TRAIL及其相关分子在HBV感染所致凋亡改变中的机制研究
摘要
乙型肝炎病毒(HBV)是一个与肝炎、肝癌形成密切相关的致病因子,其致肝脏损伤以及细胞恶性变的机制迄今尚未完全阐明。乙肝病毒感染后所导致的机体免疫调节功能紊乱及肝细胞凋亡的失衡,是造成肝脏不同类型的病理变化及临床转归的主要原因之一。探讨HBV与机体免疫监视分子的相互作用机制,对于进一步理解HBV的致病机理和探索有效的治疗方案有着重要意义,是一个十分有研究价值的问题。
TNF相关的凋亡诱导配体(TNF related apoptosis inducing ligand,TRAIL)、TNF相似的凋亡诱导分子(TNF-like weak inducer of apoptosis,TWEAK)是继FasL之后发现的TNF家族中的新成员,具有其独特的凋亡诱导特性。它们分布广泛,对正常生理状态下的机体组织没有毒性,而只是在病理状态下被激活来参与机体的免疫反应。但是,作为机体的免疫监视分子和免疫效应分子,TRAIL、TWEAK是否参与了HBV的致病过程,及其在HBV相关疾病中的作用机制至今尚不清楚。我们率先开展了此项研究,并取得了一定的研究成果。
目的:
1.研究HBV转染对TRAIL诱导细胞凋亡的影响及其机制。
2.研究IFN-γ/对TRAIL诱导HBV转染细胞凋亡的影响,并初步探讨其机制。
3.研究TRAIL-TRAIL受体系统在慢性乙肝患者外周血单个核细胞凋亡中的作用,探讨它与临床分期、肝脏损伤程度的关系。
Hepatitis B virus (HBV) is a confirmed carcinogenesis related factor.It is not clear why HBV could induce the hepatocyte injury and lead to the malignant transformation of the liver tissue cells in most cases. The disorder of immune regulation and the imbalance of hepatocyte apoptosis after HBV infection is the main cause which result in the different pathological process and clinical prognosis. Investigation of the mechanism between HBV and the immune surveillance molecule will help to understand the pathogenesis of HBV and find an effective treatment for the HBV related diseases.TRAIL(TNF related apoptosis inducing ligand )、 TWEAK (TNF-like weak inducer of apoptosis) are the new members of TNF family,which have inimitable apoptosis inducing characters.TRAIL、 TWEAK are widely distributed and have no cytoxicity on human tissues under physiological condition.Only in pathological condition, they are activated to participate in the immune response. As potent immune surveillance and immune effective molecules,whether TRAIL and TWEAK play roles in the pathogenesis of HBV infection is not yet known.We took the lead in carrying out the study on the mechanism of TRAIL and TWEAK that may involve in the pathogenesis of HBV infection. OBJECTIVES1. To investigate whether HBV will influence TRAIL induced cell apoptosis and its mechanism.2. To explore the regulative effect of IFN-γ on TRAIL induced apoptosis in HBV transfected cell and its mechanism.
3. To elucidate whether TRAIL-TRAIL receptors contribute to the increased apoptosis of peripheral blood mononuclear cell (PBMC) in chronic Hepatitis B patients and to clarify the relativity between the expression of TRAIL receptors and the clinical incidence in chronic Hepatitis B patients.4. To elucidate whether Hepatitis B virus will influence TWEAK induced cell apoptosis and the regulative effect of IFN-y on TWEAK induced apoptosis in HBV transfected cell.METHODS1. Establishment of Human hepatoma cell lines which were transfected with HBV (adr subtype) stably1.1 Construction of the HBV gene eukaryotic expression vectors pcDNA3-l.lHBV, pcDNA3-3.0HBV respectivelya the construction of pcDNA3-l.lHBV p3.6ll which contains 1.1HBV DNA was digested with pVU II .The 3907bp fragment was obtained and cloned into pcDNA3 vector digested with EcoRV. Restriction endonuclease assay was used to select and identify the positive clones.Automatic DNA sequencing was used for the anlysis of HBV sequences.b the construction of pcDNA3-3.0HBV pUC19-3.0HBV which contains 3.0HBV DNA was digested with EcoRI and Hindlll.The 9600bp fragment was obtained and cloned into pcDNA3 vector digested with EcoRI and Hindlll.Restriction endonuclease assay was used to select and identify the positive clones.1.2 Establishment of Human hepatoma cell lines which were transfected with HBV (adr subtype) stablyBEL-7402 ^ HepG2 were transfected with the pcDNA3-l.lHBV > pcDNA3-3.0HBV mediated by lipofectin respectively.Geneticin (G418) was added into the medium after 24h.Cell clones could be observered 3-4 weeks after G418 added. The expression of HBx^ HBpreS2 mRNA in cell clones were detected by RT-PCR.The expression of HBsAg> HBeAg in cell clones were calculated by ELISA.2. Study the influence of HBV transfection on TRAIL induced cell apoptosis and its mechanism8
2.1 Study on the effect of HBV transfection on TRAIL induced apoptosisBEL-7402/l.lHBV and its controls (empty cell control: BEL -7402; empty vector control: BEL-7402/pcDNA3)> HepG2/l.lHBV and its controls (empty cell control: HepG2; empty vector control: HepG2/pcDNA3) were treated with TRAIL (10ng/mL),24h later,the apoptosis induced by TRAIL in these cell lines were examined by TUNEL assay ^ DNA Ladder> Caspase 3 activity assay and Caspase 3 activation.2.2 Study on the mechanism of apoptosis change in BEL-7402/l.lHBV > BEL-7402/pcDNA3x BEL-7402a Extracellular level The expressions of DR4> DR5> DcRK DcR2 in BEL-7402/l.lHBV > BEL-7402/pcDNA3, BEL-7402 were assayed by RT-PCR and fiowcytometery.b Intracellular level The activation of Caspase8 >. Caspase9 in BEL-7402/l.lHBV and its controls were assayed by Westemblot. The expressions of Bax> FLIP in BEL-7402/l.lHBV and its controls were detected by Westemblot. The activity of nuclear transcription factor - Kappa B (NF-kB) in BEL-7402/l.lHBV and its controls were detected by dual luciferase report gene assay system.3. Study on the effect of IFN-y on TRAIL induced cell apoptosis in HepG2/1.1 HBV and its mechanism3.1 Apoptosis of HepG2/l.lHBV cell induced by IFN-y> TRAIL * IFN-y plus TRAIL was detected by TUNELHepG2/l.lHBV was pretreated with IFN-y (200IU/mL) ,12h later, TRAIL (lOng/mL) was added.Another 24h later, the apoptosis in HepG2/l.lHBV was detected by TUNEL.3.2 The mRNA of DR4> DR5> DcRl, DcR2 and FLIP in HepG2/l.lHBV were assayed by RT-PCR.4. Study on the expressions of TRAIL receptors in the PBMC of chronic hepatitis B patients and its relativity with the clinical incidenceThe expressions of DR4> DR5^ DcRl and DcR2 in 55 cases of chronic hepatitis B patients and 30 cases of normal people were assayed by RT-RCR and
Flowcytometery. The relativity of the expression of TRAIL receptors and the clinical incidence was analysed.5. Study on the effect of HBV on TWEAK induced apoptosisThe apoptosis of BEL-7402/1.1 HBV, HepG2/l.lHBV and their corresponding controls induced by TWEAK were calculated by TUNEL.6. Study on the effect of IFN-y on TWEAK induced cell apoptosis in BEL -7402/1.1HBV and HepG2/l.lHBVApoptosis of BEL-7402/1.1HBV, HepG2/l.lHBV cell induced by IFN-y plus TRAIL, TWEAK, IFN-y were detected by TUNEL. RESULTS1. The human hepatoma cell lines transfected with HBV (adr) were established successfullyThe HBV eukaryotic expression vectors pcDNA3-l.lHBV, pcDNA3-3.0HBV were constructed successfully. They were verified by endonuclease digestion and DNA sequencing.BEL-7402 , HepG2 were transfected with the pcDNA3-l.lHBV , pcDNA3-3.0HBV mediated by lipofectin respectively.Geneticin (G418) was added into the medium after 24h.Cell clones could be observed 3-4 weeks later.They were named as BEL-7402/1.1 HBV , HepG2/l.lHBV > BEL-7402/3.0HBV and HepG2/3 .OHBVrespectively.The expression of HBx mRNA, HBpreS2 mRNA , HBeAg and HBsAg in BEL-7402/1.1HBV,HepG2/l.lHBV,BEL-7402/3.0HBV and HepG2/3.0HBV are all positive. Moreover, the expression level of HBeAg and HBsAg is higher in pcDNA3-l.lHBV transfected cell lines than pcDNA3-3.0HBV transfected cell lines(p <0.05). Maybe it was caused by the large size of pcDNA3-3.0HBV vector, which was unstable in the infected cells.So we will select pcDNA3-l.lHBV transfected cell lines as cell models in the next research work.2. HBV transfection promote TRAIL induced apoptosis and its mechanism2.1 HBV transfection promote TRAIL induced apoptosis
BEL-7402/l.lHBV, HepG2/l.lHBV cells showed higher sensitivity to TRAIL induced apoptosis than their corresponding controls ( P<0.01). Moreover, apoptosis change is more obvious in BEL-7402 series than in HepG2 series. 2.2 Study on the molecular mechanism of the increased apoptosis induced by TRAIL after HBV transfectionThe molecular mechanism of the increased apoptosis induced by TRAIL in BEL-7402/1.1 HBV, BEL-7402/pcDNA3, BEL-7402 was investigated.a Extracellular level There was no significant difference in the expression of TRAIL receptors among BEL-7402/1.1 HBV, BEL-7402/pcDNA3 and BEL-7402 (p > 0.05).b Intracellular level The activation of Caspase 8 and Caspase 9 is more thoroughly in BEL-7402/l.lHBV than its controls(p<0.05). Compared with its control, the expression of Bax was upregulated in BEL-7402/1.1HBV(/K0.05).There was no significant difference in the expression of FLIP among BEL-7402/l.lHBV and its controls (/J>0.05). The activity of NF-kB, an important nuclear transcription factor, inhibiting apoptosis by initiating apoptosis inhibiting gene expression, was drastically lower on BEL-7402/l.lHBV cells(/?<0. 05).3. IFN-y promote TRAIL induced apoptosis in HepG2/l.lHBV and its mechanismIFN-y could make HepG2/l.lHBV more sensitive to TRAIL-induced apoptosis (p<0.05). This might be realized by the downregulated expression of DcRl and FLIP.4. The expression of TRAIL receptors on the PBMC in chronic hepatitic B patients and its relativity with the clinical incidenceAmong the four receptors, the expression level of DcRl in the PBMC of chronic B hepatitis patients was much lower than that of control group (p<0.05). There was high relativity among the expression of DcRl-. the clinical stage and the degree ofliver injury (including ALT and albumin).5. HBV transfection promote TWEAK induced apoptosisBEL-7402/1.1 HBV, HepG2/l .1HBV showed higher sensitivity to TWEAK induced apoptosis than their corresponding controls (p<0.05). Moreover, apoptosis
change is more obvious in BEL-7402 series than in HepG2 series.6. IFN^y promote TWEAK induced apoptosis in BEL-7402/1.1HBV .HepG2/l.lHBVIFN-y could make BEL-7402/1.1HBV, HepG2/l.lHBV more sensitive to TWEAK-induced apoptosis (p<0.05).CONCLUSIONS1. HBV gene eukaryotic expression vectors pcDNA3-l.lHBV> pcDNA3-3.0HBVwere constructed successfully. Human hepatoma cell lines transfected with HBV(adr) were established successfully.2. HBV transfection could make cells sensitive to TRAIL induced apoptosis, this may be realized the following steps: 1) Up-regulated the expression of Bax; 2) Downregulated the activity of NF-kB.3. IFN-y could sensitize HepG2/l.lHBV cell to TRAIL-induced apoptosis to great extent.lt may be realized by downregulating the expression of DcR2 and FLIP.4. The expression level of DcRl on PBMC in chronic hepatitis B patients was down-regulated, which might contribute to the increased apoptosis of PBMC in chronic B hepatitis patients. The expression of DcRl can reflect the clinical stage and the degree of liver injury in chronic hepatitis B patients to some degree.5. HBV transfection could make cells sensitive to TWEAK induced apoptosis. IFN-y could sensitize HBV transfected cell to TWEAK-induced apoptosis to great extent.
TNF相关的凋亡诱导配体(TNF related apoptosis inducing ligand,TRAIL)、TNF相似的凋亡诱导分子(TNF-like weak inducer of apoptosis,TWEAK)是继FasL之后发现的TNF家族中的新成员,具有其独特的凋亡诱导特性。它们分布广泛,对正常生理状态下的机体组织没有毒性,而只是在病理状态下被激活来参与机体的免疫反应。但是,作为机体的免疫监视分子和免疫效应分子,TRAIL、TWEAK是否参与了HBV的致病过程,及其在HBV相关疾病中的作用机制至今尚不清楚。我们率先开展了此项研究,并取得了一定的研究成果。
目的:
1.研究HBV转染对TRAIL诱导细胞凋亡的影响及其机制。
2.研究IFN-γ/对TRAIL诱导HBV转染细胞凋亡的影响,并初步探讨其机制。
3.研究TRAIL-TRAIL受体系统在慢性乙肝患者外周血单个核细胞凋亡中的作用,探讨它与临床分期、肝脏损伤程度的关系。
Hepatitis B virus (HBV) is a confirmed carcinogenesis related factor.It is not clear why HBV could induce the hepatocyte injury and lead to the malignant transformation of the liver tissue cells in most cases. The disorder of immune regulation and the imbalance of hepatocyte apoptosis after HBV infection is the main cause which result in the different pathological process and clinical prognosis. Investigation of the mechanism between HBV and the immune surveillance molecule will help to understand the pathogenesis of HBV and find an effective treatment for the HBV related diseases.TRAIL(TNF related apoptosis inducing ligand )、 TWEAK (TNF-like weak inducer of apoptosis) are the new members of TNF family,which have inimitable apoptosis inducing characters.TRAIL、 TWEAK are widely distributed and have no cytoxicity on human tissues under physiological condition.Only in pathological condition, they are activated to participate in the immune response. As potent immune surveillance and immune effective molecules,whether TRAIL and TWEAK play roles in the pathogenesis of HBV infection is not yet known.We took the lead in carrying out the study on the mechanism of TRAIL and TWEAK that may involve in the pathogenesis of HBV infection. OBJECTIVES1. To investigate whether HBV will influence TRAIL induced cell apoptosis and its mechanism.2. To explore the regulative effect of IFN-γ on TRAIL induced apoptosis in HBV transfected cell and its mechanism.
3. To elucidate whether TRAIL-TRAIL receptors contribute to the increased apoptosis of peripheral blood mononuclear cell (PBMC) in chronic Hepatitis B patients and to clarify the relativity between the expression of TRAIL receptors and the clinical incidence in chronic Hepatitis B patients.4. To elucidate whether Hepatitis B virus will influence TWEAK induced cell apoptosis and the regulative effect of IFN-y on TWEAK induced apoptosis in HBV transfected cell.METHODS1. Establishment of Human hepatoma cell lines which were transfected with HBV (adr subtype) stably1.1 Construction of the HBV gene eukaryotic expression vectors pcDNA3-l.lHBV, pcDNA3-3.0HBV respectivelya the construction of pcDNA3-l.lHBV p3.6ll which contains 1.1HBV DNA was digested with pVU II .The 3907bp fragment was obtained and cloned into pcDNA3 vector digested with EcoRV. Restriction endonuclease assay was used to select and identify the positive clones.Automatic DNA sequencing was used for the anlysis of HBV sequences.b the construction of pcDNA3-3.0HBV pUC19-3.0HBV which contains 3.0HBV DNA was digested with EcoRI and Hindlll.The 9600bp fragment was obtained and cloned into pcDNA3 vector digested with EcoRI and Hindlll.Restriction endonuclease assay was used to select and identify the positive clones.1.2 Establishment of Human hepatoma cell lines which were transfected with HBV (adr subtype) stablyBEL-7402 ^ HepG2 were transfected with the pcDNA3-l.lHBV > pcDNA3-3.0HBV mediated by lipofectin respectively.Geneticin (G418) was added into the medium after 24h.Cell clones could be observered 3-4 weeks after G418 added. The expression of HBx^ HBpreS2 mRNA in cell clones were detected by RT-PCR.The expression of HBsAg> HBeAg in cell clones were calculated by ELISA.2. Study the influence of HBV transfection on TRAIL induced cell apoptosis and its mechanism8
2.1 Study on the effect of HBV transfection on TRAIL induced apoptosisBEL-7402/l.lHBV and its controls (empty cell control: BEL -7402; empty vector control: BEL-7402/pcDNA3)> HepG2/l.lHBV and its controls (empty cell control: HepG2; empty vector control: HepG2/pcDNA3) were treated with TRAIL (10ng/mL),24h later,the apoptosis induced by TRAIL in these cell lines were examined by TUNEL assay ^ DNA Ladder> Caspase 3 activity assay and Caspase 3 activation.2.2 Study on the mechanism of apoptosis change in BEL-7402/l.lHBV > BEL-7402/pcDNA3x BEL-7402a Extracellular level The expressions of DR4> DR5> DcRK DcR2 in BEL-7402/l.lHBV > BEL-7402/pcDNA3, BEL-7402 were assayed by RT-PCR and fiowcytometery.b Intracellular level The activation of Caspase8 >. Caspase9 in BEL-7402/l.lHBV and its controls were assayed by Westemblot. The expressions of Bax> FLIP in BEL-7402/l.lHBV and its controls were detected by Westemblot. The activity of nuclear transcription factor - Kappa B (NF-kB) in BEL-7402/l.lHBV and its controls were detected by dual luciferase report gene assay system.3. Study on the effect of IFN-y on TRAIL induced cell apoptosis in HepG2/1.1 HBV and its mechanism3.1 Apoptosis of HepG2/l.lHBV cell induced by IFN-y> TRAIL * IFN-y plus TRAIL was detected by TUNELHepG2/l.lHBV was pretreated with IFN-y (200IU/mL) ,12h later, TRAIL (lOng/mL) was added.Another 24h later, the apoptosis in HepG2/l.lHBV was detected by TUNEL.3.2 The mRNA of DR4> DR5> DcRl, DcR2 and FLIP in HepG2/l.lHBV were assayed by RT-PCR.4. Study on the expressions of TRAIL receptors in the PBMC of chronic hepatitis B patients and its relativity with the clinical incidenceThe expressions of DR4> DR5^ DcRl and DcR2 in 55 cases of chronic hepatitis B patients and 30 cases of normal people were assayed by RT-RCR and
Flowcytometery. The relativity of the expression of TRAIL receptors and the clinical incidence was analysed.5. Study on the effect of HBV on TWEAK induced apoptosisThe apoptosis of BEL-7402/1.1 HBV, HepG2/l.lHBV and their corresponding controls induced by TWEAK were calculated by TUNEL.6. Study on the effect of IFN-y on TWEAK induced cell apoptosis in BEL -7402/1.1HBV and HepG2/l.lHBVApoptosis of BEL-7402/1.1HBV, HepG2/l.lHBV cell induced by IFN-y plus TRAIL, TWEAK, IFN-y were detected by TUNEL. RESULTS1. The human hepatoma cell lines transfected with HBV (adr) were established successfullyThe HBV eukaryotic expression vectors pcDNA3-l.lHBV, pcDNA3-3.0HBV were constructed successfully. They were verified by endonuclease digestion and DNA sequencing.BEL-7402 , HepG2 were transfected with the pcDNA3-l.lHBV , pcDNA3-3.0HBV mediated by lipofectin respectively.Geneticin (G418) was added into the medium after 24h.Cell clones could be observed 3-4 weeks later.They were named as BEL-7402/1.1 HBV , HepG2/l.lHBV > BEL-7402/3.0HBV and HepG2/3 .OHBVrespectively.The expression of HBx mRNA, HBpreS2 mRNA , HBeAg and HBsAg in BEL-7402/1.1HBV,HepG2/l.lHBV,BEL-7402/3.0HBV and HepG2/3.0HBV are all positive. Moreover, the expression level of HBeAg and HBsAg is higher in pcDNA3-l.lHBV transfected cell lines than pcDNA3-3.0HBV transfected cell lines(p <0.05). Maybe it was caused by the large size of pcDNA3-3.0HBV vector, which was unstable in the infected cells.So we will select pcDNA3-l.lHBV transfected cell lines as cell models in the next research work.2. HBV transfection promote TRAIL induced apoptosis and its mechanism2.1 HBV transfection promote TRAIL induced apoptosis
BEL-7402/l.lHBV, HepG2/l.lHBV cells showed higher sensitivity to TRAIL induced apoptosis than their corresponding controls ( P<0.01). Moreover, apoptosis change is more obvious in BEL-7402 series than in HepG2 series. 2.2 Study on the molecular mechanism of the increased apoptosis induced by TRAIL after HBV transfectionThe molecular mechanism of the increased apoptosis induced by TRAIL in BEL-7402/1.1 HBV, BEL-7402/pcDNA3, BEL-7402 was investigated.a Extracellular level There was no significant difference in the expression of TRAIL receptors among BEL-7402/1.1 HBV, BEL-7402/pcDNA3 and BEL-7402 (p > 0.05).b Intracellular level The activation of Caspase 8 and Caspase 9 is more thoroughly in BEL-7402/l.lHBV than its controls(p<0.05). Compared with its control, the expression of Bax was upregulated in BEL-7402/1.1HBV(/K0.05).There was no significant difference in the expression of FLIP among BEL-7402/l.lHBV and its controls (/J>0.05). The activity of NF-kB, an important nuclear transcription factor, inhibiting apoptosis by initiating apoptosis inhibiting gene expression, was drastically lower on BEL-7402/l.lHBV cells(/?<0. 05).3. IFN-y promote TRAIL induced apoptosis in HepG2/l.lHBV and its mechanismIFN-y could make HepG2/l.lHBV more sensitive to TRAIL-induced apoptosis (p<0.05). This might be realized by the downregulated expression of DcRl and FLIP.4. The expression of TRAIL receptors on the PBMC in chronic hepatitic B patients and its relativity with the clinical incidenceAmong the four receptors, the expression level of DcRl in the PBMC of chronic B hepatitis patients was much lower than that of control group (p<0.05). There was high relativity among the expression of DcRl-. the clinical stage and the degree ofliver injury (including ALT and albumin).5. HBV transfection promote TWEAK induced apoptosisBEL-7402/1.1 HBV, HepG2/l .1HBV showed higher sensitivity to TWEAK induced apoptosis than their corresponding controls (p<0.05). Moreover, apoptosis
change is more obvious in BEL-7402 series than in HepG2 series.6. IFN^y promote TWEAK induced apoptosis in BEL-7402/1.1HBV .HepG2/l.lHBVIFN-y could make BEL-7402/1.1HBV, HepG2/l.lHBV more sensitive to TWEAK-induced apoptosis (p<0.05).CONCLUSIONS1. HBV gene eukaryotic expression vectors pcDNA3-l.lHBV> pcDNA3-3.0HBVwere constructed successfully. Human hepatoma cell lines transfected with HBV(adr) were established successfully.2. HBV transfection could make cells sensitive to TRAIL induced apoptosis, this may be realized the following steps: 1) Up-regulated the expression of Bax; 2) Downregulated the activity of NF-kB.3. IFN-y could sensitize HepG2/l.lHBV cell to TRAIL-induced apoptosis to great extent.lt may be realized by downregulating the expression of DcR2 and FLIP.4. The expression level of DcRl on PBMC in chronic hepatitis B patients was down-regulated, which might contribute to the increased apoptosis of PBMC in chronic B hepatitis patients. The expression of DcRl can reflect the clinical stage and the degree of liver injury in chronic hepatitis B patients to some degree.5. HBV transfection could make cells sensitive to TWEAK induced apoptosis. IFN-y could sensitize HBV transfected cell to TWEAK-induced apoptosis to great extent.
引文
1. Ando K, Moriyama T Guidotti LG, et al. Mechanism of class I restricted immunopthology. A transgenic mouse model of fulminate hepatitis[J]. J Exp Med. 1993, 178 (5) : 1541-54.
2. P. B. Hammond, D. J. Minema PA Succop. Reversibility of lead-induced depression of growth [J]. Foxicology and Applied pharmacology. 1993, 123(1), 9-15.
3. Eichhorst ST. Modulation of apoptosis as a target for liver disease. Expert Opin Ther Targets. 2005, 9 (1) : 83-99.
4. Dockrell, D. H. , Apoptotic cell death in the pathogenesis of infectious diseases[J]. J Infect. 2001, 42 (4) : 227-34.
5. Feldmann G, Lamboley C, Moreau A, et al. , Fas-mediated apoptosis of hepatic cells[J]. Biomed Pharmacother. 1998, 52 (9) : 378-85.
6. Arbuthnot, P. and M. Kew, Hepatitis B virus and hepatocellular carcinoma[J]. Int J Exp Pathol. 2001, 82 (2) : 77-100.
7. Murakami, S. , Hepatitis B virus X protein: a multifunctional viral regulator[J]. J Gastroentero. 2001, 36 (10) : 651-60.
8. Buendia, M. A. , Hepatitis B viruses and cancerogenesis[J]. Biomed Pharmacother. 1998, 52 (1) : 34-43.
9. Garcia Buey L, Gonzalez Mateos F, Garcia Monzon C, et al. Immune lesion of hepatitis B[J]. Gastroenterol Hepatol. 2001, 24 Suppl 1: 15-28.
10. Rabe, C. and W. H. Caselmann, Interaction of Hepatitis B virus with cellular processes in liver carcinogenesis[J]. Crit Rev Clin Lab Sci. 2000, 37 (5) : 407-29.
11. Hayashi, N. and E. Mita, Involvement of Fas system-mediated apoptosis in pathogenesis of viral hepatitis[J]. J Viral Hepat. 1999, 6 (5) : 357-65.
12. Nita, M. E. , Alves VA, Carrilho FJ, et al. , Molecular aspects of hepatic carcinogenesis[J]. Rev Inst Med Trop Sao Paulo. 2002, 44 (1) : 39-48.
13. Rabe, C. , B. Cheng, and W. H. Caselmann, Molecular mechanisms of hepatitis B virus-associated liver cancer[J]. Dig Dis. 2001, 19 (4) : 279-87.
14. Arbuthnot, P. , A. Capovilla, and M. Kew. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways [J]. J Gastroenterol Hepatol. 2000, 15 (4) : 357-68.
15. Diao, J. , R. Garces, and C. D. Richardson, X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis [J]. Cytokine Growth Factor Rev. 2001, 12 (2-3) : 189-205.
16. Yin XM, Ding WX. Death receptor activation-induced hepatocyte apoptosis and liver injury [J]. Curr Mol Med. 2003, 3 (6) : 491-508.
17. Wiley, S. R. , Schooley K, Smolak PJ, et al. , Identification and characterization of a new member of the TNF family that induces apoptosis[J]. Immunity. 1995, 3 (6) : 673-82.
18. Clarke, P. , Meintzer SM, Spalding AC, et al. , Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection[J]. Oncogene. 2001,20(47): 6910-9.
19. Khanolkar A., H. Yagita, M.J. Cannon, Preferential utilization of the perforin/granzyme pathway for lysis of Epstein-Barr virus-transformed lymphoblastoid cells by virus-specific CD4+ T cells[J]. Virology. 2001, 287(1): 79-88.
20. Thome, M., Schneider P, Hofmann K, et al., Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors[J]. Nature. 1997,386(6624): 517-21.
21. Abe, K., Kurakin A, Mohseni-Maybodi M,The complexity of TNF-related apoptosis-inducing ligand[J]. Ann N Y Acad Sci. 2000,926: 52-63.
22. LeBlanc HN, Ashkenazi A.Apo2L/TRAIL and its death and decoy receptors[J]. Cell Death Differ. 2003,10(l):66-75.
23. Ahmad M.,Y. Shi, TRAIL-induced apoptosis of thyroid cancer cells: potential for therapeutic intervention[J]. Oncogene.2000,19(30): 3363-71.
24. Ashkenazi, A. and V.M. Dixit, Apoptosis control by death and decoy receptors[J]. Curr Opin Cell Biol. 1999,11(2): 255-60.
25. Baetu, T.M. and J. Hiscott, On the TRAIL to apoptosis[J]. Cytokine Growth Factor Rev. 2002,13(3): 199-207.
26. Kim, C.H. and S. Gupta, Expression of TRAIL (Apo2L), DR4 (TRAIL receptor 1), DR5 (TRAIL receptor 2) and TRID (TRAIL receptor 3) genes in multidrug resistant human acute myeloid leukemia cell lines that overexpress MDR 1 (HL60/Tax) or MRP (HL60/AR) [J]. Int J Oncol.2000, 16(6): 1137-9.
27. Emery JG, McDonnell P, Burke MB, et al., Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL[J]. J Biol Chem. 1998,273(23): 14363-7.
28. Holen I, Croucher PI, Hamdy FC, et al., Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells[J]. Cancer Res. 2002,62(6): 1619-23.
29. Baetu TM, Kwon H, Sharma S, et al., Disruption of NF-kappaB signaling reveals a novel role for NF-kappaB in the regulation of TNF-related apoptosis-inducing ligand expression[J]. J Immunol.2001,167(6): 3164-73.
30.David Bernard, Brigitte Quatannens, Bernard Vandenbunder,et al., Rel/NF-kappaB transcription factors protect against tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by up-regulating the TRAIL decoy receptor DcRl[J]. J Biol Chem.2001,276(29): 27322-8.
31. Degli-Esposti MA, Dougall WC, Smolak PJ, et al., The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain[J]. Immunity. 1997,7(6): 813-20.
32.MacFarlane M.TRAIL-induced signalling and apoptosis[J].Toxicol Lett. 2003 ,139(2-3):89-97.
33.Hussein MR, Haemel AK, Wood GS.Apoptosis and melanoma:molecular mechanisms[J].J Pathol. 2003 ,199(3):275-88.
34. Srivastava RK.Intracellular mechanisms of TRAIL and its role in cancer therapy [J]. Mol Cell Biol Res Commun. 2000,4(2):67-75.
35. Marsters, S.A., Pitti RA, Sheridan JP, et al., Control of apoptosis signaling by
Apo2 ligand[J]. Recent Prog Horm Res.1999,54: 225-34.
36. Meng, R.D., McDonald ER 3rd, Sheikh MS, et al., The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis[J]. Mol Ther. 2000,1(2): 130-44.
37. Phillips, T.A., Ni J, Pan G,et al., TRAIL (Apo-2L) and TRAIL receptors in human placentas: implications for immune privilege. J Immunol. 1999,162(10): 6053-9.
38. Bartke,T., Siegmund D, Peters N, et al.,p53 upregulates cFLIP, inhibits transcription of NF-kappaB-regulated genes and induces caspase-8-independent cell death in DLD-1 cells[J]. Oncogene. 2001,20(5): 571-80.
39. Bullani, R.R., Huard B, Viard-Leveugle I, et al., Selective expression of FLIP in malignant melanocytic skin lesions[J]. J Invest Dermatol. 2001,117(2): 360-4.
40. Eggert, A., Grotzer MA, Zuzak TJ, et al., Resistance to TRAIL-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression[J]. Med Pediatr Oncol.2000,35(6): 603-7.
41. Garvey, T.L., Bertin J, Siegel RM, et al., Binding of FADD and caspase-8 to molluscum contagiosum virus MC159 v-FLIP is not sufficient for its antiapoptotic function[J]. J Virol. 2002, 76(2): 697-706.
42. Degli-Esposti, M., To die or not to die—the quest of the TRAIL receptors[J]. J Leukoc Biol.1999,65(5): 535-42.
43. Burns, T.F. and W.S. E1-Deiry, Identification of inhibitors of TRAIL-induced death (ITIDs) in the TRAIL-sensitive colon carcinoma cell line SW480 using a genetic approach[J]. J Biol Chem. 2001,276(41): 37879-86.
44. Bin, L., Li X, Xu LG, et al., The short splice form of Casper/c-FLIP is a major cellular inhibitor of TRAIL-induced apoptosis[J]. FEBS Lett. 2002, 510(1-2):37-40.
45. Griffith, T.S.,Chin WA, Jackson GC,et al.,Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells[J]. J Immunol. 1998,161(6):2833-40.
46. Leverkus, M., Walczak H, McLellan A, et al., Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand-mediated apoptosis[J]. Blood. 2000, 96(7): 2628-31.
47. Kreuz, S., Siegmund D, Scheurich P, et al., NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling[J]. Mol Cell Biol. 2001, 21(12): 3964-73.
48. MacFarlane, M., Merrison W, Bratton SB, et al., Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro[J]. J Biol Chem. 2002,277(39): 36611-6.
49. Ng, C.P. and B. Bonavida, X-linked inhibitor of apoptosis (XIAP) blocks Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of prostate cancer cells in the presence of mitochondrial activation: sensitization by overexpression of second mitochondria-derived activator of caspase/direct IAP-binding protein with low p1 (Smac/DIABLO) [J]. Mol Cancer
Ther.2002,l(12): 1051-1058.
50. Dharminder Chauhan, Pramod Pandey,Atshnshi Ogata,et al.Cytochrome c-dependent and-independent Induction of Apoptosis in MultipleMyeloma Cells[J].J Biol Chem. 1997,272(48): 29995-29997.
51. Deng Y, Lin Y, Wu X. TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO[J].Genes Dev. 2002,16(1):33-45.
52. Neuzil J, Swettenham E, Gellert N. Sensitization of mesothelioma to TRAIL apoptosis by inhibition of histone deacetylase: role of Bcl-xL down-regulation[J].Biochem Biophys Res Commun. 2004,314(1):186-91.
53. Fehlberg S, Gregel CM, Goke A, et al.Bisphenol A diglycidyl ether-induced apoptosis involves Bax/Bid-dependent mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and Smac/DIABLO[J].Br J Pharmacol. 2003,139(3):495-500.
54. Kandasamy K, Srinivasula SM, Alnemri ES, et al.Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome c and Smac/DIABLO release[J]. Cancer Res. 2003 ,63(7):1712-21.
55. Hao JH, Yu M, Liu FT, et al.Bcl-2 inhibitors sensitize tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by uncoupling of mitochondrial respiration in human leukemic CEM cells[J] .Cancer Res. 2004 ,64(10):3607-16.
56. Sinicrope FA, Penington RC, Tang XM. Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis is inhibited by Bcl-2 but restored by the small molecule Bcl-2 inhibitor, HA 14-1, in human colon cancer cells[J]. Clin Cancer Res. 2004,10(24):8284-92.
57. Carthy CM, Yanagawa B, Luo H, et al. Bcl-2 and Bcl-xL overexpression inhibits cytochrome c release, activation of multiple caspases, and virus release following coxsackievirus B3 infection[J]. Virology.2003 ,313(1):147-57.
58. Lamothe B, Aggarwal BB. Ectopic expression of Bcl-2 and Bcl-xL inhibits apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) through suppression of caspases-8, 7, and 3 and BID cleavage in human acute myelogenous leukemia cell line HL-60[J].J Interferon Cytokine Res.2002,22(2):269-79.
59. Johnson TR, Stone K, Nikrad M, et al.The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells[J].Oncogene. 2003 ,22(32):4953-63.
60. Han J, Goldstein LA, Gastman BR, et al. Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells[J].Leukemia. 2004,18(10):1671-80.
61. Kim M, Park SY, Pai HS, et al. Hypoxia inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by blocking Bax translocation[J].Cancer Res. 2004,64(12):4078-81.
62. Kim JY, Kim YH, Chang I, et al. Resistance of mitochondrial DNA-deficient cells to TRAIL: role of Bax in TRAIL-induced apoptosis[J]. Oncogene.
2002,21(20):3139-48.
63. von Haefen C, Gillissen B, Hemmati PG, et al.Multidomain Bcl-2 homolog Bax but not Bak mediates synergistic induction of apoptosis by TRAIL and 5-FU through the mitochondrial apoptosis pathway[J].Oncogene. 2004,23(50):8320-32.
64. Robbins MA, Maksumova L, Pocock E,et al.Nuclear factor-kappaB translocation mediates double-stranded ribonucleic acid-induced NIT-1 beta-cell apoptosis and up-regulates caspase-12 and tumor necrosis factor receptor-associated ligand (TRAIL) [J]. Endocrinology. 2003,144(10):4616-25.
65. Wajant H. TRAIL and NF-kappaB signaling—a complex relationship[J].Vitam Horm. 2004,67:101-32.
66. Chawla-Sarkar M, Bauer JA, Lupica JA, et al. Suppression of NF-kappa B survival signaling by mtrosylcobalamin sensitizes neoplasms to the anti-tumor effects of Apo2L/TRAIL[J]. J Biol Chem. 2003 ,278(41):39461-9.
67. Ehrhardt H, Fulda S, Schmid I, et al.TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB[J]. Oncogene. 2003 ,22(25):3842-52.
68. Thomas, W.D., Zhang XD, Franco AV, et al., TNF-related apoptosis-inducing ligand-induced apoptosis of melanoma is associated with changes in mitochondrial membrane potential and perinuclear clustering of mitochondria[J]. J Immunol. 2000,165(10): 5612-20.
69. Mariani, S.M. and P.H. Krammer, Surface expression of TRAIL/Apo-2 ligand in activated mouse T and B cells[J]. Eur J Immunol. 1998,28(5): 1492-8.
70. Knight, M.J., et al., Analysis of FasL and TRAIL induced apoptosis pathways in gliomacells[J]. Oncogene.2001,20(41): 5789-98.
71. Snell V, Clodi K, Zhao S, et al., Activity of TNF-related apoptosis-inducing ligand (TRAIL) in haematological malignancies[J]. Br J Haematol.1997,99(3): 618-24.
72. Lutz W, et al., Myc and IFN gamma cooperate in apoptosis of human neuroblastoma cells[J]. Oncogene. 1998,17(3): 339-46.
73. Truneh A, Sharma S, Silverman C, et al., Temperature-sensitive differential affinity of TRAIL for its receptors. DR5 is the highest affinity receptor [J]. J Biol Chem. 2000,275(30): 23319-25.
74. Jeremias I, Herr I, Boehler T, et al., TRAIL/Apo-2-ligand-induced apoptosis in human T cells[J]. Eur J Immunol. 1998,28(1): 143-52.
75. Sedger LM, Shows DM, Blanton RA, et al., IFN-gamma mediates a novel antiviral activity through dynamic modulation of TRAIL and TRAIL receptor expression[J]. J Immunol. 1999,163(2): 920-6.
76. Clarke P, Meintzer SM, Gibson S, et al., Reovirus-induced apoptosis is mediated by TRAIL[J]. J Virol. 2000, 74(17): 8135-9.
77. Benedict CA, Norris PS, Prigozy TI,et al., Three adenovirus E3 proteins cooperate to evade apoptosis by tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2[J]. J Biol Chem, 2001.276(5): 3270-8.
78. Burgert HG, Ruzsics Z, Obermeier S,et al., Subversion of host defense mechanisms by adenoviruses[J]. Curr Top Microbiol Immunol.2002.269: 273-318.
79. Kawanishi M., S. Tada-Oikawa, and S. Kawanishi. Epstein-Barr virus BHRF1
functions downstream of Bid cleavage and upstream of mitochondrial dysfunction to inhibit TRAIL-induced apoptosis in BJAB cells[J]. Biochem Biophys Res Commun. 2002,297(3): 682-7.
80. Kabsch, K. and A. Alonso. The human papillomavirus type 16 E5 protein impairs TRAIL- and FasL-mediated apoptosis in HaCaT cells by different mechanisms[J]. J Virol. 2002,76(23): 12162-72.
81. Wold, W.S., Doronin K, Toth K, et al., Immune responses to adenoviruses: viral evasion mechanisms and their implications for the clinic[J]. Curr Opin Immunol. 1999,11(4): 380-6.
82. Yves Chicheportiche, Paul R. Bourdon, Haoda Xu. TWEAK, a New Secreted Ligand in the Tumor Necrosis FactorFamily That Weakly Induces Apoptosis[J]. J Biological Chemistry. 1997,272(51): 32401-32410.
83. Mueller AM, Pedre X, Kleiter I,et al. Targeting fibroblast growth factor -inducible-14 signaling protects from chronic relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol. 2005 ,159(1-2):55-65.
84. Xu H, Okamoto A, Ichikawa J,et al.TWEAK/Fn14 interaction stimulates human bronchial epithelial cells to produce IL-8 and GM-CSF[J]. Biochem Biophys Res Commun. 2004 ,318(2):422-7.
85. Jakubowski A, Browning B, Lukashev M, et al. Dual role for TWEAK in angiogenic regulation[J].J Cell Sci. 2002 ,115(Pt 2):267-74.
86. Lynch CN, Wang YC, Lund JK, et al. TWEAK induces angiogenesis and proliferation of endothelial cells[J]. J Biol Chem. 1999,274 (13):8455-9.
87. Ho DH, Vu H, Brown SA, et al.Soluble tumor necrosis factor-like weak inducer of apoptosis overexpression in HEK293 cells promotes tumor growth and angiogenesis in athymic nude mice[J]. Cancer Res. 2004,64(24):8968-72.
88. Kawakita T, Shiraki K, Yamanaka Y,et al.Functional expression of TWEAK in human colonic adenocarcinoma cells[J]. Int J Oncol. 2005,26(1):87-93.
89. Kawakita T, Shiraki K, Yamanaka Y, et al.Functional expression of TWEAK in human hepatocellular carcinoma: possible implication in cell proliferation and tumor angiogenesis[J]. Biochem Biophys Res Commun. 2004,318(3):726-33.
90. Kaptein A, Jansen M, Dilaver G, et al. Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3) [J]. FEBS Lett. 2000,485(2-3):135-41.
91. Chicheportiche Y, Chicheportiche R, Sizing I, et al. Proinflammatory activity of TWEAK on human dermal fibroblasts and synoviocytes: blocking and enhancing effects of anti-TWEAK monoclonal antibodies[J]. Arthritis Res. 2002,4(2):126-33.
92. Kaplan MJ, Ray D, Mo RR, et al. TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell killing of antigen-presenting macrophages. J Immunol[J]. 2000,164(6):2897-904.
93. Polek TC, Talpaz M, Darnay BG, et al. TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor[J]. J Biol Chem. 2003 ,278(34):32317-23.
94. Masafumi Nakayama, Kazumi Ishidoh, Nobuhiko Kayagaki, Multiple Pathways
of TWEAK-Induced Cell Death[J].The Journal of Immunology. 2002, 168(2):734-743.
95. Lynch CN, Wang YC, Lund JK, Chen YW, Leal JA, Wiley SR.TWEAK induces angiogenesis and proliferation of endothelial cells[J]. J Biol Chem.1999,274(13):8455-9.
96. Kaplan MJ, Ray D, Mo RR, et al. TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell killing of antigen-presenting macrophages[J]. J Immunol, 2000,164(6):2897-2904.
97. Nakayama M, Kayagaki N, Yamaguchi N, et al. Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity [J]. J Exp Med.2000, 192(9):1373-1380.
98. Schaller H, Mason S, et al. Transcriptional control of hepadnavirus gene expression. Current Topics in Microbiology and Immunology [J]. Berlin Heidelberg Press.1991,168: 21- 40.
99. Toillais P, et al. Hepatitis B virus[J]. Scientific American. 1991,264: 48- 54.
100. Youhua Xie, Mei Li,Yuan Wang,et al, Site-specific mutation of the hepatitis B virus enhancer II Blelement: effect on virus transcription and replication. Journal of General Virology.2001, 82( Pt 3):531-535.
101. Kohno K, Nishizono A, Terao H, et al. Reduced transcription and progeny virus production of hepatitis B virus containing an 8-bp deletion in basic core promoterJ Med Virol. 2000,61(l):15-22.
102. Feigner PL, Gadek TR, Holm M,et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure[J]. Proc Natl Acad Sci USA. 1987 ,84(21):7413-7417.
103. Feigner PL, Ringold GM. Cationic liposome-mediated transfection[J]. Nature. 1989,337(6205):387-388.
104. Naoki Itano, Fukiko Atsumi, Takahiro Sawai, et al. Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration[J].PNAS. 2002, 99(6):3609-3614.
105. Makiko Umezu-Goto, Yasuhiro Kishi, Akitsu Taira, et al. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production[J]. J Cell Biol.2002,15(2), 227-233.
106. K.Yagyu, K. Kitagawa, T. Irie, et al. InagakiAmyloid 6 proteins inhibit Cl~--ATPase activity in cultured rat hippocampal neurons[J] Journal of Neurochemistry. 2001, 78(3): 569-576.
107. Jianguo Hu, Akira Igarashi, Makiko Kamata, et al. Angiotensin-converting Enzyme Degrades Alzheimer Amyloid P-Peptide (AP); Retards Aβ Aggregation, Deposition, Fibril Formation; and Inhibits Cytotoxicity [J]. J Biological Chemistry. 2001,276(51): 47863-47868.
108. Daisuke Yoshimura, Kunihiko Sakumi, Mizuki Ohno, et al. An Oxidized Purine Nucleoside Triphosphatase, MTH1, Suppresses Cell Death Caused by Oxidative Stress[J].J Biological Chemistry. 2003,278(39): 37965-37973.
109. Vermes I, Haanen C , Steffens-Nakken H, et al. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptosis cells using fluorescein labeled Annexin V[J]. J Immunol Methods. 1995,184
(1):39-42.
110. Fadok V A , Voelker D R ,Campbell P A, et al. Exposure of phosphatidyl-serine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophage[J]. J Immuol. 1992 ,148(7):2207-12.
111. Nicoletti I , Migliorati G, Pagliacci M C.A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry[J]. J Immunol Methods. 1991 ,139(2):271-274.
112. Gorczyca W, Gong J P , Darzynkiewicz Z. Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assay[J]. Cancer Res.l993,53(8):1945-50.
113. Hussein MR, Haemel AK, Wood GS. Apoptosis and melanoma: molecular mechanisms[J].J Pathol. 2003 ,199(3):275-88.
114. Fukazawa T, Fujiwara T, Uno F,et al., Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells[J]. Oncogene. 2001,20(37): 5225-31.
115. Hao C, Beguinot F, Condorelli G, et al., Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells[J]. Cancer Res.2001,61(3): 1162-70.
116. Mitsiades N, Mitsiades CS, Poulaki V, et al., Intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human multiple myeloma cells[J]. Blood.2002, 99(6): 2162-71.
117. Poulaki V, Mitsiades CS, Kotoula V, et al., Regulation of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in thyroid carcinoma cells[J]. Am J Pathol. 2002,161(2): 643-54.
118. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation[J]. Science. 1998,281(5381):1305-8.
119.Muzio M, Chinnaiyan AM, Kischkel FC, et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex[J]. Cell. 1996,85(6):817-27.
120. Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death[J]. Cell. 1996,85(6):803-15.
121. Zou H, Li Y, Liu X, Wang X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9[J]. J Biol Chem. 1999,274(17):11549-56.
122. Hirsch T , Susin SA , Marzo I , et al. Mitochondrial permeability transition in apopotosis and necrosis[J ]. Cell Biol Toxicol. 1998 ,14 (2) :141-145.
123. Bradham CA , Qian T , Streetz K, et al. The mitochondrial permeability transition is required for tumor necrosis factor alpha ,mediated apoptosis and cytochrome C release [ J ]. Mol Cell Biol.1998 ,18 (11) :6353 - 6364.
124. Cregan SP, Dawson VL, Slack RS.Role of AIF in caspase-dependent and caspase-independent cell death[J]. Oncogene. 2004,23(16):2785-96.
125. Hansen TM, Nagley P. AIF: a multifunctional cog in the life and death machine [J].Sci STKE. 2003 ,29(193):PE31.
126. Susin SA Lorenzo HK, Zamzami N , et al. Mitochondrial realease of caspase - 2 and - 9 during the apoptotic process [J]. J Exp Med .1999,189 (18) :381 - 391.
127. Twiddy D, Brown DG, Adrain C, et al.Pro-apoptotic proteins released from the mitochondria regulate the protein composition and caspase-processing activity of the native Apaf-1/caspase-9 apoptosome complex[J].J Biol Chem.2004,279(19):19665-82.
128. Stewart CL, Schuetze S, Vanek M, et al. Expression of retroviral vectors in transgenic mice obtained by embryo infection[J]. EMBO J. 1987,6(2):383-388.
129. Wagner EF, Vanek M, Vennstrom B. Transfer of genes into embryonal carcinoma cells by retrovirus infection: efficient expression from an internal promoter[J].EMBO J. 1985,4(3):663-666.
130. Wood KV, de Wet JR., Dewji N,et al. Synthesis of active firefly luciferase by in vitro translation of RNA obtained from adult lanterns[J]. Biochem Biophys Res Commun. 1984 ,124(2):592-596.
131. de Wet JR, Wood KV, Helinski DR, DeLuca M. Cloning of firefly luciferase cDNA and the expression of active luciferase in Escherichia coli[J]. Proc Natl Acad Sci U S A.1985,82(23):7870-7873.
132. Matthews JC, Hori K, Cormier MJ. Purification and properties of Renilla reniformis luciferase[J]. Biochemistry. 1977,16(1):85-91.
133. Mitsiades CS, Mitsiades N, Poulaki V, et al., Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications[J]. Oncogene. 2002, 21(37): 5673-83.
134. Bouchier-Hayes L, Conroy H, Egan H, et al., CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways[J]. J Biol Chem.2001,276(47): 44069-77.
135. Trauzold A, Wermann H, Arlt A, et al., CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-kappaB contributes to apoptosis resistance in ductal pancreatic adenocaracinom cells[J]. Oncogene. 2001,20(31): 4258-69.
136. Oya M, Ohtsubo M, Takayanagi A, et al., Constitutive activation of nuclear factor-kappaB prevents TRAIL-induced apoptosis in renal cancer cells[J]. Oncogene. 2001,20(29): 3888-96.
137. Jeremias I, Jeremias I, Kupatt C, Baumann B, et al., Inhibition of nuclear factor kappaB activation attenuates apoptosis resistance in lymphoid cells[J]. Blood. 1998, 91(12): 4624-31.
138. Clarke P, Meintzer SM, Spalding AC, et al., Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection[J]. Oncogene.2001,20(47): 6910-9.
139. Hou CS, Wang GQ, Lu SL, et al. Role of activation-induced cell death in pathogenesis of patients with chronic hepatitis B[J].World J Gastroenterol. 2003, 9(10):2356-8.
140. Boomer JS , Derks RA , Lee GW, et al. Regeneration and tolerance factor is expressed during Thymphocyte activation and plays a role in apoptosis[J].Hum Immunol. 2001, 62(6):577-88.
141. Schuchmann M, Varfolomeev EE, Hermann F, et al. Dominant negative MORT1/ FADD rescues mice from CD95 and TNF-induced liver failure. Hepatology. 2002, 37(1): 129-135.
142. Chen CJ, Makino S. Murine coronavirus-induced apoptosis in 17C121 cells involves a mitochondria2mediated pathway and its downstream caspase-8 activation and bid cleavage[J]. Virology. 2002 ,302(2) :321-332.
143. Le Blanc HN, Ashkenazi A.Apo2L/TRAIL and its death and decoy receptors[J]. Cell Death Differ. 2003 ,10(1):66-75.
144. Masafumi Nakayama, Kazumi Ishidoh, Nobuhiko Kayagaki. Multiple Pathways of TWEAK-Induced Cell Death[J].The Journal of Immunology.2002,168(2):734-43.
145. Jeremias I, C Kupatt, B Baumann, et al. Inhibition of nuclear factor κB activation attenuates apoptosis resistance in lymphoid cells[J]. Blood1998,91(12):4624-31.
146. Lichtner M, Maranon C, Vidalain PO,et al.HIV type 1-infected dendritic cells induce apoptotic death in infected and uninfected primary CD4 T lymphocytes[J]. AIDS Res Hum Retroviruses. 2004 ,20(2):175-82.
2. P. B. Hammond, D. J. Minema PA Succop. Reversibility of lead-induced depression of growth [J]. Foxicology and Applied pharmacology. 1993, 123(1), 9-15.
3. Eichhorst ST. Modulation of apoptosis as a target for liver disease. Expert Opin Ther Targets. 2005, 9 (1) : 83-99.
4. Dockrell, D. H. , Apoptotic cell death in the pathogenesis of infectious diseases[J]. J Infect. 2001, 42 (4) : 227-34.
5. Feldmann G, Lamboley C, Moreau A, et al. , Fas-mediated apoptosis of hepatic cells[J]. Biomed Pharmacother. 1998, 52 (9) : 378-85.
6. Arbuthnot, P. and M. Kew, Hepatitis B virus and hepatocellular carcinoma[J]. Int J Exp Pathol. 2001, 82 (2) : 77-100.
7. Murakami, S. , Hepatitis B virus X protein: a multifunctional viral regulator[J]. J Gastroentero. 2001, 36 (10) : 651-60.
8. Buendia, M. A. , Hepatitis B viruses and cancerogenesis[J]. Biomed Pharmacother. 1998, 52 (1) : 34-43.
9. Garcia Buey L, Gonzalez Mateos F, Garcia Monzon C, et al. Immune lesion of hepatitis B[J]. Gastroenterol Hepatol. 2001, 24 Suppl 1: 15-28.
10. Rabe, C. and W. H. Caselmann, Interaction of Hepatitis B virus with cellular processes in liver carcinogenesis[J]. Crit Rev Clin Lab Sci. 2000, 37 (5) : 407-29.
11. Hayashi, N. and E. Mita, Involvement of Fas system-mediated apoptosis in pathogenesis of viral hepatitis[J]. J Viral Hepat. 1999, 6 (5) : 357-65.
12. Nita, M. E. , Alves VA, Carrilho FJ, et al. , Molecular aspects of hepatic carcinogenesis[J]. Rev Inst Med Trop Sao Paulo. 2002, 44 (1) : 39-48.
13. Rabe, C. , B. Cheng, and W. H. Caselmann, Molecular mechanisms of hepatitis B virus-associated liver cancer[J]. Dig Dis. 2001, 19 (4) : 279-87.
14. Arbuthnot, P. , A. Capovilla, and M. Kew. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways [J]. J Gastroenterol Hepatol. 2000, 15 (4) : 357-68.
15. Diao, J. , R. Garces, and C. D. Richardson, X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis [J]. Cytokine Growth Factor Rev. 2001, 12 (2-3) : 189-205.
16. Yin XM, Ding WX. Death receptor activation-induced hepatocyte apoptosis and liver injury [J]. Curr Mol Med. 2003, 3 (6) : 491-508.
17. Wiley, S. R. , Schooley K, Smolak PJ, et al. , Identification and characterization of a new member of the TNF family that induces apoptosis[J]. Immunity. 1995, 3 (6) : 673-82.
18. Clarke, P. , Meintzer SM, Spalding AC, et al. , Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection[J]. Oncogene. 2001,20(47): 6910-9.
19. Khanolkar A., H. Yagita, M.J. Cannon, Preferential utilization of the perforin/granzyme pathway for lysis of Epstein-Barr virus-transformed lymphoblastoid cells by virus-specific CD4+ T cells[J]. Virology. 2001, 287(1): 79-88.
20. Thome, M., Schneider P, Hofmann K, et al., Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors[J]. Nature. 1997,386(6624): 517-21.
21. Abe, K., Kurakin A, Mohseni-Maybodi M,The complexity of TNF-related apoptosis-inducing ligand[J]. Ann N Y Acad Sci. 2000,926: 52-63.
22. LeBlanc HN, Ashkenazi A.Apo2L/TRAIL and its death and decoy receptors[J]. Cell Death Differ. 2003,10(l):66-75.
23. Ahmad M.,Y. Shi, TRAIL-induced apoptosis of thyroid cancer cells: potential for therapeutic intervention[J]. Oncogene.2000,19(30): 3363-71.
24. Ashkenazi, A. and V.M. Dixit, Apoptosis control by death and decoy receptors[J]. Curr Opin Cell Biol. 1999,11(2): 255-60.
25. Baetu, T.M. and J. Hiscott, On the TRAIL to apoptosis[J]. Cytokine Growth Factor Rev. 2002,13(3): 199-207.
26. Kim, C.H. and S. Gupta, Expression of TRAIL (Apo2L), DR4 (TRAIL receptor 1), DR5 (TRAIL receptor 2) and TRID (TRAIL receptor 3) genes in multidrug resistant human acute myeloid leukemia cell lines that overexpress MDR 1 (HL60/Tax) or MRP (HL60/AR) [J]. Int J Oncol.2000, 16(6): 1137-9.
27. Emery JG, McDonnell P, Burke MB, et al., Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL[J]. J Biol Chem. 1998,273(23): 14363-7.
28. Holen I, Croucher PI, Hamdy FC, et al., Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells[J]. Cancer Res. 2002,62(6): 1619-23.
29. Baetu TM, Kwon H, Sharma S, et al., Disruption of NF-kappaB signaling reveals a novel role for NF-kappaB in the regulation of TNF-related apoptosis-inducing ligand expression[J]. J Immunol.2001,167(6): 3164-73.
30.David Bernard, Brigitte Quatannens, Bernard Vandenbunder,et al., Rel/NF-kappaB transcription factors protect against tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by up-regulating the TRAIL decoy receptor DcRl[J]. J Biol Chem.2001,276(29): 27322-8.
31. Degli-Esposti MA, Dougall WC, Smolak PJ, et al., The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain[J]. Immunity. 1997,7(6): 813-20.
32.MacFarlane M.TRAIL-induced signalling and apoptosis[J].Toxicol Lett. 2003 ,139(2-3):89-97.
33.Hussein MR, Haemel AK, Wood GS.Apoptosis and melanoma:molecular mechanisms[J].J Pathol. 2003 ,199(3):275-88.
34. Srivastava RK.Intracellular mechanisms of TRAIL and its role in cancer therapy [J]. Mol Cell Biol Res Commun. 2000,4(2):67-75.
35. Marsters, S.A., Pitti RA, Sheridan JP, et al., Control of apoptosis signaling by
Apo2 ligand[J]. Recent Prog Horm Res.1999,54: 225-34.
36. Meng, R.D., McDonald ER 3rd, Sheikh MS, et al., The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis[J]. Mol Ther. 2000,1(2): 130-44.
37. Phillips, T.A., Ni J, Pan G,et al., TRAIL (Apo-2L) and TRAIL receptors in human placentas: implications for immune privilege. J Immunol. 1999,162(10): 6053-9.
38. Bartke,T., Siegmund D, Peters N, et al.,p53 upregulates cFLIP, inhibits transcription of NF-kappaB-regulated genes and induces caspase-8-independent cell death in DLD-1 cells[J]. Oncogene. 2001,20(5): 571-80.
39. Bullani, R.R., Huard B, Viard-Leveugle I, et al., Selective expression of FLIP in malignant melanocytic skin lesions[J]. J Invest Dermatol. 2001,117(2): 360-4.
40. Eggert, A., Grotzer MA, Zuzak TJ, et al., Resistance to TRAIL-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression[J]. Med Pediatr Oncol.2000,35(6): 603-7.
41. Garvey, T.L., Bertin J, Siegel RM, et al., Binding of FADD and caspase-8 to molluscum contagiosum virus MC159 v-FLIP is not sufficient for its antiapoptotic function[J]. J Virol. 2002, 76(2): 697-706.
42. Degli-Esposti, M., To die or not to die—the quest of the TRAIL receptors[J]. J Leukoc Biol.1999,65(5): 535-42.
43. Burns, T.F. and W.S. E1-Deiry, Identification of inhibitors of TRAIL-induced death (ITIDs) in the TRAIL-sensitive colon carcinoma cell line SW480 using a genetic approach[J]. J Biol Chem. 2001,276(41): 37879-86.
44. Bin, L., Li X, Xu LG, et al., The short splice form of Casper/c-FLIP is a major cellular inhibitor of TRAIL-induced apoptosis[J]. FEBS Lett. 2002, 510(1-2):37-40.
45. Griffith, T.S.,Chin WA, Jackson GC,et al.,Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells[J]. J Immunol. 1998,161(6):2833-40.
46. Leverkus, M., Walczak H, McLellan A, et al., Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand-mediated apoptosis[J]. Blood. 2000, 96(7): 2628-31.
47. Kreuz, S., Siegmund D, Scheurich P, et al., NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling[J]. Mol Cell Biol. 2001, 21(12): 3964-73.
48. MacFarlane, M., Merrison W, Bratton SB, et al., Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro[J]. J Biol Chem. 2002,277(39): 36611-6.
49. Ng, C.P. and B. Bonavida, X-linked inhibitor of apoptosis (XIAP) blocks Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of prostate cancer cells in the presence of mitochondrial activation: sensitization by overexpression of second mitochondria-derived activator of caspase/direct IAP-binding protein with low p1 (Smac/DIABLO) [J]. Mol Cancer
Ther.2002,l(12): 1051-1058.
50. Dharminder Chauhan, Pramod Pandey,Atshnshi Ogata,et al.Cytochrome c-dependent and-independent Induction of Apoptosis in MultipleMyeloma Cells[J].J Biol Chem. 1997,272(48): 29995-29997.
51. Deng Y, Lin Y, Wu X. TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO[J].Genes Dev. 2002,16(1):33-45.
52. Neuzil J, Swettenham E, Gellert N. Sensitization of mesothelioma to TRAIL apoptosis by inhibition of histone deacetylase: role of Bcl-xL down-regulation[J].Biochem Biophys Res Commun. 2004,314(1):186-91.
53. Fehlberg S, Gregel CM, Goke A, et al.Bisphenol A diglycidyl ether-induced apoptosis involves Bax/Bid-dependent mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and Smac/DIABLO[J].Br J Pharmacol. 2003,139(3):495-500.
54. Kandasamy K, Srinivasula SM, Alnemri ES, et al.Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome c and Smac/DIABLO release[J]. Cancer Res. 2003 ,63(7):1712-21.
55. Hao JH, Yu M, Liu FT, et al.Bcl-2 inhibitors sensitize tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by uncoupling of mitochondrial respiration in human leukemic CEM cells[J] .Cancer Res. 2004 ,64(10):3607-16.
56. Sinicrope FA, Penington RC, Tang XM. Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis is inhibited by Bcl-2 but restored by the small molecule Bcl-2 inhibitor, HA 14-1, in human colon cancer cells[J]. Clin Cancer Res. 2004,10(24):8284-92.
57. Carthy CM, Yanagawa B, Luo H, et al. Bcl-2 and Bcl-xL overexpression inhibits cytochrome c release, activation of multiple caspases, and virus release following coxsackievirus B3 infection[J]. Virology.2003 ,313(1):147-57.
58. Lamothe B, Aggarwal BB. Ectopic expression of Bcl-2 and Bcl-xL inhibits apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) through suppression of caspases-8, 7, and 3 and BID cleavage in human acute myelogenous leukemia cell line HL-60[J].J Interferon Cytokine Res.2002,22(2):269-79.
59. Johnson TR, Stone K, Nikrad M, et al.The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells[J].Oncogene. 2003 ,22(32):4953-63.
60. Han J, Goldstein LA, Gastman BR, et al. Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells[J].Leukemia. 2004,18(10):1671-80.
61. Kim M, Park SY, Pai HS, et al. Hypoxia inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by blocking Bax translocation[J].Cancer Res. 2004,64(12):4078-81.
62. Kim JY, Kim YH, Chang I, et al. Resistance of mitochondrial DNA-deficient cells to TRAIL: role of Bax in TRAIL-induced apoptosis[J]. Oncogene.
2002,21(20):3139-48.
63. von Haefen C, Gillissen B, Hemmati PG, et al.Multidomain Bcl-2 homolog Bax but not Bak mediates synergistic induction of apoptosis by TRAIL and 5-FU through the mitochondrial apoptosis pathway[J].Oncogene. 2004,23(50):8320-32.
64. Robbins MA, Maksumova L, Pocock E,et al.Nuclear factor-kappaB translocation mediates double-stranded ribonucleic acid-induced NIT-1 beta-cell apoptosis and up-regulates caspase-12 and tumor necrosis factor receptor-associated ligand (TRAIL) [J]. Endocrinology. 2003,144(10):4616-25.
65. Wajant H. TRAIL and NF-kappaB signaling—a complex relationship[J].Vitam Horm. 2004,67:101-32.
66. Chawla-Sarkar M, Bauer JA, Lupica JA, et al. Suppression of NF-kappa B survival signaling by mtrosylcobalamin sensitizes neoplasms to the anti-tumor effects of Apo2L/TRAIL[J]. J Biol Chem. 2003 ,278(41):39461-9.
67. Ehrhardt H, Fulda S, Schmid I, et al.TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB[J]. Oncogene. 2003 ,22(25):3842-52.
68. Thomas, W.D., Zhang XD, Franco AV, et al., TNF-related apoptosis-inducing ligand-induced apoptosis of melanoma is associated with changes in mitochondrial membrane potential and perinuclear clustering of mitochondria[J]. J Immunol. 2000,165(10): 5612-20.
69. Mariani, S.M. and P.H. Krammer, Surface expression of TRAIL/Apo-2 ligand in activated mouse T and B cells[J]. Eur J Immunol. 1998,28(5): 1492-8.
70. Knight, M.J., et al., Analysis of FasL and TRAIL induced apoptosis pathways in gliomacells[J]. Oncogene.2001,20(41): 5789-98.
71. Snell V, Clodi K, Zhao S, et al., Activity of TNF-related apoptosis-inducing ligand (TRAIL) in haematological malignancies[J]. Br J Haematol.1997,99(3): 618-24.
72. Lutz W, et al., Myc and IFN gamma cooperate in apoptosis of human neuroblastoma cells[J]. Oncogene. 1998,17(3): 339-46.
73. Truneh A, Sharma S, Silverman C, et al., Temperature-sensitive differential affinity of TRAIL for its receptors. DR5 is the highest affinity receptor [J]. J Biol Chem. 2000,275(30): 23319-25.
74. Jeremias I, Herr I, Boehler T, et al., TRAIL/Apo-2-ligand-induced apoptosis in human T cells[J]. Eur J Immunol. 1998,28(1): 143-52.
75. Sedger LM, Shows DM, Blanton RA, et al., IFN-gamma mediates a novel antiviral activity through dynamic modulation of TRAIL and TRAIL receptor expression[J]. J Immunol. 1999,163(2): 920-6.
76. Clarke P, Meintzer SM, Gibson S, et al., Reovirus-induced apoptosis is mediated by TRAIL[J]. J Virol. 2000, 74(17): 8135-9.
77. Benedict CA, Norris PS, Prigozy TI,et al., Three adenovirus E3 proteins cooperate to evade apoptosis by tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2[J]. J Biol Chem, 2001.276(5): 3270-8.
78. Burgert HG, Ruzsics Z, Obermeier S,et al., Subversion of host defense mechanisms by adenoviruses[J]. Curr Top Microbiol Immunol.2002.269: 273-318.
79. Kawanishi M., S. Tada-Oikawa, and S. Kawanishi. Epstein-Barr virus BHRF1
functions downstream of Bid cleavage and upstream of mitochondrial dysfunction to inhibit TRAIL-induced apoptosis in BJAB cells[J]. Biochem Biophys Res Commun. 2002,297(3): 682-7.
80. Kabsch, K. and A. Alonso. The human papillomavirus type 16 E5 protein impairs TRAIL- and FasL-mediated apoptosis in HaCaT cells by different mechanisms[J]. J Virol. 2002,76(23): 12162-72.
81. Wold, W.S., Doronin K, Toth K, et al., Immune responses to adenoviruses: viral evasion mechanisms and their implications for the clinic[J]. Curr Opin Immunol. 1999,11(4): 380-6.
82. Yves Chicheportiche, Paul R. Bourdon, Haoda Xu. TWEAK, a New Secreted Ligand in the Tumor Necrosis FactorFamily That Weakly Induces Apoptosis[J]. J Biological Chemistry. 1997,272(51): 32401-32410.
83. Mueller AM, Pedre X, Kleiter I,et al. Targeting fibroblast growth factor -inducible-14 signaling protects from chronic relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol. 2005 ,159(1-2):55-65.
84. Xu H, Okamoto A, Ichikawa J,et al.TWEAK/Fn14 interaction stimulates human bronchial epithelial cells to produce IL-8 and GM-CSF[J]. Biochem Biophys Res Commun. 2004 ,318(2):422-7.
85. Jakubowski A, Browning B, Lukashev M, et al. Dual role for TWEAK in angiogenic regulation[J].J Cell Sci. 2002 ,115(Pt 2):267-74.
86. Lynch CN, Wang YC, Lund JK, et al. TWEAK induces angiogenesis and proliferation of endothelial cells[J]. J Biol Chem. 1999,274 (13):8455-9.
87. Ho DH, Vu H, Brown SA, et al.Soluble tumor necrosis factor-like weak inducer of apoptosis overexpression in HEK293 cells promotes tumor growth and angiogenesis in athymic nude mice[J]. Cancer Res. 2004,64(24):8968-72.
88. Kawakita T, Shiraki K, Yamanaka Y,et al.Functional expression of TWEAK in human colonic adenocarcinoma cells[J]. Int J Oncol. 2005,26(1):87-93.
89. Kawakita T, Shiraki K, Yamanaka Y, et al.Functional expression of TWEAK in human hepatocellular carcinoma: possible implication in cell proliferation and tumor angiogenesis[J]. Biochem Biophys Res Commun. 2004,318(3):726-33.
90. Kaptein A, Jansen M, Dilaver G, et al. Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3) [J]. FEBS Lett. 2000,485(2-3):135-41.
91. Chicheportiche Y, Chicheportiche R, Sizing I, et al. Proinflammatory activity of TWEAK on human dermal fibroblasts and synoviocytes: blocking and enhancing effects of anti-TWEAK monoclonal antibodies[J]. Arthritis Res. 2002,4(2):126-33.
92. Kaplan MJ, Ray D, Mo RR, et al. TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell killing of antigen-presenting macrophages. J Immunol[J]. 2000,164(6):2897-904.
93. Polek TC, Talpaz M, Darnay BG, et al. TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor[J]. J Biol Chem. 2003 ,278(34):32317-23.
94. Masafumi Nakayama, Kazumi Ishidoh, Nobuhiko Kayagaki, Multiple Pathways
of TWEAK-Induced Cell Death[J].The Journal of Immunology. 2002, 168(2):734-743.
95. Lynch CN, Wang YC, Lund JK, Chen YW, Leal JA, Wiley SR.TWEAK induces angiogenesis and proliferation of endothelial cells[J]. J Biol Chem.1999,274(13):8455-9.
96. Kaplan MJ, Ray D, Mo RR, et al. TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell killing of antigen-presenting macrophages[J]. J Immunol, 2000,164(6):2897-2904.
97. Nakayama M, Kayagaki N, Yamaguchi N, et al. Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity [J]. J Exp Med.2000, 192(9):1373-1380.
98. Schaller H, Mason S, et al. Transcriptional control of hepadnavirus gene expression. Current Topics in Microbiology and Immunology [J]. Berlin Heidelberg Press.1991,168: 21- 40.
99. Toillais P, et al. Hepatitis B virus[J]. Scientific American. 1991,264: 48- 54.
100. Youhua Xie, Mei Li,Yuan Wang,et al, Site-specific mutation of the hepatitis B virus enhancer II Blelement: effect on virus transcription and replication. Journal of General Virology.2001, 82( Pt 3):531-535.
101. Kohno K, Nishizono A, Terao H, et al. Reduced transcription and progeny virus production of hepatitis B virus containing an 8-bp deletion in basic core promoterJ Med Virol. 2000,61(l):15-22.
102. Feigner PL, Gadek TR, Holm M,et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure[J]. Proc Natl Acad Sci USA. 1987 ,84(21):7413-7417.
103. Feigner PL, Ringold GM. Cationic liposome-mediated transfection[J]. Nature. 1989,337(6205):387-388.
104. Naoki Itano, Fukiko Atsumi, Takahiro Sawai, et al. Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration[J].PNAS. 2002, 99(6):3609-3614.
105. Makiko Umezu-Goto, Yasuhiro Kishi, Akitsu Taira, et al. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production[J]. J Cell Biol.2002,15(2), 227-233.
106. K.Yagyu, K. Kitagawa, T. Irie, et al. InagakiAmyloid 6 proteins inhibit Cl~--ATPase activity in cultured rat hippocampal neurons[J] Journal of Neurochemistry. 2001, 78(3): 569-576.
107. Jianguo Hu, Akira Igarashi, Makiko Kamata, et al. Angiotensin-converting Enzyme Degrades Alzheimer Amyloid P-Peptide (AP); Retards Aβ Aggregation, Deposition, Fibril Formation; and Inhibits Cytotoxicity [J]. J Biological Chemistry. 2001,276(51): 47863-47868.
108. Daisuke Yoshimura, Kunihiko Sakumi, Mizuki Ohno, et al. An Oxidized Purine Nucleoside Triphosphatase, MTH1, Suppresses Cell Death Caused by Oxidative Stress[J].J Biological Chemistry. 2003,278(39): 37965-37973.
109. Vermes I, Haanen C , Steffens-Nakken H, et al. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptosis cells using fluorescein labeled Annexin V[J]. J Immunol Methods. 1995,184
(1):39-42.
110. Fadok V A , Voelker D R ,Campbell P A, et al. Exposure of phosphatidyl-serine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophage[J]. J Immuol. 1992 ,148(7):2207-12.
111. Nicoletti I , Migliorati G, Pagliacci M C.A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry[J]. J Immunol Methods. 1991 ,139(2):271-274.
112. Gorczyca W, Gong J P , Darzynkiewicz Z. Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assay[J]. Cancer Res.l993,53(8):1945-50.
113. Hussein MR, Haemel AK, Wood GS. Apoptosis and melanoma: molecular mechanisms[J].J Pathol. 2003 ,199(3):275-88.
114. Fukazawa T, Fujiwara T, Uno F,et al., Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells[J]. Oncogene. 2001,20(37): 5225-31.
115. Hao C, Beguinot F, Condorelli G, et al., Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells[J]. Cancer Res.2001,61(3): 1162-70.
116. Mitsiades N, Mitsiades CS, Poulaki V, et al., Intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human multiple myeloma cells[J]. Blood.2002, 99(6): 2162-71.
117. Poulaki V, Mitsiades CS, Kotoula V, et al., Regulation of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in thyroid carcinoma cells[J]. Am J Pathol. 2002,161(2): 643-54.
118. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation[J]. Science. 1998,281(5381):1305-8.
119.Muzio M, Chinnaiyan AM, Kischkel FC, et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex[J]. Cell. 1996,85(6):817-27.
120. Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death[J]. Cell. 1996,85(6):803-15.
121. Zou H, Li Y, Liu X, Wang X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9[J]. J Biol Chem. 1999,274(17):11549-56.
122. Hirsch T , Susin SA , Marzo I , et al. Mitochondrial permeability transition in apopotosis and necrosis[J ]. Cell Biol Toxicol. 1998 ,14 (2) :141-145.
123. Bradham CA , Qian T , Streetz K, et al. The mitochondrial permeability transition is required for tumor necrosis factor alpha ,mediated apoptosis and cytochrome C release [ J ]. Mol Cell Biol.1998 ,18 (11) :6353 - 6364.
124. Cregan SP, Dawson VL, Slack RS.Role of AIF in caspase-dependent and caspase-independent cell death[J]. Oncogene. 2004,23(16):2785-96.
125. Hansen TM, Nagley P. AIF: a multifunctional cog in the life and death machine [J].Sci STKE. 2003 ,29(193):PE31.
126. Susin SA Lorenzo HK, Zamzami N , et al. Mitochondrial realease of caspase - 2 and - 9 during the apoptotic process [J]. J Exp Med .1999,189 (18) :381 - 391.
127. Twiddy D, Brown DG, Adrain C, et al.Pro-apoptotic proteins released from the mitochondria regulate the protein composition and caspase-processing activity of the native Apaf-1/caspase-9 apoptosome complex[J].J Biol Chem.2004,279(19):19665-82.
128. Stewart CL, Schuetze S, Vanek M, et al. Expression of retroviral vectors in transgenic mice obtained by embryo infection[J]. EMBO J. 1987,6(2):383-388.
129. Wagner EF, Vanek M, Vennstrom B. Transfer of genes into embryonal carcinoma cells by retrovirus infection: efficient expression from an internal promoter[J].EMBO J. 1985,4(3):663-666.
130. Wood KV, de Wet JR., Dewji N,et al. Synthesis of active firefly luciferase by in vitro translation of RNA obtained from adult lanterns[J]. Biochem Biophys Res Commun. 1984 ,124(2):592-596.
131. de Wet JR, Wood KV, Helinski DR, DeLuca M. Cloning of firefly luciferase cDNA and the expression of active luciferase in Escherichia coli[J]. Proc Natl Acad Sci U S A.1985,82(23):7870-7873.
132. Matthews JC, Hori K, Cormier MJ. Purification and properties of Renilla reniformis luciferase[J]. Biochemistry. 1977,16(1):85-91.
133. Mitsiades CS, Mitsiades N, Poulaki V, et al., Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications[J]. Oncogene. 2002, 21(37): 5673-83.
134. Bouchier-Hayes L, Conroy H, Egan H, et al., CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways[J]. J Biol Chem.2001,276(47): 44069-77.
135. Trauzold A, Wermann H, Arlt A, et al., CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-kappaB contributes to apoptosis resistance in ductal pancreatic adenocaracinom cells[J]. Oncogene. 2001,20(31): 4258-69.
136. Oya M, Ohtsubo M, Takayanagi A, et al., Constitutive activation of nuclear factor-kappaB prevents TRAIL-induced apoptosis in renal cancer cells[J]. Oncogene. 2001,20(29): 3888-96.
137. Jeremias I, Jeremias I, Kupatt C, Baumann B, et al., Inhibition of nuclear factor kappaB activation attenuates apoptosis resistance in lymphoid cells[J]. Blood. 1998, 91(12): 4624-31.
138. Clarke P, Meintzer SM, Spalding AC, et al., Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection[J]. Oncogene.2001,20(47): 6910-9.
139. Hou CS, Wang GQ, Lu SL, et al. Role of activation-induced cell death in pathogenesis of patients with chronic hepatitis B[J].World J Gastroenterol. 2003, 9(10):2356-8.
140. Boomer JS , Derks RA , Lee GW, et al. Regeneration and tolerance factor is expressed during Thymphocyte activation and plays a role in apoptosis[J].Hum Immunol. 2001, 62(6):577-88.
141. Schuchmann M, Varfolomeev EE, Hermann F, et al. Dominant negative MORT1/ FADD rescues mice from CD95 and TNF-induced liver failure. Hepatology. 2002, 37(1): 129-135.
142. Chen CJ, Makino S. Murine coronavirus-induced apoptosis in 17C121 cells involves a mitochondria2mediated pathway and its downstream caspase-8 activation and bid cleavage[J]. Virology. 2002 ,302(2) :321-332.
143. Le Blanc HN, Ashkenazi A.Apo2L/TRAIL and its death and decoy receptors[J]. Cell Death Differ. 2003 ,10(1):66-75.
144. Masafumi Nakayama, Kazumi Ishidoh, Nobuhiko Kayagaki. Multiple Pathways of TWEAK-Induced Cell Death[J].The Journal of Immunology.2002,168(2):734-43.
145. Jeremias I, C Kupatt, B Baumann, et al. Inhibition of nuclear factor κB activation attenuates apoptosis resistance in lymphoid cells[J]. Blood1998,91(12):4624-31.
146. Lichtner M, Maranon C, Vidalain PO,et al.HIV type 1-infected dendritic cells induce apoptotic death in infected and uninfected primary CD4 T lymphocytes[J]. AIDS Res Hum Retroviruses. 2004 ,20(2):175-82.