994,424(5):459-464
31.Waldherr R,Noronha IL,Niemir Z,et al.Expression of cytokines and growth factors in human glomerulonephritis[J].Pediatr Nephrol,1993,7(4):471-478
32.Neale T J,Ruger BM,Macaulay H,et al.Tumor necrosis factor-alpha is expressed by glomerular visceral epithelial cells in human membranous nephropathy[J].Am J Pathol,1995,146(6):1444-1454
33.Bertani T,Abbate M,Zoja C,et al.Tumor necresis factor induces glomerular damage in the rabbit[J].Am J Pathol,1989,134(2):419-430
34.Tomosugi NI, Cashman SJ, Hay H, et al. Modulation of antibody-mediated glomerular injury in vivo by bacterial lipopolysaccharide, tumor necrosis factor, and IL-1 [J]. J Immunol, 1989,142(9):3083-3090
35.Le Hir M, Haas C, Marino M, et al. Prevention of crescentic glomerulonephritis induced by anti-glomerular menbrane antibody in tumor necrosis factor-deficient mice[J]. Lab Invest, 1998,78(12): 1625-1631
36.Timoshanko JR, Sedgwick JD, Holdsworth SR, et al. Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis[J]. J Am Soc Nephrol, 2003, 14(7): 1785-1793
37.Karkar AM, Koshino Y, Cashman SJ, et al. Passive immunization against tumor necrosis factor-alpha (TNF-alpha) and IL-1 beta protects LPS enhancing glomerular injury in nephrotoxic nephritis in rats[J]. Clin Exp Immunol, 1992,90(2):312-318
38.Karkar Am, Smith J, Pusey CD. Prevention and treatment of experimental crescentic glomerulonephritis by blocking tumor necrosis factor-alpha[J]. Nephrol Dial Transplant, 2001,16(3):518-524
39.Karkar Am, Tarn FW, Steinkasserer A, et al. Modulation of antibody-mediated glomerular injury in vivo by IL-lra, soluble IL-lreceptor, and soluble TNF receptor[J].Kidney Int, 1995,48(6):1738-1746
40.Khan SB, Cook HT, Bhangal G, et al. Antibody blockade of TNF-alpha reduces inflammation and scarring in experimental crescentic glomerulonephritis[J]. Kidney Int, 2005,67(5): 1812-1820
41.Little MA, Bhangal G, Smyth CL, et al. Therapeutic effect of anti-TNF-alpha antibodies in an experimental model of anti-neutrophil cytoplasm antibody-associated systemic vasculitis[J]. J Am Soc Nephrol, 2006, 17(1): 160-139
42.Ortiz A, Bustos C, Alonso J, et al. Involvement of tumor necrosis factor-alpha in the pathogenesis of tumor necrosis factor-alpha in the pathogenesis of experimental and human glomerulonephritis[J]. Adv Nephrol Necker Hosp, 1995, 24:53-77
43.Booth A, Harper L, Hammad T, et al. Prospective study of TNFalpha blokade with infiiximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis[J]. J Am Soc Nephrol, 2004,15(3):717-721
44.Dinarello CA. Interleukin-1 and interleukin-1 antagonism[J]. Blood, 1991, 77(8):1627-1652
45.Tomosugi NI, Cashman SJ, Hay H, et al. Modulation of antibody- mediated glomerular injury in vivo by bacterial lipopolysaccharide, tumor necrosis factor, and IL-1[J]. J Immunol, 1989, 142(9):3083-3090
46.Karkar AM, Tarn FW, Steinkasserer A, et al. Modulation of antibody-mediated glomerular injury in vivo by IL-lra, soluble IL-1 receptor, and soluble TNF receptor[J]. Kidney Int, 1995,48(6): 1738-1746
47.Lan HY, Nikolic-Paterson DJ, Mu W, et al. Interleukin-1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat[J]. Kidney Int, 1995,47(5):1303-1309
48.Tesch GH, Yang N, Yu H, et al. Intrinsic renal cells are the major source of interleukin-1 beta synthesis in normal and diseased rat kidney[J]. Nephrol Dial Transplant, 1997,12(6): 1109-1115
49.Werber HI, Emancipator SN, Tykocinski ML, et al. The interleukin 1 gene is expressed by rat glomerular mesangial cells and is augmented in immune complex glomerulonephritis[J]. J Immunol, 1987, 138(10):3207-3212
50.Richardson CA, Gordon KL, Couser WG, et al. IL-1 beta increases laminin B2 chain mRNA levels and activates NF-kappa B in rat glomerular epithelial cells[J]. Am J Physiol,1995, 268(2): F273-F278,
51.Massy ZM, Guijarro C, Micheal P, et al. The central role of nuclear factor-??????????????B in mesangial cell activation[J]. Kidney Int, 1999, Suppl, 71:S76-S79
52.Dinarello CA. Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist[J]. Int Rev Immunol, 1998,16(5-6):457-499
53.Niemir ZI, Stein H, Dworacki G, et al. Podocytes are the major source of IL-1 alpha and IL-1 beta in human glomerulonephritides[J]. Kidney Int, 1997,52(2):393-403
54.Lonnemann G, Engler-Blum G, Mullar GA, et al. Cytokines in humanrenal interstitial fibrosis. Ⅱ. Intrinsic interleukin(IL)-l synthesis and IL-1-dependent production of IL-6 and IL-8 by cultured kidney fibroblasts[J]. Kidney Int, 1995, 47(3):845-854
55.Sims JE, Gayle MA, Slack JL, et al. Interleukin-1 signaling occurs exclusively via the type I receptor[J]. Proc Natl Acad Sci USA,1993,90(13):6155-6159
56.Sims JE, Giri JG, Dower SK. The two interleukin-1 recepts play different roles in IL-1 actions[J]. Clin Immunol Immunopathol,1994,72(l):9-14
57.Noronha IL, Kruger C, Andrassy K, et al. In situ productionof TNF-alpha, IL-1 beta and IL-2R in ANCA-positive glomerulonephritis[J]. Kidney Int, 1993, 43(3):682-692
58.Matsumoto K, Dowling J, Atkins RC. Production of interleukin 1 in glomerular cell cultured from patients with rapidly progressive crescentic glomerulonephritis[J]. Am J Nephrol, 1988,8(6):463-470
59.Tesch GH, Yang N, Yu H, et al. Intrinsic renal cells are the major source of interleukin-1 beta synthesis in normal and diseasedrat kidney [J]. Nephrol Dial Transplant, 1997,12(6): 1109-1115
60.Tipping PG, Lowe MG, Holdsworth SR. Glomerular interleukin 1 production is dependent on macrophage infiltration in anti-GBM glomerulonephritisfJ]. Kidney Int,1991,39(1):103-110
61.Timoshanko JR, Kitching AR, Iwakura Y, et al. Contributions of IL-1beta and IL-1 alpha to crescentic glomerulonephritis in mice[J]. J Am Soc Nephrol,2004,15(4):910-918
62.Lan HY, Nikolic-Paterson DJ, Zarama M, et al. Supression of ecperimental crescentic glomerulonephritis by the interleukin-1 receptor antagonist[J]. Kidney Int,1993,43(2):479-485
63.Nikolic-Paterson DJ, Lan HY, Hill PA, et al. Suppression of experimental glomerulonephritis by the interleukin-1 receptor antagonist: inhibition of intercellular adhesion molecule-1 expression[J]. J Am Soc Nephrol, 1994, 4(9): 1695-1700
64.Tang WW, Feng L, Vannice JI, et al. Interleukin-1 receptor antagonist ameliorates experimental anti-glomerular basement membrane antibody-associated glomerulonephritis[J]. J Clin Invest, 1994, 93(1):273-279
65.Yu XQ, Fan JM, Nikolic-Peterson DJ, et al. IL-1 up-regulates osteopontin expression in experimental crescentic glomerulonephritis in the rat[J]. Am J Pathol,1999,154(3):833-841
66.Lan HY, Nikolic-Paterson DJ, Mu W, et al. Interleukin-1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat[J]. Kidney Int,1995,47(5):1303-1309
67.Yokoo T, Kitamura M. Gene trandfer of interleukin-1 receptor antagonist into the renal glomerulus via a mesangial cell vector[J]. Biochem Biophys Res Commun,1996,226(3):883-888
68.Yokoo T, Ohashi T, Utsunomiya Y, et al. Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppressed renal injury in mouse Goodpasture syndrome[J]. Blood, 2001,98(l):57-64
69.Timoshanko JR, Kitching AR, Iwakura Y, et al. Lekocyte-derived interleukin-1 beta interacts with renal interleukin-1 receptor I to promote renal tumor necrosis factor and glomerular injury in murine crescentic glomerulonephritis[J]. Am J Pathol,2004,164(6):1967-1977
70.Horii Y, Muraguchi Z, Iwano M, et al. Involement of IL-6 in mesangial proliferative glomerulonephritis[J]. J Immunol,1989, 143(12):3949-3955
71.Zoja C, Betton S, Morigi M, et al. Interluekin-1 regulates cytokine gene expression in human mesangial cells through the interluekin-1 receptor type Ⅰ[J]. J Am Soc Nephrol,1992,2(12): 1709-1715
72.Abbott F, Ryan JJ, Ceska M, et al. Interluekin-1βstimulates human mesangial cells to synthesize and release Interluekins-6 and -8[J]. Kidney Int, 1991,40(4):597-605
73.Coleman DL, Rufe C. Interleukin-6: An autocrine regulator of mesangial cell growth[J].Kidney Int, 1992,41(3):604-606
74.Fukatsu A, Matsuo S, Tamai H, et al. Distribution of interleukin-6 in normal and diseased human kidney[J]. Lab Invest, 1991, 65(l):61-66
75.Murakami S. Hepatitis B virus X protein: structure, function and biology[J].Intervirology,1999, 42(2-3):81-99
76.Lara-Pezzi E, Majano PL, Gomez-Gonzalo M, et al. The hepatitis B virus X protein up-regulates tumor necrosis factor a gene expression in hepatocytes[J]. Hepatology,1998,28(4):1013-1021
77.Doria M, Klein N, Lucito R, et al. The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors[J].EMBPJ,1995,14(19):4747-4757
78.Tsai EY, Jain J, Pesavento PA, et al. Tumor necrosis factor alpha gene regulation in activited T cells involves ATF-2/Jun and NFATp[J]. Mol Cell Biol, 1996,16(2):459-467
79.Tsai EY, Yie J, Thanos D, et al. Cell-type-specific regulation of the human tumor necrosis factor-alpha gene in B cell and T cell by NFATp and ATF-2/Jun [J]. Mol Cell Biol, 1996,16(10):5232-5244
80.Koike K, Moriya K, Yotsuyanagi H, et al. Induction of cell cycle progression in quiescent mouse fibroblasts[J]. J Clin Invest, 1994, 94(1):44-49
81.Cooker LA, Peterson D, Rambow J, et al. TNF-alpha, but not IFN-gamma, regulates CCN2 (CTGF), collagen type I, and proliferation in mesangial cells: possible roles in the progression of renal fibrosis[J]. Am J Physiol Renal Physiol, 2007,293(1):F157-F165
82.Hideki Ohno, Shuichi Kaneko,Yong Lin. Human Hepatitis B Virus X Protein Augments the DNA binding of nuclear factor for IL-6 through its basic-leucine zipper domain[J]. J Med Virol, 1999, 58(1):11-18
83. Kim JS , Rho BY , Lee TH, et al. The interaction of hepatitis B virus X protein and protein phosphatase type 2 Ca and its effect on IL-6[J]. Bioch Biophys Res Commun,2006, 351(1):253-258
1.Han SH. Extrahepatic manifestation of chronic hepatitis B[J].Clin Liver Dis, 2004,8(2):403-418
2.Wang SN, Wu ZL, Zhang YE, et al. Existence and significance of hepatitis B virus DNA in kidneys of IgA nephropathy[J]. World J Gastroenterol, 2005, 11(5):712-716
3.Venkataseshan VS, Lieberman K, Kim UD, et al. Hepatitis B-associated glomerulonephritis: pathology, pathogenesis, and clinical course[J]. Medicine(Baltimore), 1990, 69(4): 200-216
4.Ren J, Wang L, Chen Z, et al. Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus associated nephropathy[J]. J Med Virol,2006,78(5):551-560
5.Colgrove R, Simon G, Ganem D. Transcriptional activation of homologous and heterologous genes by the hepatitis B virus X gene product in cells permissive for virol replication[J]. J Virol, 1989,63(9):4019-4026
6.Kekule A, Lauer U, Weiss L, et al. Hepatitis B virus transactivator HBx uses a tumor promoter signalling pathway[J]. Nature, 1993, 361(6414):742-745
7.Maguire HF, Hoeffler JP, Siddiqui A. HBV X protein alters the DNA bingding specificity of CREB and ATF-2 by protein-protein interactional[J]. Science, 1991,252():842-844
8.Yoo Y, Ueda H, Park K, et al. Regulation of transforming growth factor-b1 expression by the hepatitis B virus(HBV) X transactivator[J]. J Clin Invest, 1996, 97(2):388-395
9.Benn J, Schneider RJ. Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade[J]. Proc Natl Acad Sci USA,1994, 91(22):10350-10354
10.Bouchard MJ, Wang L, Schneider RJ. Activation of focal adhesion kinase by hepatitis B virus HBx protein: multiple functions in viral replication[J]. J Virol, 2006,80(9):4406-4414
11.Benn J, Su F, Doria M, et al. Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signaling-regulated and c-Jun N-terminal mitogen-activated protein linases[J]. J Virol, 1996, 70(8):4978-4985
12.Klein NP, Schneider RJ. Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras[J]. Mol Cell Biol, 1997, 17(11):6427-6436
13.Lee YI, Kang-Park S, Do S, et al. The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent xurvival signaling cascade[J]. J Biol Chem,2001, 276(20): 16969-16977
14.Lee YH, Yun Y. HBx protein of hepatitis B virus activates Jak1-STAT signaling[J]. J Biol Chem, 1998, 273(39):25510-25515
15.Egido J, Gomez-Chiarri M, Ortiz A, et al. Role of tumor necrosis factor-a in the pathogenesis of glomerilar diseases[J]. Kidney Int, 1993, 43(Suppl 39): S59-S64
16.Makino T, Ito M, Kiuchiu F, et al. Inhibitory effect of decoction of Perilla frutescens on cultured murine mesangial cell proliferation and quantitative analysis of its active constituents[J]. Planta Med, 2001, 67(1):24-28
17.Ho AW, Wong CK, Lam CW, et al. Tumor necrosis factor-alpha up-regulates the expression of CCL2 and adhesion molecules of human proximal tubular epithelial cells through MAPK signaling pathways[J]. Immunobiology, 2008, 213(7):533-544
18.Makino T, Ito M, Kiuchiu F, et al. Inhibitory effect of decoction of Perilla frutescens on cultured murine mesangial cell proliferation and quantitative analysis of its active constituents[J]. Planta Med, 2001, 67(1):24-28
19.Noiri E, Kuwata S, Nosaka K, et al. Tumor necrosis factor-a mRNA expression in lipopolysaccharide-stimulated rat kindey[J]. Am J Pathol, 1994, 144(6):1159- 1166
20.Delgado M, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibite expression of Fas ligand in activated T lymphocytes by regulating c-Myc, NF-kappa B, NF-AT, and early growth factors2/3[J].J Immulo, 2001, 166(2): 1028-1040
21.Gilmore TD. The Rel/NF-kappa B/I kappa B signal transduction pathway and cancer[J]. Cancer Treat Res, 2003, 115:241-265
22.Amit S, Ben-Neriah Y. NF-kappa B activation in cancer: a challenge for ubiquitination-and proteasome-based therapeutic approach[J]. Semin CancerBiol, 2003,13(1): 15-28
23.Nakshatri H, Goulet RJ Jr. NF-kappa B and breast cancer[J]. Curr Probl Cancer,2002,26(5):282-309
24.Bell S, Degitz K, Quirling M, et al. Involvement of NF-kappa B signaling in skin physiology and disease[J]. Cell Signal, 2003,15(1):1-7
25.Li Q, Verma IM. NF-kappa B regulation in the immune system[J]. Nat Rev Immunol,2002,2(10):725-734
26.Bharti AC, Aggarwal BB. Nuclear factor-kappa B and cancer:its role in prevenrion and therapy[J]. Biochem Pharmacol,2002,64(5-6):883-888
27.Sun Z, Andersson R. NF-kappa B activation and inhibition: a review[J]. Shock, 2002,18(2):99-106
28.Yamamoto Y, Gaynor RB. Role of the NF-kappa B pathway in the pathogenesis of human disease states[J]. Curr Mol Med, 2001, 1(3):287-296
29.Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathwayby protein interactions[J]. Biochem J, 2000,351(pt2):289-305
30.Guan J; Chen XP; Zhu H, et al. Involvement of extracellular signal-regulated kinase/mitogen-activated protein kinase pathway in multidrug resistance induced by HBx in hepatoma cell line[J]. World J Gastroenterol. 2004,10(23):3522-3527
31.Chung TW, Lee YC, Kim CH. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential[J]. FASEB J. 2004, 18(10): 1123-1125
32.Matsumoto K; Nagahara T; Okano J, et al. The growth inhibition of hepatocellular and cholangiocellular carcinoma cells by gemcitabine and the roles of extracellular signal-regulated and checkpoint kinases[J]. Oncol Rep. 2008, 20(4):863-872
33．郭晓，潘崚．ERK阻滞剂U0126对白血病细胞K562细胞周期的作用及机制[J]．第三军医大学学报，2008，30(5)：393-395
34.Wolf I,Rubinfeld H,Yoon S,et al.Involvement of the activation loop of ERK in the detachment from cytosolic anchoring[J].J Biol Chem,2001,276(27):24490-24497
35.Kumar S,Boehm J,Lee JC.p38 MAPK kinases inhibitors:key signaling molecules as therapeutic targets for inflammatory diseases[J].Nat Rev Drug Discov,2003,2(9):717-726
36.Kothapalli D,Zhao L,Hawthorne EA,et al.Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells[J].J Cell Biol,2007,176(4):535-544.
1.Murakami S,Cheong J,Kaneko S,et al.Transactivation of human hepatitis B virus X protein,HBx operates through a mechanism distinct from protein kinase C and okadaic acid activation pathways[J].J Virol,1994;199(1):243-246
2.Murakami S,Cheong J,Kaneko S,et al.Autoregulation of human hepatitis B virus X gene.In:Nishioka,K,Suzuki,H,Mishiro,S,Oda,T,eds.Viral Hepatitis and Liver Diseases.Tokyo:Springer Verlauf,1994;743-747
3.Cheong JH,Yi MK,Murakami S,et al.Human RPB5,a subunit shared eukaryotic nuclear polymerases,binds human hepatitis B virus X protein and may play a role in X transactivation[J].EMBO J,1995;14(1):143-150
4.Murakami S.Hepatitis B Virus X protein:a multifunctional regulatory protein[J].J Gastroenterol, 2001, 36(10): 651-660
5.Doitsh G, Shaul Y. HBV transcription repression in response to genotoxic stress is p53-dependent and abrogated by pX[J]. Oncogene, 1999; 18(52): 7506-7513
6.Dewantoro O, Gani RA, Akbar N. Hepatocarcinogenesis in viral Hepatitis B infection:the role of HBx and p53[J]. Acta Med Indones, 2006,38(3):154-159
7.Ahn JY, Chung EY, Jang KL, et al. Transcriptional repression of p21 (wafl) promoter by hepatitis B virus X protein via a p53-independent pathway[J]. Gene, 2001,275 (1):163-168
8.Zhang Z, Torii N, Liang TJ, et al. Structural and functional characterization of interaction between hepatitis B virus X protein and the proteasome complex[J]. J Biol Chem, 2000, 275 (20): 15157-15165
9.Lee TH, Elledge SJ, Butel JS. Hepatitis B virus X protein interacts with a probable cellular DNA repair protein[J]. J Virol, 1995, 69(2): 1107-1114
10.Bouchard MJ, Wang LH, Schneider RJ, et al. Calcium signaling by HBx protein in hepatitis B virus DNA replication[J]. Science, 2001; 294 (5550): 2376-2378.
11.Bouchard MJ, Wang LH, Schneider RJ. Activation of focal adhesion kinase by hepatitis B virus HBx protein: Multiple functions in viral replication[J]. J Virol, 2006;80 (9): 4406-4414
12.Jia L, Wang XW, Harris CC. Hepatitis B virus X protein inhibits nucleotideexcision repair[J]. Int J Cancer, 1999, 80(6): 875-79.
13.Klein NP, Schneider RJ. Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras[J]. Mol Cell Biol, 1997, 17(11): 6427-6436
14.Huh KW, Siddiqui A. Characterization of the mitochondrial association of hepatitis B virus X protein, HBx[J]. Mitochondrion, 2002; 1 (4): 349-359
15.Tanaka Y, Kanai F, Omata M, et al. Interaction of the hepatitis B virus X protein (HBx) with heat shock protein 60 enhances HBx-mediated apoptosis[J]. Biochem Biophys Res Commun, 2004,318 (2): 461-69
16.Zhang SM, Sun DC, Wang SQ, et al. HBx protein of hepatitis B virus (HBV) can form complex with mitochondrial HSP60 and HSP70[J]. Arch Virol, 2005, 150(8):1579-1590
17.Takada S, Shirakata Y, Koike K et al. Association of hepatitis B virus X protein with mitochondria causes mitochondrial aggregation at the nuclear periphery, leading to cell death[J]. Oncogene, 1999, 18(50): 6965-6973.
18.Tanaka Y, Kanai F, Omata M, et al. Interaction of the hepatitis B virus X protein (HBx)with heat shock protein 60 enhances HBx-mediated apoptosis[J]. Biochem Biophys Res Commun, 2004, 318(2): 461-469.
19.Pang R, Lee TK, Poon RT, et al. Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis[J]. Gastroenterology, 2007, 1323(3): 1180-1183
20.Chen J, Siddiqui A. Hepatitis B virus X protein stimulates the mitochondrial translocation of Raf-1 via oxidative stress[J]. J Viro,. 2007,81(12):6757-6760
21.Blum HE, Zhang ZS, Galun E, et al. Hepatitis B virus X protein is not central to the viral life cycle in vitro[J]. J Virol, 1992, 66(2): 1223-1227
22.Chen HS, Kaneko S, Miller RH, et al. The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks[J]. J Virol, 1993, 67(3):1218-1226
23.Reifenberg K, Nusser P, Lohler J, et al.Virus replication and virion export in X-deficient hepatitis B virus transgenic mice[J]. J Gen Virol, 2002, 83(5):991-996
24.Zhang Z, Torii N, Hu Z, et al. X-deficient woodchuck hepatitis virus mutations behave like attenuated viruses and induce protective immunity in vivo[J]. J Clin Investig, 2001,108(10):1523-1531
25.Zoulim F, Saputelli J, Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo[J]. J Virol, 1994, 68(3): 2026-2030
26.Xu Z, Yen TS, Ou JH, et al. Enhancement of hepatitis B virus replication by its X protein in transgenic mice[J]. J Virol, 2002, 76(5): 2579-2584
27.Bouchard MJ, Puro RJ, Schneider RJ, et al. Activation and inhibition of cellular calcium and tyrosine kinase signaling pathways identify targets of the HBx protein involved in hepatitis B virus replication[J]. J Virol, 2003, 77(14): 7713-7719
28.Melegari M, Wolf SK, Schneider RJ. Hepatitis B virus DNA replication is coordinated by core protein serine phosphorylation and HBx expression[J]. J Virol, 2005, 79 (15):9810-9820
29.Tang H, Delgermaa L, Huang F, et al. The transcriptional transactivation function of HBx protein is important for its augmentation role in hepatitis B virus replication[J]. J Virol, 2005,79(9):5548-5556
30.Zheng Y, Johnson DL, Ou JH. Regulation of hepatitis B virus replication by the ras-mitogen-activated protein kinase signaling pathway[J]. J Viro,l 2003, 77 (14):7707-7712
31.Xu Z, Yen TS, Ou JH et al. Enhancement of hepatitis B virus replication by its X protein in transgenic mice[J]. J Viro,l 2002, 76 (5): 2579-2584
32.Bouchard MJ, Puro RJ, Schneider RJ, et al. Activation and inhibition of cellular calcium and tyrosine kinase signaling pathways identify targets of the HBx protein involved in hepatitis B virus replication[J]. J Virol, 2003,77 (14): 7713- 7719
33.Zhang Z, Protzer U, Liang J, et al. Inhibition of cellular proteasome activities enhances hepadnavirus replication in an HBX-dependent manner[J]. J Virol, 2004, 78 (9):4566-4572
34.Leupin O, Bontron S, Strubin M, et al. Hepatitis B virus X protein stimulates viral genome replication via a DDB1-dependent pathway distinct from that leading to cell death[J]. J Virol, 2005, 79 (7): 4238-4245
35.Hu Z, Zhang Z, Liang TJ, et al. Altered proteolysis and global gene expression in hepatitis B virus X transgenic mouse liver[J]. J Virol, 2006,80 (3):1405-1413
36.Kim CM, Koike I, Miyamura T, et al. HBx gene of hepatitis B virus induces liver cancer in transgenic mice[J]. Nature ,1991 , 353(6324):317-320
37.Klein A, Guhl E, Tzeng YJ, et al. HBx cause cyclin D1 over expression and development of breast cancer in transgenic animals that are heterozygous for p53[J].Oncogene, 2003, 22(19):2910-2919
38.Koike K, Moriya K, Yotsuyanagi H, et al. Compensatory apoptosis in preneoplastic liver of a transgenic mouse model for viral hepatocarcinogenesis[J]. Cancer Letter,1998, 134(2): 181-186
39.Schuster R, Gerlich WH, Schaefer S. Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts[J]. Oncogene, 2000, 19(9):1173-1180
40.Schuster R, Hildt E, Chang SF, et al. Conserved transactivating and proapoptotic functions of hepadnaviral X protein in ortho- and avihepadnaviruses[J]. Oncogene,2002, 21(43): 6606-6613.
41.Artandi SE, DePinho RA. Mice without telomerase: what can they teach us about human cancer[J]? Nat Med, 2000, 6(8): 852-855.
42.Sharpless NE, DePinho RA. Cancer: crime and punishment[J]. Nature, 2005,436(7051): 636-637.
43.Braig M, Lee S, Loddenkemper C, et al. Oncogene-induced senescence as an initial barrier in lymphoma development[J]. Nature, 2005, 436(7051): 660-665
44.Tang H, Oishi N, Kaneko S, et al. Molecular functions and biologecal roles of hepatitis B virus X protein[J]. Cancer Sci, 2006,97(10):977-983
45.Klein NP ,Schneider RJ . Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras[J]. Mol Cell Biol ,1997, 17(11): 6427-6436
46.Benn J ,Su F ,Doria M,et al. Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases[J]. J Virol ,1996 ,70 (8) :4978-4985
47.Henkler F ,Lopes AR Jones M, et al . Erk-independent partial activation of AP-1 sites by the hepatitis B virus HBx protein[J]. J Gen Virol, 1998 , 79(11): 2737-2742
48.Henkler FF , Koshy R. Hepatitis B virus transcriptional activators :mechanisms and possible role in oncogenesis[J]. J Viral Hepat ,1996, 3 (3) :109-121
49.Chan DW, Ng IO. Knock-down of hepatitis B virus X protein reduces the tumorigenicity of hepatocellular carcinoma cells[J]. J Pathol, 2006, 208 (3): 372- 380
1.Bhimma R,Coovadia HM.Hepatitis B virus-associated nephropathy[J].Am J Nephrol,2004,24(2):205-206
2.Ozdamar SO,Gucer S,Tinaztepe K.HepatitisB virus associated nephropathies:a clinicopathological study in 14 children[J].Pediatr Nephrol,2003,18(1):23-28
3． 陈楠，王朝晖，任红，等．肾组织中乙型肝炎病毒DNA和RNA的存在及其意义[J]．中华医学杂志，2001，81(21)：1309-1312
4.He XY,Fang L J,Zhang YF,et al.In situ hybridization of hepatitis B DNA in hepatitis B-associated glomerulonephritis[J].Pediatr Nephrol,1998,12(2):117-120
5.Wang NS,Wu ZL,Zhang YE,et al.Role of hepatitis B virus infection in pathogenesis of IgA nephropathy[J].World J Gastroenterol,2003,9(9):2004-2008
6.Wang NS,Wu ZL,Zhang YE,et al.Existense and significance of hepatitis B virusDNA in kidneys of IgA nephropathy[J].World J Gastroenterol,2005,11(5):712-716
7．王素霞，邹万忠，王盛兰，等．乙型肝炎病毒相关性肾炎的超微结构及免疫电镜观察[J]．中华病理学杂志．2001，30(4)：289
8.Lin CY.Hepatitis B virus deoxyribonucleic acid in kidney cells probably leading to viral pathogenesis among hepatitis B virus associated membranous nephropathy patients[J].Nephron.1993,63(1):58-64
9.Kim SE,Park YH,Chung WY.Study on hepatitis B virus pre-S/S gene mutations of renal tissues in children with hepatitis B virus-associated memberanous nephropathy[J].Pediatr Nephrol,2006,21(8):1097-1103
10.Kusakabe A,Tanaka Y,Kurbanov F,et al.Virological features of hepatitis B virus-associated nephropathy in Japan[J].J Med Virol,2007,79(9):1305-1311.
11．李少稚，冯江敏．乙肝病毒相关性肾炎与人白细胞抗原相关性的探讨[J]．中国医科大学学报，2001，30(4)：290-292
12.Vaughan RW,Zurowska A,Moszkowska G,et al.HLA-DRB and-DQB1 alleles in Polish patients with hepatitis B associated membranous nephropathy[J].Tissue Antigens,1998,52(2):130-134
13.Bhimma R,HammondMG,Coovadia HM,et al.HLA class Ⅰ and Ⅱ in black children with hepatitis B virus-associated membranousnephropathy[J].Kidney Int,2002,61(4):1510-1515
14.Park MH,Song EY,Ahn C,et al.Two subtypes of hepatitisB virus-associated glomerulonephritis are associated with different HLA-DR2 alleles in Koreans[J].Tissue Antigens,2003,62(6):505-511
15.Lin CY,Lin CC,Chang G J J,et al.Defect of cell-mediated immune response against hepatitisB virus:An indication of pathogenesis of hepatitis B virus-associated membranous nephropathy[J].Nephron,1997,76(2):176-185
16．张国娟，冯江敏，周希静．乙肝病毒感染者T细胞亚群状态与肾脏损害的关系[J]．中国医科大学学报，1999，28(5)：357-358
17．陈佳，李秋．儿童乙型肝炎病毒相关性肾炎30例临床病理分析[J]．重庆医学，2005，34(10)：1453-1455
18.Ren J,Wang L,Chen Z,et al.Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus associated nephropathy[J].J Med Virol,2006,78(4):551-560
19.Han SH.Extrahepatic manifestations of chronic hepatitis B[J].Clin Liver Dis,2004,8(2):03-418
20.Lai FM,To KF,Wang AY,et al.Hepatitis B virus-related nephropathy and lupus nephritis:morphologic similarities of two clinical entities[J].Mod Pathol,2000,13(2):166-172
21.Bhimma R,Coovadia HM.Characterization of proteinuria in asymptomatic family members and household contacts of children with hepatitis B virus-associated membranous nephropathy[J].Am J Kidney Dis,2001,37(1):125-126
22.Bhimma R,Coovadia HM,Hammond MG,et al.HLA associations with HBV carriage and proteinuria[J].Pediatr Nephrol,2002,17(9):724-729