视黄酸依赖Fas/RARα融合基因表达载体构建及其诱导肿瘤细胞凋亡的研究
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摘要
肿瘤发生机制及治疗对策的研究是当今医学研究的重点，其中以诱导分化治疗、基因治疗和“启动细胞天然自杀机制------细胞凋亡”三大治疗模式尤为引人注目。视黄酸(retinoic acid,RA)是维生素A的体内活性代谢产物，具有多种生理生化功能。RA的许多生物学效应是通过其胞内核受体介导的，视黄酸核受体可分为RAR和RXR两个超家族，每个超家族都含有α、β和γ三个成员。RA与其受体的同源或异源二聚体(RXR／RXR、RAR／RXR)结合后，活化的受体能与靶基因上的视黄酸反应元件(retinoic acid response element,RARE)结合而调节下游基因表达。近年来通过体内外及临床实验研究表明，RA可抑制肿瘤细胞增殖、诱导肿瘤细胞分化和凋亡。目前全反式视黄酸(ATRA)和13顺式视黄酸(13-cRA)已用于血液肿瘤、肺癌、肾癌、黑色素细胞瘤、神经胶质细胞瘤等多种癌症的临床治疗，并取得了较好的疗效。但是，近年来发现应用RA治疗存在一定的缺点，即易复发或肿瘤患者对RA出现抵抗或耐药，推测其机理可能与视黄酸胞内核受体RAR基因易位和／或突变，以及异常融合基因的形成有关，但确切分子机制尚不清楚，因此探索克服RA耐药的方法、发挥RA疗效具有重要的临床意义。
细胞凋亡(程序性死亡)是机体生长、分化、发育和病理过程中由基因编码调控的细胞主动自杀现象，是近年来基础研究领域的热点之一，本课题拟通过直接诱导肿瘤细胞凋亡，进而对分子机制尚不清楚的RA抗性细胞进行有效治疗。
Fas抗原是细胞凋亡机制中启动凋亡的信号分子之一，亦称APO-1或CD95，是与细胞凋亡密切相关的细胞表面分子之一，其与特异性配体FasL
结合后可诱导ras（＋）细胞的“自杀”，现己证实ras诱发的细胞自杀与
其胞内 60J0个氨基酸组成的“死亡区（Death domain，DD＊’有关，Fas
与抗干as或FasL结合能引起Fas死亡区交联或聚化，启动死亡信号传导，
引发下游凋亡效应的发生。RA与其核受体 RARa的配体结合区（LBD）
作用可导致受体形成三聚体，根据这一特性推测构建含Fas抗原死亡区和
RAR LBD区的融合蛋白，外源性RA即可经KARa聚合作用启动融合蛋 一
白中 Fas介导的死亡信号。本课题中构建含Fas死亡区和RARa LBD融
合基因表达载体的同时，在融合基因上游插入RARE调控序列的启动子，
使其自身表达亦受RA调控，转导肿瘤细胞后，进而观察RA依赖细胞凋
亡效应的发生，为克服s抗性提供实验基础，并进一步分析凋亡发生的
分子机制。
本研究首先构建了含有RARE调控元件的绿色荧光蛋白（eGFP）报。
告基因表达载体，并验证了RA可调控带有KARE的eGFP表达，初步确
定了该载体模型的可应用性；进而，应用DNA重组技术构建了带有RAILE
的融合基因 Fas／RAR a表达载体中RAREIas／RAR a人 并采用 RTICR
和荧光显微镜直接观测方法证实了 pRAREFas／KAR a转染细胞后融合基
因的表达受KA精确调控；同时运用MTT试验、’－m－aEL检测、透射电镜
观测、DNA梯形带检测、流式细胞分析、RT－PCR以及蛋白免疫印迹等W
技术手段，探讨了 RA及其诱导的融合基因 Fas／RAR a表达启动的凋亡效
应及其可能的分子机制。
本课题主要研究结果如下：
1．运用DNA重组技术构建了带有3个RARE重复序列的eGFP真核
表达载体中RARE七GFP），经脂质体方法转染 HL60细胞，G4筛选稳
定表达后，分别以IX10”’mol／L、SX10”mol／L和IX10“mol／LRA处理l～
Zd，RT．PCR和荧光显微镜直接观测发现eGFP蛋白表达明显升高，撤除
RA处理因素后表达有所下降。提示RA可诱导带有RARE－TK启动子的
外源基因表达，且呈限时高效表达，推测以此为模板构建RA依赖融合基
因 Fas／RAR a表达载体是可行的。
x
二．成功构建了含有 RARE－TK启动子和报告基因 eGFP的 FasffLAR a真
核表达载体中趴REfas／RAR a人 转染HL60和MCF刀细胞，经G418
筛选阳性细胞克隆后，以不同剂量RA分别处理24、48、72小时，RT｛CR
和荧光显微镜直接观测报告基因eGFP表达，结果显示eGFP表达呈Aw
时间剂量依赖性升高，提示融合蛋白 Fas用AR a表达亦呈 RA时间剂量依
－赖性上升。说明 RA可调控的 FSS爪人R。融合基因表达载体模型构建成功。
3．p…＊as／RAR a转染和未转染的 HL60和 MCF刁细胞经 RA处理
后，经荧光显微镜观测绿色荧光蛋白（即融合蛋白）分布于细胞整体，进
一步提取细胞胞浆和胞膜蛋白组分行SDS－PAGE证实融合蛋白主要定位
于细胞膜上。
4．pRAREIas／RAR a转染和未转染的 HL60和 MCFJ细胞经 RA处理
。后，细胞生长减慢、细胞周期被阻滞在G；G。期、凋亡率增加，并可检测
到DNA梯形带，透射电镜和TUNEL法发现其形态结构呈凋亡性变，凋
亡阳性细胞率增加。其中，以融合基因转染细胞经RA处理后变化更为显
著。说明RA可经RARE调控融合基因表达诱发细胞凋亡，且该效应与RA
自身抑制增殖、促进凋亡作用相互协同。
5．
Retinoic acid (RA) plays an important role in normal cell growth and tissue development. Because of its activity on acute promyelocytic leukemia (APL) cells RA has been used for clinical differentiative therapy from 1980s. And RA can produce a high remission rate in APL patients by its anti-proliferative action and inducing differentiation. All of these functions are mediated through its specific nuclear receptors, i.e., RARs and RXRs. These activated nuclear receptors, in turn, bind to specific DNA sequences called as retinoic acid response element (RARE) that are located in the regulatory portions of genes and thus modulate gene activity. But now there are occasionally early tolerance to RA, relapse of the disease and retinoic acid syndrome which limit the application of RA during the period of RA treatment. Several studies in vitro indicated that resistance of RA therapy was closely related to RAR gene mutation or translocation which produced fusion proteins such as PML-RAR alpha or PLZF-RAR alpha, as well as up-regulation of metabolic enzyme of RA. So it is necessary to take optimal strategies to overcome the resistance to RA and decrease ill effects in clinical treatment.
Apoptosis, or programmed cell death, is essential for organogenesis during development, for proper function of the immune system. And apoptosis is also the main response of cells to chemotherapeutic agents. ATRA combined with chemotherapy can significantly induce apoptosis of malignant cells. It is a good idea to directly trigger cell apoptosis in order to overcome resistance of RA during tumor therapy. Apoptosis is a highly regulated process controlled by
IV
numerous genes that determine a proper response to death signals. The relative levels of expression of pro- and anti- apoptosis genes appear to be particularly important. Studies have demonstrated that there are two major cell-intrinsic pathways for inducing apoptosis, one that begins with ligation of cell surface death receptors and another that involves mitochondrial release of cytochrome C. The Fas antigen(APO-l/CD95) is one of the most important death receptors. Ligation of Fas by FasL or a cross-linking antibody results in receptor trimerization followed by binding of the adapter molecule FADD to the cytoplasmic domain (death domain, DD) of the Fas. Then activated FADD mediates the caspases or transcription factors and finally induces cell apoptosis. It is well known that RAR alpha has the similar character of trimerization during binding to RA. So, in this paper we constructed a novel expression vector of fusion gene Fas/RAR alpha containing RARE-TK promoter and reporter gene eGFP controlled by ATRA and observed the effect of apoptosis initiated by fusion protein Fas/RAR alpha after transfection to HL-60 and MCF-7 malignant cells.
At present gene therapy targeted at tumor suppressor genes, oncogenes, or central signaling molecules, as well as "suicide gene" is reported in several studies in vivo and in vitro. And cancer has become by far the most important indication for gene therapy in clinical trials. Exogenous fusion gene-Fas/RAR alpha dependent on RA maybe significantly cause apoptosis of tumor cells which have low Fas expression. Application of fusion gene is one kind of important gene therapy methods. It is a key to construct an optimal expression vector of fusion gene and must follow these rules: 1) all of cDNA fragments of fusion gene in the same open-reading frame; 2) active sites of each cDNA independent and respective; 3) a high-copy expression vector or plasmid. The reporter gene enhanced green fluorescent protein (eGFP) has an extensive
application of location and trace of novel gene or protein. In this research eGFP
v
can trace the Fas/RAR alpha fusion protein and directly reflect changes of fusion protein.
In order to verify the model of expression vector induced by RA, at first we constructed a vector engineered to incorporate eGFP under the RARE-TK promoter in this paper. Results showed that the reporter gene was up-regulated induce
细胞凋亡(程序性死亡)是机体生长、分化、发育和病理过程中由基因编码调控的细胞主动自杀现象，是近年来基础研究领域的热点之一，本课题拟通过直接诱导肿瘤细胞凋亡，进而对分子机制尚不清楚的RA抗性细胞进行有效治疗。
Fas抗原是细胞凋亡机制中启动凋亡的信号分子之一，亦称APO-1或CD95，是与细胞凋亡密切相关的细胞表面分子之一，其与特异性配体FasL
结合后可诱导ras（＋）细胞的“自杀”，现己证实ras诱发的细胞自杀与
其胞内 60J0个氨基酸组成的“死亡区（Death domain，DD＊’有关，Fas
与抗干as或FasL结合能引起Fas死亡区交联或聚化，启动死亡信号传导，
引发下游凋亡效应的发生。RA与其核受体 RARa的配体结合区（LBD）
作用可导致受体形成三聚体，根据这一特性推测构建含Fas抗原死亡区和
RAR LBD区的融合蛋白，外源性RA即可经KARa聚合作用启动融合蛋 一
白中 Fas介导的死亡信号。本课题中构建含Fas死亡区和RARa LBD融
合基因表达载体的同时，在融合基因上游插入RARE调控序列的启动子，
使其自身表达亦受RA调控，转导肿瘤细胞后，进而观察RA依赖细胞凋
亡效应的发生，为克服s抗性提供实验基础，并进一步分析凋亡发生的
分子机制。
本研究首先构建了含有RARE调控元件的绿色荧光蛋白（eGFP）报。
告基因表达载体，并验证了RA可调控带有KARE的eGFP表达，初步确
定了该载体模型的可应用性；进而，应用DNA重组技术构建了带有RAILE
的融合基因 Fas／RAR a表达载体中RAREIas／RAR a人 并采用 RTICR
和荧光显微镜直接观测方法证实了 pRAREFas／KAR a转染细胞后融合基
因的表达受KA精确调控；同时运用MTT试验、’－m－aEL检测、透射电镜
观测、DNA梯形带检测、流式细胞分析、RT－PCR以及蛋白免疫印迹等W
技术手段，探讨了 RA及其诱导的融合基因 Fas／RAR a表达启动的凋亡效
应及其可能的分子机制。
本课题主要研究结果如下：
1．运用DNA重组技术构建了带有3个RARE重复序列的eGFP真核
表达载体中RARE七GFP），经脂质体方法转染 HL60细胞，G4筛选稳
定表达后，分别以IX10”’mol／L、SX10”mol／L和IX10“mol／LRA处理l～
Zd，RT．PCR和荧光显微镜直接观测发现eGFP蛋白表达明显升高，撤除
RA处理因素后表达有所下降。提示RA可诱导带有RARE－TK启动子的
外源基因表达，且呈限时高效表达，推测以此为模板构建RA依赖融合基
因 Fas／RAR a表达载体是可行的。
x
二．成功构建了含有 RARE－TK启动子和报告基因 eGFP的 FasffLAR a真
核表达载体中趴REfas／RAR a人 转染HL60和MCF刀细胞，经G418
筛选阳性细胞克隆后，以不同剂量RA分别处理24、48、72小时，RT｛CR
和荧光显微镜直接观测报告基因eGFP表达，结果显示eGFP表达呈Aw
时间剂量依赖性升高，提示融合蛋白 Fas用AR a表达亦呈 RA时间剂量依
－赖性上升。说明 RA可调控的 FSS爪人R。融合基因表达载体模型构建成功。
3．p…＊as／RAR a转染和未转染的 HL60和 MCF刁细胞经 RA处理
后，经荧光显微镜观测绿色荧光蛋白（即融合蛋白）分布于细胞整体，进
一步提取细胞胞浆和胞膜蛋白组分行SDS－PAGE证实融合蛋白主要定位
于细胞膜上。
4．pRAREIas／RAR a转染和未转染的 HL60和 MCFJ细胞经 RA处理
。后，细胞生长减慢、细胞周期被阻滞在G；G。期、凋亡率增加，并可检测
到DNA梯形带，透射电镜和TUNEL法发现其形态结构呈凋亡性变，凋
亡阳性细胞率增加。其中，以融合基因转染细胞经RA处理后变化更为显
著。说明RA可经RARE调控融合基因表达诱发细胞凋亡，且该效应与RA
自身抑制增殖、促进凋亡作用相互协同。
5．
Retinoic acid (RA) plays an important role in normal cell growth and tissue development. Because of its activity on acute promyelocytic leukemia (APL) cells RA has been used for clinical differentiative therapy from 1980s. And RA can produce a high remission rate in APL patients by its anti-proliferative action and inducing differentiation. All of these functions are mediated through its specific nuclear receptors, i.e., RARs and RXRs. These activated nuclear receptors, in turn, bind to specific DNA sequences called as retinoic acid response element (RARE) that are located in the regulatory portions of genes and thus modulate gene activity. But now there are occasionally early tolerance to RA, relapse of the disease and retinoic acid syndrome which limit the application of RA during the period of RA treatment. Several studies in vitro indicated that resistance of RA therapy was closely related to RAR gene mutation or translocation which produced fusion proteins such as PML-RAR alpha or PLZF-RAR alpha, as well as up-regulation of metabolic enzyme of RA. So it is necessary to take optimal strategies to overcome the resistance to RA and decrease ill effects in clinical treatment.
Apoptosis, or programmed cell death, is essential for organogenesis during development, for proper function of the immune system. And apoptosis is also the main response of cells to chemotherapeutic agents. ATRA combined with chemotherapy can significantly induce apoptosis of malignant cells. It is a good idea to directly trigger cell apoptosis in order to overcome resistance of RA during tumor therapy. Apoptosis is a highly regulated process controlled by
IV
numerous genes that determine a proper response to death signals. The relative levels of expression of pro- and anti- apoptosis genes appear to be particularly important. Studies have demonstrated that there are two major cell-intrinsic pathways for inducing apoptosis, one that begins with ligation of cell surface death receptors and another that involves mitochondrial release of cytochrome C. The Fas antigen(APO-l/CD95) is one of the most important death receptors. Ligation of Fas by FasL or a cross-linking antibody results in receptor trimerization followed by binding of the adapter molecule FADD to the cytoplasmic domain (death domain, DD) of the Fas. Then activated FADD mediates the caspases or transcription factors and finally induces cell apoptosis. It is well known that RAR alpha has the similar character of trimerization during binding to RA. So, in this paper we constructed a novel expression vector of fusion gene Fas/RAR alpha containing RARE-TK promoter and reporter gene eGFP controlled by ATRA and observed the effect of apoptosis initiated by fusion protein Fas/RAR alpha after transfection to HL-60 and MCF-7 malignant cells.
At present gene therapy targeted at tumor suppressor genes, oncogenes, or central signaling molecules, as well as "suicide gene" is reported in several studies in vivo and in vitro. And cancer has become by far the most important indication for gene therapy in clinical trials. Exogenous fusion gene-Fas/RAR alpha dependent on RA maybe significantly cause apoptosis of tumor cells which have low Fas expression. Application of fusion gene is one kind of important gene therapy methods. It is a key to construct an optimal expression vector of fusion gene and must follow these rules: 1) all of cDNA fragments of fusion gene in the same open-reading frame; 2) active sites of each cDNA independent and respective; 3) a high-copy expression vector or plasmid. The reporter gene enhanced green fluorescent protein (eGFP) has an extensive
application of location and trace of novel gene or protein. In this research eGFP
v
can trace the Fas/RAR alpha fusion protein and directly reflect changes of fusion protein.
In order to verify the model of expression vector induced by RA, at first we constructed a vector engineered to incorporate eGFP under the RARE-TK promoter in this paper. Results showed that the reporter gene was up-regulated induce
引文
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29.Hoque AT,Liu X,Kagami H,et al. Construction and function of a recombinant adenovirus encoding a human aquaporin 1-green fluorescent protein fusion product.Cancer Gene Ther. 2000 ;7(3):476-85
30.Costa-Giomi MP,Gaub MP,Chambon P,et al.Characterization of a retinoic acid responsive element isolated by whole genome PCR. Nucleic Acids Res. 1992;20(12):3223-32
31.Chelbi-Alix MK,Pelicano L. Retinoic acid and interferon signaling cross talk in normal and RA-resistant APL cells. Leukemia. 1999;13(8):1167-1174
32.Stephanou A, Sarlis NJ, Richards R, Expression of retinoic acid receptor subtypes and cellular retinoic acid binding protein-II mRNAs during differentiation of human trophoblast cells. Biochem Biophys Res Commun. 1994 ;202(2):772-80
33.Doerksen LF, Bhattacharya A, Kannan P,Functional interaction between a RARE and an AP-2 binding site in the regulation of the human HOX A4 gene promoter. Nucleic Acids Res. 1996 ;24(14):2849-56
34.Miquel C, Clusel C, Semat A,et al. Retinoic acid receptor isoform RAR gamma 1:an antagonist of the transactivation of the PAR beta PARE in epithelial cell lines and normal human keratinocytes. Mol Biol Rep.1992;17(1):35-45
35.Itoh N, Yonehara S, Ishii A, et al.The polypeptide encoded by the cDNA for human cell surface antigen fas can mediate apoptosis. Cell 1991; 66: 233-243
36.Bulens F,Ibanez-Tallon I, Van Acker P,et al.Retinoic acid induction of human tissue-type plasminogen activator gene expression via a direct
repeat element (DR5) located at-7 kilobases.J Biol Chem.1995;270(13):7167-75
37.Didenko VV,Ngo HN, Minchew C,Apoptosis of T lymphocytes invading glioblastomas multiforme:a possible tumor defense mechanism.J Neurosurg 2002;96(3):580-4
38.Haisma HJ,Grill J,Curiel DT,et al.Targeting of adenoviral vectors through a bispecific single-chain antibody.Cancer Gene Ther. 2000;7(6):901-4
39.Izquierdo JM,Cuezva JM.Internal-ribosome-entry-site functional activity of the 3'-untranslated region of the mRNA for the beta subunit of mitochondrial H+-ATP synthase.Biochem J. 2000;346 Pt 3:849-55
40.Paquin A,Jaalouk DE,Galipeau J.et al.Retrovector encoding a green fluorescent protein-herpes simplex virus thymidine kinase fusion protein serves as a versatile suicide/reporter for cell and gene therapy applications.Hum Gene Ther 2001;12(1):13-23
41.Jansen JH, Lowenberg B.Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein.Semin Hematol 2001 ;38(1):37-41
42.Lode HN, Reisfeld RA.Targeted cytokines for cancer immunotherapy.Immunol Res.2000;21 (2-3):279-88
43.Xiang J.Antitumor vaccination with gene-transduced tumor cells expressing a fusion protein RM4/IFN-tau.Cancer Biother Radiopharm.1997;12(2):123-30
44.Prud'homme G J, Chang Y.Prevention of autoimmune diabetes by intramuscular gene therapy with a nonviral vector encoding an interferon-gamma receptor/IgG1 fusion protein.Gene Ther. 1999;6(5):771-7
45.Ashkenazi A, Dixit VM. Death receptors: signaling and modulation.Science.1998;281:1305-8
46.Liu J,Guo L,Jun-Wei L,et al.All-trans retinoic acid modulates fas
expression and enhances chemosensitivity of human medulloblastoma cells.Int J Mol Med. 2000;5(2):145-9
47. Stennicke HR,J(?)rgensmeier JM,Shin H,et al.Pro-caspase-3 is a major physiologic target of caspase-8.J Biol Chem.1998; 273(42): 27084-27090
48. Zheng TS, Hunot S, Kuida K,et al. Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation.Nat Med. 2000;6(11):1241-7
49. Gianni M, Ponzanelli I, Mologni L,et al. Retinoid-dependent growth inhibition,differentiation and apoptosis in acute promyelocytic leukemia cells.Expression and activation of caspases.Cell Death Differ.2000;7(5):447-60
50．陈军松，柴敏强，宋建国。佛波酯对A-549细胞株中蛋白激酶C的调节。生物化学与生物物理学报2000；32(6)：645-648
51. Murphy S J, Chong H, Bell S,et al. Novel integrating adenoviral/retroviral hybrid vector for gene therapy. Hum Gene Ther.2002;13(6):745-60
52. Arrington J, Braun RP, Dong L, et al.Plasmid Vectors Encoding Cholera Toxin or the Heat-Labile Enterotoxin from Escherichia coli Are Strong Adjuvants for DNA Vaccines.J Virol. 2002;76(9):4536-46
53. Kobayashi T, Ruan S, Clodi K,et al.Overexpression of Bax gene sensitizes K562 erythroleukemia cells to apoptosis induced by selective chemotherapeutic agents. Oncogene. 1998; 16(12): 1587-91
54. Koch B,Jensen LE, Nybroe O.A panel of Tn7-based vectors for insertion of the gfp marker gene or for delivery of cloned DNA into Gram-negative bacteria at a neutral chromosomal site.J Microbiol Methods. 2001 ;45(3):187-95
55. Wolter KG, Hsu YT, Smith CL,et al. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol. 1997; 139(5): 1281-92
56. Mahajan NP,Linder K,Berry G,et al. Bcl-2 and Bax interactions in mitochondria probed with green fluorescent protein and fluorescence
resonance energy transfer.Nat Biotechnol.1998;16(6):547-52
57. Chatterjee M, Wu S. Involvement of Fas receptor and not tumor necrosis factor-alpha receptor in ultraviolet-induced activation of acid sphingomyelinase.Mol Carcinog 2001;30(1):47-55
58. 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.Cell.1996;85(6):817-27
59．熊世勤，朱锡华，黄云辉。一种快速分离细胞凋亡片段化DNA的简单方法——NP-40法。免疫学杂志，2000；16(3)：228-31
60. Horiuchi T, Himeji D, Tsukamoto H, et al. Dominant expression of a novel splice variant of caspase-8 in human peripheral blood lymphocytes.Biochem Biophys Res Commun 2000; 272(3):877-881
61．陈汉春，罗志勇，罗赛群等。Hu联合GM-CSF对K562细胞生长凋亡相关基因表达的影响。癌症2000；19(7)：627-630
62. Donoghue S, Baden HS, Lauder I,et al.Immunohistochemical locali-zation of caspase-3 correlates with clinical outcome in B-cell diffuse large-cell lymphoma.Cancer Res.1999;59(20):5386-91
63. Brustmann H.Apoptotic bodies as a morphological feature in serous ovarian carcinoma:correlation with nuclear grade,Ki-67 and mitotic indices.Pathol Res Pract. 2002; 198(2):85-90
64. Yen A, Placanica L, Bloom S, et al. Polyomavirus small t antigen prevents retinoic acid-induced retinoblastoma protein hypophosphorylation and redirects retinoic acid-induced GO arrest and differentiation to apoptosis.J Virol 2001;75(11):5302-14
65. Castleberry RP,Emanuel PD,Zuckerman KS,et al. A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N Engl J Med. 1994;331(25):1680-4
66. Cheng AL,Su I J,Chen CC, et al.Use of retinoic acids in the treatment of
peripheral T-cell lymphoma: a pilot study. J Clin Oncol. 1994; 12(6): 1185-92
67.Buer J,Probst M,Duensing S, et al. Clinical and in vitro response to 13-cis-retinoie acid in interferon-alpha resistant renal cell carcinoma. Cancer Biother Radiopharm.1997; 12(3): 143-7
68.Russo D, Marin L, Bertone A,et al. Pilot study of combined therapy with interferon-alpha,arabinosyl cytosine and all-trans retinoic acid in patients with chronic myeloid leukemia in the chronic phase.Haematologiea.1999;84(2):185-7
69.Guo W,Wang H,Zhao W,et al.Effect of all-trans retinoic acid and arsenic trioxide on tissue factor expression in acute promyeloeytie leukemia cells.Chin Med J (Engl). 2001 ;114(1):30-4
70.Lallemand-Breitenbach V, Zhu J,Puvion F,et al.Role of promyelocytie leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment,and As203-induced PML or PML/retinoic acid receptor alpha degradation.J Exp Med. 2001; 193 (12): 1361-71
71.Muschen M, Warskulat U, Schmidt B, et al. Regulation of CD95 (Apo-1/Fas) ligand and receptor expression in human embryonal carcinoma cells by interferon gamma and all-trans retinoic acid. Biol Chem. 1998;379(8-9):1083-91
72.Kim KM,Lee K,Hong YS,Fas-mediated apoptosis and expression of related genes in human malignant hematopoietic cells. Exp Mol Med 2000;32(4):246-54
73.He W, Zhao Y, Song F,et al. Factors influencing the expression of Fas and Fas ligand on newborn murine keratinocytes and fibroblasts. Chin Med J (Engl) 2000; 113(9):833-5
74.Nevala H, Karenko L, Vakeva L, Proapoptotic and antiapoptotic markers in cutaneous T-cell lymphoma skin infiltrates and lymphomatoid papulosis.
Br J Dermatol. 2001; 145(6):928-37
75.Milner AE, Palmer DH, Hodgkin EA,et al. Induction of apoptosis by chemotherapeutic drugs: the role of FADD in activation of caspase-8 and synergy with death receptor ligands in ovarian carcinoma cells. Cell Death Differ. 2002;9(3):287-300
76.Jin K, Graham SH, Mao X, et al. Fas (CD95) may mediate delayed cell death in hippocampal CA1 sector after global cerebral ischemia.J Cereb Blood Flow Metab.2001;21 (12):1411-21
77.Van de Craen M,Vandenabeele P,Declercq W,et al. Characterization of seven murine caspase family members. FEBS Lett.1997;403 (1):61-9
78.Yuan J, Shaham S, Ledoux S,et al.The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme.Cell.1993;75(4):641-52
79.Zhu XF, Liu ZC, Xie BF,et al. Involvement of caspase-3 activation in squamocin-induced apoptosis in leukemia cell line HL-60. Life Sci 2002;70(11):1259-69
80.Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases.J Biol Chem.1999;274(29):20049-52
81.Wang J, Charboneau R, Balasubramanian S,Morphine modulates lymph node-derived T lymphocyte function:role of caspase-3,-8,and nitric oxide.J Leukoc Biol. 2001;70(4):527-36
82.Alas S,Ng CP,Bonavida B.Rituximab Modifies the Cisplatin-mitochondrial Signaling Pathway, Resulting in Apoptosis in Cisplatin- resistant Non-Hodgkin's Lymphoma. Clin Cancer Res 2002;8(3):836-45
83.Gianni M, Ponzanelli I, Mologni L,et al. Retinoid-dependent growth inhibition,differentiation and apoptosis in acute promyelocytic leukemia cells.Expression and activation of caspases.Cell Death Differ.2000;7(5):447-60
84.Oda E, Ohki R,Murasawa H,et al.Noxa,a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science.2000;288(5468):1053-8
85.Korsmeyer S J, Wei MC, Saito M, et al. Pro-apoptotic cascade activates BID,which oligomerizes BAK or BAX into pores that result in the release of cytochrome c.Cell Death Differ.2000;7(12): 1166-1173
86.Ararat WO,Gomez-Navarro J,Xiang J,et al.An adenovirus encoding proapoptotic Bax induces apoptosis and enhances the radiation effect in human ovarian cancer. Mol Ther.2000; 1(6):545-54
87.Lee WR, Shen SC, Lin HY, et al. Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease.Biochem Pharmacol.2002;63(2):225-36
2.Lotan R. Retinoids in cancer chemoprevention. FASEB J. 1996;10:1031-1039
3.Liu M,Lavarone A,Freedman LP.Transcriptional activation of the p21(WAF/CIP1) gene by retinoic acid receptor:Correlation with retinoid induction of U937 cell differentiation. J Biol Chem. 1996;271 (49):31723-31728
4.De Luca LM. Retinoids and their receptors in differentiation,embryogenesis,and neoplasia.FASEB J.1991;5(14):2924-33
5.Evans TR, Kaye SB.Retinoids: present role and future potential.Br J Cancel 1999;80(1-2):1-8
6.Chomienne C,Fenaux P,Degos L.Retinoid differentiation therapy in promyelocytic leukemia.FASEB J.1996;10(9):1025-30
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8.Kizaki M, Ueno H, Matsushita H, et al. Retinoid resistance in leukemic cells. Leuk Lymphoma. 1997;25(5-6):427-34
9.Lin CP, Huang MJ,Chang IY,et al.Successful treatment of all-trans retinoic acid resistant and chemotherapy naive acute promyelocytic patients with arsenic trioxide--two case reports.Leuk Lymphoma.2000;38(1-2): 191-4
10.Lengfelder E, Reichert A, Schoch C, et al. Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid:
effects in patients with newly diagnosed acute promyelocytic leukemia.German AML Cooperative Group.Leukemia 2000; 14(8): 1362-70
11.MacLean G, Abu-Abed S,Dolle P,et al.Cloning of a novel retinoic-acid metabolizing cytochrome P450, Cyp26B1, and comparative expression analysis with Cyp26A1 during early murine development. Mech Dev.2001; 107(1-2):195-201
12.Sheard MA.Ionizing radiation as a response-enhancing agent for CD95-mediated apoptosis, Int J Cancer 2001;96(4):213-20
13.Perlman H,Pagliari L J, Nguyen N, et al. The Fas-FasL death receptor and PI3K pathways independently regulate monocyte homeostasis.Eur J Immunol 2001;31 (8):2421-30
14.Mori S,Murakami-Mori K,Nakamura S,et al. Actinomycin D-mediated sensitization of AIDS-Kaposi's sarcoma cells to Fas-mediated apoptosis:Involvement of the mitochondrion-dependent pathway.Iht J Oncol 2002;20(4):819-26
15.Imanishi T,Han DK,Hofstra L,et al.Apoptosis of vascular smooth muscle cells is induced by Fas ligand derived from monocytes/macrophage.Atherosclerosis 2002; 161 (1):143-51
16.Luo X, Budihardjo I, Zou H,et al. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell.1998;94(4):481-90
17.McIlroy D,Tanaka M,Sakahira H,et al.An auxiliary mode of apoptotic DNA fragmentation provided by phagocytes. Genes Dev. 2000;14(5):549-58
18.Naka K,Yokozaki H, Domen T,Growth inhibition of cultured human gastric cancer cells by 9-cis-retinoic acid with induction of cdk inhibitor Wall/Cip 1/Sdi 1/p21 protein. Differentiation.1997;61 (5):313-20.
19.Doyle BT, O'Neill AJ, et al. The loss of IAP expression during HL-60 cell
differentiation is caspase-independent.Newsholme P,J Leukoc Biol 2002;71(2):247-254
20.Pettersson F,Colston KW,Dalgleish AG.Retinoic acid enhances the cytotoxic effects of gemcitabine and cisplatin in pancreatic adenocarcinoma cells.Pancreas 2001;23(3):273-9
21.Rozenfeld-Granot G,Toren A,et al. Mutation analysis of the FAS and TNFR apoptotic cascade genes in hematological malignancies.Exp Hematol 2001;29(2):228-33
22.Robertson KA,Emami B,Mueller L,et al.Multiple members of the retinoic acid receptor family are capable of mediating the granulocytic differentiation of HL-60 cells. Mol Cell Biol 1992; 12(9):3743-9
23.Stagno F,Guglielmo P, Consoli U,In vitro apoptotic response of freshly isolated chronic myeloid leukemia cells to all-trans retinoic acid and cytosine arabinoside.Acta Haematol.2000;104(2-3):57-64.
24.Arrington J,Braun RP, Dong L, et al.Plasmid Vectors Encoding Cholera Toxin or the Heat-Labile Enterotoxin from Escherichia coli Are Strong Adjuvants for DNA Vaccines. J Virol.2002;76(9):4536-46
25.Leong MK, Wong KK, Leung CK,et al.Successful pregnancy in a case of azoospermic infertility by using testicular sperm for intracytoplasmic injection into the oocyte. Hong Kong Med J. 1999;5(1):69-71
26.Ashley WW Jr,Russell BTenotomy decreases reporter protein synthesis via the 3'-untranslated region of the beta-myosin heavy chain mRNA. Am J Physiol Cell Physiol. 2000;279(1):C257-65
27.Baust C,Redpath L,Schwarz E. Different ligand responsiveness of human retinoic-acid-receptor beta-gene transcription in tumorigenic and non-tumorigenic cervical-carcinoma-derived cell lines is mediated through a large retinoic-acid-response domain.Int J Cancer. 1996;67(3):409-16
28.Cinelli RA,Ferrari A,Pellegrini V,et al.The enhanced green fluorescent
protein as a tool for the analysis of protein dynamics and localization: local fluorescence study at the single-molecule level.Photochem Photobiol 2000 ;71(6):771-6
29.Hoque AT,Liu X,Kagami H,et al. Construction and function of a recombinant adenovirus encoding a human aquaporin 1-green fluorescent protein fusion product.Cancer Gene Ther. 2000 ;7(3):476-85
30.Costa-Giomi MP,Gaub MP,Chambon P,et al.Characterization of a retinoic acid responsive element isolated by whole genome PCR. Nucleic Acids Res. 1992;20(12):3223-32
31.Chelbi-Alix MK,Pelicano L. Retinoic acid and interferon signaling cross talk in normal and RA-resistant APL cells. Leukemia. 1999;13(8):1167-1174
32.Stephanou A, Sarlis NJ, Richards R, Expression of retinoic acid receptor subtypes and cellular retinoic acid binding protein-II mRNAs during differentiation of human trophoblast cells. Biochem Biophys Res Commun. 1994 ;202(2):772-80
33.Doerksen LF, Bhattacharya A, Kannan P,Functional interaction between a RARE and an AP-2 binding site in the regulation of the human HOX A4 gene promoter. Nucleic Acids Res. 1996 ;24(14):2849-56
34.Miquel C, Clusel C, Semat A,et al. Retinoic acid receptor isoform RAR gamma 1:an antagonist of the transactivation of the PAR beta PARE in epithelial cell lines and normal human keratinocytes. Mol Biol Rep.1992;17(1):35-45
35.Itoh N, Yonehara S, Ishii A, et al.The polypeptide encoded by the cDNA for human cell surface antigen fas can mediate apoptosis. Cell 1991; 66: 233-243
36.Bulens F,Ibanez-Tallon I, Van Acker P,et al.Retinoic acid induction of human tissue-type plasminogen activator gene expression via a direct
repeat element (DR5) located at-7 kilobases.J Biol Chem.1995;270(13):7167-75
37.Didenko VV,Ngo HN, Minchew C,Apoptosis of T lymphocytes invading glioblastomas multiforme:a possible tumor defense mechanism.J Neurosurg 2002;96(3):580-4
38.Haisma HJ,Grill J,Curiel DT,et al.Targeting of adenoviral vectors through a bispecific single-chain antibody.Cancer Gene Ther. 2000;7(6):901-4
39.Izquierdo JM,Cuezva JM.Internal-ribosome-entry-site functional activity of the 3'-untranslated region of the mRNA for the beta subunit of mitochondrial H+-ATP synthase.Biochem J. 2000;346 Pt 3:849-55
40.Paquin A,Jaalouk DE,Galipeau J.et al.Retrovector encoding a green fluorescent protein-herpes simplex virus thymidine kinase fusion protein serves as a versatile suicide/reporter for cell and gene therapy applications.Hum Gene Ther 2001;12(1):13-23
41.Jansen JH, Lowenberg B.Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein.Semin Hematol 2001 ;38(1):37-41
42.Lode HN, Reisfeld RA.Targeted cytokines for cancer immunotherapy.Immunol Res.2000;21 (2-3):279-88
43.Xiang J.Antitumor vaccination with gene-transduced tumor cells expressing a fusion protein RM4/IFN-tau.Cancer Biother Radiopharm.1997;12(2):123-30
44.Prud'homme G J, Chang Y.Prevention of autoimmune diabetes by intramuscular gene therapy with a nonviral vector encoding an interferon-gamma receptor/IgG1 fusion protein.Gene Ther. 1999;6(5):771-7
45.Ashkenazi A, Dixit VM. Death receptors: signaling and modulation.Science.1998;281:1305-8
46.Liu J,Guo L,Jun-Wei L,et al.All-trans retinoic acid modulates fas
expression and enhances chemosensitivity of human medulloblastoma cells.Int J Mol Med. 2000;5(2):145-9
47. Stennicke HR,J(?)rgensmeier JM,Shin H,et al.Pro-caspase-3 is a major physiologic target of caspase-8.J Biol Chem.1998; 273(42): 27084-27090
48. Zheng TS, Hunot S, Kuida K,et al. Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation.Nat Med. 2000;6(11):1241-7
49. Gianni M, Ponzanelli I, Mologni L,et al. Retinoid-dependent growth inhibition,differentiation and apoptosis in acute promyelocytic leukemia cells.Expression and activation of caspases.Cell Death Differ.2000;7(5):447-60
50．陈军松，柴敏强，宋建国。佛波酯对A-549细胞株中蛋白激酶C的调节。生物化学与生物物理学报2000；32(6)：645-648
51. Murphy S J, Chong H, Bell S,et al. Novel integrating adenoviral/retroviral hybrid vector for gene therapy. Hum Gene Ther.2002;13(6):745-60
52. Arrington J, Braun RP, Dong L, et al.Plasmid Vectors Encoding Cholera Toxin or the Heat-Labile Enterotoxin from Escherichia coli Are Strong Adjuvants for DNA Vaccines.J Virol. 2002;76(9):4536-46
53. Kobayashi T, Ruan S, Clodi K,et al.Overexpression of Bax gene sensitizes K562 erythroleukemia cells to apoptosis induced by selective chemotherapeutic agents. Oncogene. 1998; 16(12): 1587-91
54. Koch B,Jensen LE, Nybroe O.A panel of Tn7-based vectors for insertion of the gfp marker gene or for delivery of cloned DNA into Gram-negative bacteria at a neutral chromosomal site.J Microbiol Methods. 2001 ;45(3):187-95
55. Wolter KG, Hsu YT, Smith CL,et al. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol. 1997; 139(5): 1281-92
56. Mahajan NP,Linder K,Berry G,et al. Bcl-2 and Bax interactions in mitochondria probed with green fluorescent protein and fluorescence
resonance energy transfer.Nat Biotechnol.1998;16(6):547-52
57. Chatterjee M, Wu S. Involvement of Fas receptor and not tumor necrosis factor-alpha receptor in ultraviolet-induced activation of acid sphingomyelinase.Mol Carcinog 2001;30(1):47-55
58. 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.Cell.1996;85(6):817-27
59．熊世勤，朱锡华，黄云辉。一种快速分离细胞凋亡片段化DNA的简单方法——NP-40法。免疫学杂志，2000；16(3)：228-31
60. Horiuchi T, Himeji D, Tsukamoto H, et al. Dominant expression of a novel splice variant of caspase-8 in human peripheral blood lymphocytes.Biochem Biophys Res Commun 2000; 272(3):877-881
61．陈汉春，罗志勇，罗赛群等。Hu联合GM-CSF对K562细胞生长凋亡相关基因表达的影响。癌症2000；19(7)：627-630
62. Donoghue S, Baden HS, Lauder I,et al.Immunohistochemical locali-zation of caspase-3 correlates with clinical outcome in B-cell diffuse large-cell lymphoma.Cancer Res.1999;59(20):5386-91
63. Brustmann H.Apoptotic bodies as a morphological feature in serous ovarian carcinoma:correlation with nuclear grade,Ki-67 and mitotic indices.Pathol Res Pract. 2002; 198(2):85-90
64. Yen A, Placanica L, Bloom S, et al. Polyomavirus small t antigen prevents retinoic acid-induced retinoblastoma protein hypophosphorylation and redirects retinoic acid-induced GO arrest and differentiation to apoptosis.J Virol 2001;75(11):5302-14
65. Castleberry RP,Emanuel PD,Zuckerman KS,et al. A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N Engl J Med. 1994;331(25):1680-4
66. Cheng AL,Su I J,Chen CC, et al.Use of retinoic acids in the treatment of
peripheral T-cell lymphoma: a pilot study. J Clin Oncol. 1994; 12(6): 1185-92
67.Buer J,Probst M,Duensing S, et al. Clinical and in vitro response to 13-cis-retinoie acid in interferon-alpha resistant renal cell carcinoma. Cancer Biother Radiopharm.1997; 12(3): 143-7
68.Russo D, Marin L, Bertone A,et al. Pilot study of combined therapy with interferon-alpha,arabinosyl cytosine and all-trans retinoic acid in patients with chronic myeloid leukemia in the chronic phase.Haematologiea.1999;84(2):185-7
69.Guo W,Wang H,Zhao W,et al.Effect of all-trans retinoic acid and arsenic trioxide on tissue factor expression in acute promyeloeytie leukemia cells.Chin Med J (Engl). 2001 ;114(1):30-4
70.Lallemand-Breitenbach V, Zhu J,Puvion F,et al.Role of promyelocytie leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment,and As203-induced PML or PML/retinoic acid receptor alpha degradation.J Exp Med. 2001; 193 (12): 1361-71
71.Muschen M, Warskulat U, Schmidt B, et al. Regulation of CD95 (Apo-1/Fas) ligand and receptor expression in human embryonal carcinoma cells by interferon gamma and all-trans retinoic acid. Biol Chem. 1998;379(8-9):1083-91
72.Kim KM,Lee K,Hong YS,Fas-mediated apoptosis and expression of related genes in human malignant hematopoietic cells. Exp Mol Med 2000;32(4):246-54
73.He W, Zhao Y, Song F,et al. Factors influencing the expression of Fas and Fas ligand on newborn murine keratinocytes and fibroblasts. Chin Med J (Engl) 2000; 113(9):833-5
74.Nevala H, Karenko L, Vakeva L, Proapoptotic and antiapoptotic markers in cutaneous T-cell lymphoma skin infiltrates and lymphomatoid papulosis.
Br J Dermatol. 2001; 145(6):928-37
75.Milner AE, Palmer DH, Hodgkin EA,et al. Induction of apoptosis by chemotherapeutic drugs: the role of FADD in activation of caspase-8 and synergy with death receptor ligands in ovarian carcinoma cells. Cell Death Differ. 2002;9(3):287-300
76.Jin K, Graham SH, Mao X, et al. Fas (CD95) may mediate delayed cell death in hippocampal CA1 sector after global cerebral ischemia.J Cereb Blood Flow Metab.2001;21 (12):1411-21
77.Van de Craen M,Vandenabeele P,Declercq W,et al. Characterization of seven murine caspase family members. FEBS Lett.1997;403 (1):61-9
78.Yuan J, Shaham S, Ledoux S,et al.The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme.Cell.1993;75(4):641-52
79.Zhu XF, Liu ZC, Xie BF,et al. Involvement of caspase-3 activation in squamocin-induced apoptosis in leukemia cell line HL-60. Life Sci 2002;70(11):1259-69
80.Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases.J Biol Chem.1999;274(29):20049-52
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