CN100338219C - 成视网膜细胞瘤蛋白的组织特异性表达 - Google Patents
成视网膜细胞瘤蛋白的组织特异性表达 Download PDFInfo
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Abstract
提供了转录因子E2F和成视网膜细胞瘤蛋白RB的融合体以及治疗高增殖性疾病的方法。
Description
发明背景
成视网膜细胞瘤基因(RB)和转录因子E2F在细胞生长控制中都具有关键作用(可参见Adams,P.和Kaelin,W.
Seminars in Cancer Biology6:99-108(1995)的综述)。在各种人类肿瘤细胞中,RB基因座常常被失活。将野生型RB基因(如Bookstein等人,
Science 247:712-715(1990))或野生型RB蛋白(pRB)(如Antelman等人,
Oncogene 10:697-704(1995))再引入RB阴性/RB突变细胞可以抑制这些细胞在培养过程中的生长以及这些细胞的体内肿瘤发生能力。
E2F的作用是激活S期基因的转录,而RB抑制它的活性。RB通过阻断从G期进入S期的出口而使细胞生长停滞(例如,Dowdy等人,
Cell73:499-511(1993)),但其阻滞作用(arrest)的准确途径还是不清楚的。
尽管E2F与RB形成复合体,但如果存在一种E2F相关蛋白DP-1的话,则复合体的形成会更有效率。E2F-1和DP-1形成稳定的异二聚体,结合DNA(例如,Qin等人,
Genes and Dev.6-:953-964(1992))。DP-1-E2F复合物的作用是协同激活依赖于E2F的基因的转录。象阻抑受E2F-1或DP-1激活的转录一样,pRB能以同样的方式阻抑这样的转录。
在一些情况下,可以通过将pRB连接到一个启动子上而获得RB对基因的转录阻抑。例如,GAL4-pRB融合体结合于GAL4 DNA结合域并阻抑从p53、Sp-1或AP-1元件的转录(Adnane等人,
J.Biol.Chem.270:8837-8843(1995);Weintraub等人,
Nature 358:259-261(1995))。Sellers等人(
Proc.Natl.Acad.Sci.92:11544-11548(1995))公开了E2F的氨基酸残基1-368和RB的氨基酸379-792或379-928的融合体。
Chang等人(
Science 267:518-521(1995))公开了用一种复制缺陷型腺病毒-RB构成物在两个再狭窄动物模型中减少新内膜的形成,其中所述再狭窄是一种高增殖性疾病。
发明概述
本发明提供了下述惊人的结果:E2F多肽与RB多肽的融合体在阻抑E2F启动子的转录中比单独的RB更有效,并且这样的融合体能在各种细胞类型中使细胞周期停滞。因此这样的融合体可以满足治疗高增殖性疾病、包括癌症的迫切需要。
本发明的一方面是包含一种转录因子与一种成视网膜细胞瘤(RB)多肽的融合体的多肽,其中所述转录因子包含一个DNA结合域,所述RB多肽包含一个生长抑制域。本发明的另一方面是编码这样一种融合多肽的DNA。可以将所述DNA***一种腺病毒载体中。
在本发明的一些实施方案中,所述转录因子是E2F。所述E2F的细胞周期蛋白A结合域可以缺失或是没有功能的。在一些实施方案中,所述E2F可以包含氨基酸残基约95到约194或约95到约286。
所述成视网膜细胞瘤多肽可以是野生型RB、RB56、或上述多肽的一种变异体或一个片段。在一些实施方案中,所述成视网膜细胞瘤多肽包含氨基酸残基约379到约928。所述RB多肽上优选的氨基酸取代包括残基2、608、788、807和811。
本发明的另一方面是包含编码一种多肽的DNA的表达载体,所述多肽包含一种转录因子与一种成视网膜细胞瘤(RB)多肽的融合体,其中所述转录因子包含一个DNA结合域,所述RB多肽包含一个生长抑制域。在一些实施方案中,一种组织特异性的启动子操纵性地连接到编码该融合多肽的DNA上。所述组织特异性启动子可以是一种平滑肌α-肌动蛋白启动子。
本发明的另一方面是一种用于治疗高增殖性疾病的方法,包括给予患者治疗有效量的一种E2F-RB融合多肽。所述高增殖性疾病可以是癌症。在一些实施方案中,所述高增殖性疾病是再狭窄。所述融合多肽和编码该融合多肽的核酸可用于包被血管成形术所使用的装置。
附图简述
图1A描述了预测的E2F的氨基酸序列(SEQ ID NO:1)。
图1B描述了转录因子E2F的核苷酸序列(SEQ ID NO:2)。
图2A描述了如Lee等人(Nature 329:642-645(1987))公开的pRB的核苷酸序列(SEQ ID NO:3)。
图2B描述了预测的pRB的氨基酸序列(SEQ ID NO:4)。
图3是pCTM的图示。
图4描述了质粒pCTM的核苷酸序列(SEQ ID NO:5),编码的肽为SEQ ID NO:6-15。
图5是pCTMI的图示。
图6描述了pCTMI的核苷酸序列(SEQ ID NO:16)。
图7是质粒pCTMIE的图示。
图8描述了pCTMIE的核苷酸序列(SEQ ID NO:17)。
图9是一个简图,描述了实施例中使用的E2F-RB构成物。所有的E2F构成物都起始于氨基酸95并且缺失部分细胞周期蛋白A结合域。E2F-437包含DNA结合域(黑)、异二聚化域(白)以及反式激活域(点描)。E2F-194仅包含DNA结合域。E2F-286包含DNA结合域以及DP-1异二聚化域。为产生E2F-194-RB56-5s和E2F-286-RB56-5s,将E2F构成物符合读框地融合到RB的密码子379上。C706F是一个致失活点突变。
图10是一个简图,描述了E2F-RB融合构成物引起的转录阻抑。
图11(A-D)描述了在哺乳类细胞系中E2F-RB蛋白的表达。由E2-CAT报道分析或FACS分析中使用的细胞制备提取物,并使用一种抗RB的单克隆抗体进行分析。板A显示了用以下转染C33A细胞得到的结果:(3)RB56-H209,(4)RB56野生型,(5)RB56-5s,(6)E2F286-5s,(7)E2F194-5s,(8)E2F194,(9)E2F286,(10)E2F437。泳道(1)是RB56蛋白标准品。泳道(2)是一个模拟转染。板B显示了用以下转染Saos-2细胞得到的结果:(1)RB56,(2,3)E2F194-5s,以及(4,5)E2F286-5s。板C显示了用以下转染5637细胞得到的结果:(2,3)RB56野生型,(4,5)RB56-5s;(6,7)E2F194-5s;(7,8)E2F286-5s。泳道(1)是RB56蛋白标准品。板D显示了用以下转染NIH-3T3得到的结果:(3)RB56,(4)E2F286-5s,(5)E2F194-5s。泳道(1)是RB56标准品;泳道(2)是RB110标准品。
图12描述了对表达RB的NIH-3T3细胞使用流式细胞术得到的频率分布图分析。
图13的组A描述了在大鼠平滑肌细胞系A7R5中进行的一个3H-胸苷摄入分析中,CMV驱动的重组腺病毒(ACN56)以及人类平滑肌α-肌动蛋白驱动的E2F-p56融合构成物的两个分离物与一种对照病毒(ACN)的效应的比较,其中所述E2F-p56融合构成物包含直接或符合读框地连接到p56(RB cDNA的氨基酸379-928)上的E2F氨基酸95到286。组B描述了同样的构成物在大鼠平滑肌细胞系A10中的效应。
图14描述了图13所述各种病毒在非肌细胞中的效应的比较。组(A)描述了在乳腺癌细胞系MDA MB468中的结果。组(B)描述了在非小细胞肺细胞癌细胞系H358中的结果。
图15上面的一组描述了腺病毒对不同细胞系的相对感染性,其中相对感染性是在用等量的一种由CMV启动子驱动表达β-gal的重组腺病毒感染细胞后,根据β-半乳糖苷酶(β-gal)染色的水平来进行判定。H358是非小细胞肺细胞癌细胞系;MB468是一种乳腺癌细胞系;A7R5和A10是平滑肌细胞系。图的下半部分描述了在用重组腺病毒ACN56感染的与上述相同的细胞系中,p56蛋白表达的相对水平,其中p56cDNA由非组织特异性的CMV启动子驱动。
图16描述了在用平滑肌α-肌动蛋白启动子驱动的E2F-p56融合构成物(ASN286-56)感染的细胞中,蛋白的相对水平。UN表示未被感染;50、100、250和500是指感染复数(MOI)。
图17是一个柱状图,描述了在受损伤并用表达β-gal、RB(ACNRB)或p56(ACN56)的重组腺病毒进行治疗的大鼠颈动脉横截面切片(n=9)上血管内膜面积与血管中层面积的比例(作为对新内膜形成的抑制的衡量),其中所述重组腺病毒中β-gal、RB或p56的表达都置于CMV启动子的控制之下。
图18是一个系列的三张照片,描述了在一个大鼠血管成形术模型中的再狭窄。左边的一幅描述了从正常动物得到的数据;中间的一幅描述了从受伤然后使用一种表达β-gal的重组病毒治疗的动物得到的数据;右边的一幅描述了从受伤然后使用一种表达p56的重组腺病毒(ACN56)治疗的动物得到的数据。
图19描述了平滑肌α-肌动蛋白启动子的组织特异性,这种组织特异性表现为其在肌细胞而不在非肌细胞中表达β-gal转基因的选择性能力。左边的组比较了在用CMV驱动β-gal(ACNBGAL)以MOI=1或平滑肌启动子构成物(ASNBGAL)以MOI=100感染的乳腺癌细胞系MB468中,β-gal的表达。右边的组描述了用ACNBGAL以MOI=1或ASNBGAL以MOI=50感染的大鼠平滑肌细胞系A7R5中β-gal的表达。在该肌细胞系中观察到了从ASNBGAL的表达,而在非肌细胞中缺乏表达,尽管ASNBGAL对非肌细胞系具有更高的感染性。
图20描述了表达RB的重组腺病毒转导大鼠颈动脉的能力。在气囊损伤(balloon injury)和感染两天后收获用重组腺病毒治疗的动脉(1×109pfu)。固定横截面切片,使用一种RB特异性抗体检测组织中RB蛋白的存在。使用的对照病毒是ACN。在ACNRB处理过的样品中,特别是在高放大倍数下,RB蛋白染色是明显的。
图21描述了一种CMV驱动的p56重组腺病毒(ACN56E4)、一种人类平滑肌α-肌动蛋白启动子驱动的E2F-p56融合构成物(ACN286-56)以及包含没有下游转基因的CMV或平滑肌α-肌动蛋白启动子(分别显示了ACNE3或ASBE3-2分离物)的对照腺病毒构成物的效应的比较。分析是在一种平滑肌细胞系(A7R5)或一种非肌细胞系(MDA-MB468,乳腺癌)中的3H-胸苷摄入分析。结果显示了使用平滑肌α-肌动蛋白启动子的肌肉组织特异性,以及p56和E2F-p56转基因与它们各自的对照相比的特异性抑制。
最佳实施方案的描述
本发明提供了RB融合构成物,包括融合多肽和编码它们的载体,以及提供使用这样的构成物治疗高增殖性疾病的方法。在本发明的一些最佳实施方案中,一种RB多肽与一种E2F多肽融合。可以使用任何E2F种类,一般是E2F-1、-2、-3、-3、或-5(参见如Wu等人,
Mol.Cell. Biol.15:2536-2546(1995);Ivey-Hoyle等人,
Mol.Cell.Biol.13:7802(1993);Vairo等人,
Genes and Dev.9:869(1995);Beijersbergen等人,Genes and Dev.8:2680(1994);Ginsberg等人,
Genes and Dev.8:2665(1994);Buck等人,
Oncogene 11:31(1995)),更一般的是E2F-1。一般所述E2F多肽至少包含E2F的DNA结合域,并且可以可任选地包含细胞周期蛋白A结合域、异二聚化域和/或反式激活域。细胞周期蛋白A结合域最好是没有功能的。本文所提到的E2F的核苷酸序列和氨基酸序列是Genbank HUME2F的核苷酸序列和氨基酸序列,如图1A和图1B所示。编码这样的一种E2F多肽的核酸,最好是DNA,符合读框地与一种RB多肽融合。所述RB多肽可以是任何一种RB多肽,包括保守氨基酸变异体、等位变异体、发生了氨基酸取代、缺失或***的突变体、或上述多肽的片段。所述RB多肽上的生长抑制域,即氨基酸残基379-928最好是有功能的(Hiebert等人,
MCB 13:3384-3391(1993);Qin等人,
Genes and Dev.6:953-964(1992))。在一些实施方案中使用了野生型pRB110。更优选使用一种被截短的RB,即RB56。RB56包含pRB110的氨基酸残基379-928(Hiebert等人,
MCB 13:3384-3391(1993);Qin等人,
Genes and Dev.6:953-964(1992))。在一些实施方案中,单独或组合使用了RB在位点2、608、612、788、807或811上的氨基酸变异体。变异体RB-5s包含在608、612、788、807和811位上具有丙氨酸取代的野生型RB56。RB氨基酸和核苷酸的编号是根据Lee等人(
Nature 329:642-645(1987))所公开的RB序列,为所有目的,特此通过引用全部结合到本文中(图2)。
编码本发明的多肽的核酸可以是RNA或DNA。词组“编码核酸序列”是指指导特定蛋白或多肽表达的核酸。所述核酸序列包含转录成RNA的DNA链序列以及翻译成蛋白的RNA序列。所述核酸序列包括全长的核酸序列以及全长的核酸序列衍生出的非全长的序列。更进一步地说,所述序列包括一种或多种天然序列的简并密码子,可以将这些简并密码子引入以在特定的宿主细胞中提供密码子优先(codonpreference)。
本文使用的术语“载体”是指病毒表达***、自主自我复制型环状DNA(质粒),并且包括表达质粒和非表达质粒。当叙述一种重组微生物或细胞培养物中带有一种“表达载体”时,这就包括染色体外环状DNA和已经***宿主染色体的DNA。当一种载体由一种宿主细胞保持时,所述载体可以或作为一种自主结构在有丝***期间由宿主细胞稳定地复制,或***宿主的基因组中。一种载体包含位置取向或顺序取向的多个遗传元件,即操纵性地连接其它必需遗传元件以便载体中的编码本发明的构成物的核酸可以在被转染的细胞中转录,并且在必要时翻译。
本文使用的术语“基因”规定是指编码多肽的核酸序列。这个定义包括各种序列多态性、变异和/或序列变异体,其中这样的改变并不影响该基因产物的功能。术语“基因”规定不仅包括编码序列,还包括调节区,如启动子、增强子和终止区。这个术语还包括从mRNA转录物剪接得到的所有内含子和其它DNA序列、以及由其它可选剪接位点得到的变异体。
术语“质粒”是指能在细胞中复制的自主环状DNA分子,包括表达型和非表达型。当叙述一种重组微生物或细胞培养物中带有一种“表达质粒”时,这就包括染色体外环状DNA分子和已经***宿主染色体的DNA。当一种质粒由一种宿主细胞保持时,所述质粒或是作为一种自主结构在有丝***期间由宿主细胞稳定地复制,或是***宿主基因组中。
词组“重组蛋白”或“重组产生的蛋白”是指使用非天然细胞产生的肽或蛋白,其中所述非天然细胞并不具有能表达所述蛋白的DNA的内源拷贝。由于已经通过向所述细胞引入合适的核酸序列而进行了遗传改变,因此所述细胞能产生所述蛋白。不会发现所述重组蛋白结合与产生该蛋白的细胞正常结合的蛋白和其它亚细胞组分。本文中术语“蛋白”和“多肽”可以互换使用。
一般来说,本发明的构成物是在一种表达载体中提供的,所述表达载体包含下列为有功能的表达以适当距离顺序连接的元件:一个组织特异性启动子、一个转录起始位点、一个3′非翻译区、一段5′mRNA前导序列、一段编码本发明的一种多肽的核酸序列以及一个多聚腺苷酸化信号。这样的连接被称为“操纵性地连接”。所述表达载体中也可以包括其它辅助表达和/或分泌的序列。所述载体中可以包括附加基因,如编码抗药性的基因以进行选择或筛选重组载体的存在。这样的附加基因可以包括如,编码新霉素抗性、多抗药性、胸苷激酶、β-半乳糖苷酶、二氢叶酸还原酶(DHFR)和氯霉素乙酰转移酶的基因。
在本发明中,本发明的RB构成物的组织特异性表达最好是通过使用一种目的组织中偏爱使用的启动子而实现。组织特异性启动子的例子包括肌酸激酶的启动子和B细胞中用于***基因表达的免疫球蛋白重链或轻链启动子(Maxwell等人,
Cancer Res.51:4299-4304(1991)),其中肌酸激酶的启动子已经用于指导肌肉组织和心脏组织中肌营养不良蛋白cDNA的表达(Cox等人,
Nature 364:725-729(1993))。也已经确定了一种内皮细胞特异性调节区的特征(Jahroudi等人,
Mol.Cell.Biol.14:999-1008(1994))。已经构建了兼嗜性逆转录病毒载体,分别携带置于清蛋白启动子或甲胎蛋白启动子控制下的单纯疱疹病毒胸苷激酶基因(Huber等人,
Proc.Natl.Acad.Sci.U.S.A.88:8039-8043(1991))到肝谱系细胞和肝癌细胞的靶细胞中。可以在逆转录病毒载体(Hartzoglou等人,
J.Biol.Chem.265:17285-17293(1990))和腺病毒载体(Friedman等人,Mol.Cell.Biol.6:3791-3797(1986);Wills等人,
Cancer Gene Therapy3:191-197(1995))中使用这样的组织特异性启动子,而仍然保持它们的组织特异性。
在本发明中,一种为外源基因的组织特异性表达所优选的启动子是人类平滑肌α-肌动蛋白启动子。Reddy等人(
J.Cell Biology 265:1683-1687(1990))公开了这种启动子的分离及其核苷酸序列,而Nakano等人(
Gene 99:285-289(1991))公开了人类平滑肌(主动脉型)α-肌动蛋白基因5′上游的转录调节元件和第一个内含子区。
Petropoulos等人(
J.Virol.66:3391-3397(1992))公开了操纵性地连接到鸡骨骼肌α-肌动蛋白启动子或胞质β-肌动蛋白启动子上的细菌氯霉素转移酶(CAT)的表达的比较。这些构成物在一种逆转录病毒载体中提供并用于感染鸡蛋。
典型的肝脏组织特异性表达元件包括但不限于HMG-CoA还原酶启动子(Luskey,
Mol.Cell.Biol.7(5):1881-1893(1987));固醇调节元件1(SRE-1;Smith等人,
J.Biol.Chem.265(4):2306-2310(1990));烯醇丙酮酸磷酸羟激酶(PEPCK)启动子(Eisenberger等人,
Mol.Cell Biol.12(3):1396-1403(1992));人类C-反应性蛋白(CRP)启动子(Li等人,
J.Biol. Chem.265(7):4136-4142(1990));人类葡糖激酶启动子(Tanizawa等人,Mol.Endocrinology 6(7):1070-81(1992));胆固醇7-α水解酶(CYP-7)启动子(Lee等人,
J.Biol.Chem.269(20):14681-9(1994));β-半乳糖苷酶α-2,6唾液酸转移酶启动子(Svensson等人,
J.Biol.Chem.265(34):20863-8(1990));***结合蛋白(IGFBP-1)启动子(Babajko等人,Biochem Biophys.Res.Comm.196(1):480-6(1993));醛缩酶B启动子(Bingle等人,
Biochem J.294(Pt2):473-9(1993));人类运铁蛋白启动子(Mendelzon等人,
Nucl.Acids Res.18(19):5717-21(1990));I型胶原蛋白启动子(Houglum等人,
J.Clin.Invest.94(2):808-14(1994))。
典型的***组织特异性表达元件包括但不限于***烷酸磷酸酶(PAP)启动子(Banas等人,
Biochim.Biophys.Acta.1217(2):188-94(1994));***分泌蛋白94(PSP94)启动子(Nolet等人,
Biochim. Biophys.ACTA 1098(2):247-9(1991));***特异性抗原复合物启动子(Casper等人,
J.Steroid Biochem.Mol.Biol.47(1-6):127-35(1993));人类腺激肽释放激素基因启动子(hgt-1)(Lilja等人,
World J.Urology11(4):188-91(1993))。
典型的胃组织组织特异性表达元件包括但不限于人类H+/K+-ATP酶α-亚单位启动子(Tanura等人,
FEBS Letters 298(2-3):137-41(1992))。
典型的胰组织特异性表达元件包括但不限于胰炎相关蛋白启动子(PAP)(Dusetti等人,
J.Biol.Chem.268(19):14470-5(1993));弹性蛋白酶1转录增强子(Kruse等人,
Genes and Development 7(5):774-86(1993));胰特异性淀粉酶和弹性蛋白酶增强子启动子(Wu等人,
Mol. Cell.Biol.11(9):4423-30(1991);Keller等人,
Genes and Dev.4(8):1316-21(1990));胰胆固醇酯酶基因启动子(Fontaine等人,
Biochemistry 30(28):7008-14(1991))。
典型的子宫内膜组织特异性表达元件包括但不限于子宫珠蛋白启动子(Helftenbein等人,
Annal.NY Acad.Sci.622:69-79(1991))。
典型的肾上腺细胞组织特异性表达元件包括但不限于胆固醇侧链切割(SCC)启动子(Rice等人,
J.Biol.Chem.265:11713-20(1990))。
典型的全身神经***组织特异性表达元件包括但不限于γ-γ烯醇化酶(神经元特异性烯醇化酶,NSE)启动子(Forss-Petter等人,
Neuron5(2):187-97(1990))。
典型的脑组织特异性表达元件包括但不限于神经丝重链(NF-H)启动子(Schwartz等人,
J.Biol.Chem.269(18):13444-50(1994))。
典型的淋巴细胞组织特异性表达元件包括但不限于人类CGL-1/粒酶B启动子(Hanson等人,
J.Biol.Chem.266(36):24433-8(1991));末端脱氧转移酶(TdT)、λ-5、Vpre B和lck(淋巴细胞特异性酪氨酸蛋白激酶p56lck)启动子(Lo等人,
Mol.Cell.Biol.11(10):5229-43(1991));人类CD2启动子及其3′转录增强子(Lake等人,
EMBO J.9(10):3129-36(1990))和人类NK细胞和T细胞特异性激活(NKG5)启动子(Houchins等人,Immunogenetics 37(2):102-7(1993))。
典型的结肠组织特异性表达元件包括但不限于pp60c-src酪氨酸激酶启动子(Talamonti等人,
J.Clin.Invest 91(1):53-60(1993));器官特异性新抗原(OSN)、分子量40kDa(p40)启动子(Ilantzis等人,
Microbiol. Immunol.37(2):119-28(1993));结肠特异性抗原P启动子(Sharkey等人,Cancer 73(增刊3)864-77(1994))。
典型的胸腺细胞组织特异性表达元件包括但不限于人类α-乳清蛋白启动子(Thean等人,
British J.Cancer.61(5):773-5(1990))。
其它在目的组织中帮助表达的特异性的元件包括分泌型前导序列、增强子、核定位信号、内体裂解(endosmolytic)肽等等。这些元件最好是从目的组织中得来以帮助特异性。
对本发明所述核酸序列进行核酸操作的技术,如将编码多肽的核酸序列亚克隆进表达载体、探针标记、DNA杂交等等,一般如Sambrook等人,
Molecular Cloning-A Laboratory Manual(第二版),第1-3卷,ColdSpring Harbor Laboratory,Cold Spring Harbor,New York,(1989)所述,这些通过引用结合到本文中。这份手册下文称为“Sambrook等人”。
一旦分离和克隆了编码目的序列的DNA,就可以在各种重组工程化的细胞中表达所编码的蛋白。预期本领域技术人员对可得到的多种用于表达编码DNA的表达***有足够的知识。这里并不准备详细地描述已知的用于在原核细胞或真核细胞中表达蛋白的各种方法。
总的来说,编码所关注序列的天然或合成核酸的表达的实现,一般是通过将所述DNA或cDNA操纵性地连接一个启动子(不是组成型就是诱导型),然后将其***一个表达载体。所述载体可以是在原核细胞或真核细胞中适于复制和整合的。典型的表达载体包含转录和翻译终止子、起始序列和对调节所关注多核苷酸序列的表达有用的启动子。为获得一个克隆基因的高水平表达,有必要构建表达质粒,所述表达质粒至少包含一个指导转录的强启动子、一个用于翻译起始的核糖体结合位点和一个转录/翻译终止子。所述表达载体还可以包含遗传表达盒以及适于原核***和真核***的选择标记,其中所述遗传表达盒至少包含一个独立的终止子序列、以及允许质粒在原核细胞和真核细胞两者中复制的序列,即穿梭质粒。参见Sambrook等人。
可以通过各种方法,将本发明的E2F-RB融合构成物在体内或离体引入目的组织。在本发明的一些实施方案中,通过如显微注射、磷酸钙沉淀、脂质体融合或生物发射(biolistics)等方法,将所述核酸、最好是DNA引入细胞中。在其它实施方案中,由目的组织直接摄入所述DNA。在其它实施方案中,将所述构成物包装进一个病毒载体***以利于将其引入细胞。
本发明的实践中有用的病毒载体***包括腺病毒、疱疹病毒、腺伴随病毒、小鼠微小病毒(MVM)、HIV、新培斯病毒、和逆转录病毒如劳斯肉瘤病毒以及MoMLV。一般将本发明的构成物***这样的载体中,以便包装所述E2F-RB表达构成物(一般是与伴行病毒DNA一起),感染一种敏感的宿主细胞并表达所述E2F-RB基因。一种特别有利的载体是Wills等人,
Human Gene Therapy 5:1079-1088(1994)公开的腺病毒载体。
在本发明其它的实施方案中,本发明的重组DNA构成物通过一个DNA连接部分连接到一种细胞受体的配体上以利于摄取(如有被小窝的内陷和内体的内化)(Wu等人,
J.Biol.Chem.263:14621-14624(1988);WO 92/06180)。例如,本发明的DNA构成物可以通过一个多聚赖氨酸部分连接脱唾液酸-oromucocid,即肝细胞脱唾液酸糖蛋白受体的配体。
相似的,可以通过加入受体的配体或特异性针对一种受体的抗体,对用于包装本发明构成物的病毒被膜进行改变,以利用受体介导的胞饮作用进入特定细胞(如WO 93/20221,WO 93/14188;WO94/06923)。在本发明的一些实施方案中,本发明的DNA构成物连接到病毒蛋白,如腺病毒颗粒上,以利于胞饮作用(Curiel等人,
Proc.Natl. Acad.Sci.U.S.A.88:8850-8854(1991))。在其它实施方案中,本发明的分子缀合物可以包括微管抑制剂(WO 94/06922);模拟流感病毒血凝素的合成肽(Plank等人,
J.Biol.Chem.269:12918-12924(1994));和核定位信号,如SV40T抗原(WO 93/19768)。
在本发明的一些实施方案中,直接将本发明的多肽给予需要治疗的患者。“治疗有效的”剂量是指足以预防或减弱高增殖性疾病的严重性的多肽的剂量。本文使用的术语“高增殖性的细胞”包括但不限于具有自主生长能力的细胞,即其独立于正常调节机制之外生存和繁殖。高增殖性疾病可以被归类为病理性的,即不同于正常细胞并且其特征构成疾病;或者可以被归类为非病理性的,即不同于从正常细胞但与疾病状态无关。病理性高增殖性细胞是以下疾病状态的特征:再狭窄、糖尿病性视网膜病、甲状腺增生、突眼性甲状腺肿、牛皮癣、良性***肥大、Li-Fraumeni综合征包括乳腺癌、肉瘤和其它肿瘤、膀胱癌、结肠癌、肺癌、各种白血病和淋巴瘤。例如,在哺乳发育期间的哺乳类导管上皮细胞中和在与损伤修复有关的细胞中已经发现了非病理性高增殖性细胞的例子。病理性高增殖性疾病细胞特征性地显示出接触抑制的丧失以及其选择性粘附能力的衰减,而这种衰减意味着细胞通讯的衰减。这些改变包括进行***的刺激和分泌蛋白水解酶的能力。
在对各种癌症和其它RB的给予是有利的病理状况的治疗中,本发明的构成物是有用的,其中所述病理状况包括但不限于外周血管疾病和糖尿病性视网膜病。虽然任何组织都可作为靶组织并且可以鉴定针对性的某种组织特异性表达元件,如启动子,但人们特别关注的是针对高增殖性疾病(如再狭窄)组织特异性地给予一种RB构成物,为此平滑肌肌动蛋白启动子是优选的。
为采用本领域内已知并且是对哺乳类受治疗者、最好是人类的给药所接受的方法给药,配制本发明的组合物。在本发明的一些实施方案中,可以将本发明的组合物通过注射直接给予一种组织,或通过给予为目的组织供血的血管而给药。在本发明的其它实施方案中,将本发明的组合物“局域性”给药,即膀胱内、损伤内和/或局部给药。在本发明的其它实施方案中,通过注射、吸入、栓剂、经皮传递等方法***地给予本发明的组合物。在本发明的其它实施方案中,通过导管或其它装置给予所述组合物,以便能达到目的远处的组织,如内脏。也可以在贮存型装置、植入物或胶囊制剂中给予本发明的组合物,以便能缓慢或持续地释放所述组合物。
本发明提供给药组合物,其中所述组合物包括溶解或悬浮于一种可接受的载体、最好是一种水性载体中的本发明的组合物的溶液。可以使用各种水性载体,如水、缓冲水、0.8%盐水、0.3%甘氨酸、透明质酸等等。可以使用常规的、广为人知的灭菌技术对这些组合物进行灭菌,或可以使用除菌过滤。可以将得到的水溶液原样包装使用,或将其冻干,并在给药前将冻干制剂与一种无菌溶液混合。所述组合物中可以根据需要含有药学上可接受的辅助物质以接近生理条件,如pH调整剂和缓冲剂、张力调整剂、润湿剂等等,例如,醋酸钠、乳酸钠、氯化钠、氯化钾、氯化钙、山梨糖醇-单月桂酸酯、三乙醇胺油酸酯等等。
在药用制剂中本发明组合物的浓度可以变化很大,即从少于0.1%(重量)直到20%到50%(重量)或更多,通常是大约2%或至少2%(重量),这主要依据选定特定给药模式,根据流体体积、粘度等等进行选择。
也可以脂质体给予本发明的组合物。脂质体包括乳液、泡沫、微团、不溶的单分子层、液晶、磷脂分散体、片层等等。在这些制剂中,把要传送的本发明组合物作为脂质体的一部分加入或是单独加入,或是与一种结合既定目标的分子(如抗体)、或是与其它治疗组合物或免疫原性组合物结合加入。这样,本发明的填充或布置有本发明组合物的脂质体,可以被***地传送到、或可以被定向到一种目的组织,然后脂质体就在所述组织中传递选定的治疗/免疫原性肽组合物。
本发明中使用的脂质体是从标准的小泡形成脂质来形成。脂质体一般包括中性和带负电荷的磷脂和一种固醇,如胆固醇。脂质选择的一般指导是考虑如在血流中脂质体的大小、脂质体的酸不稳定性和稳定性。已经有各种可用的制备脂质体的方法,如Szoka等人,
Ann.Rev. Biophys.Bioeng.9:467(1980),美国专利第4,235,871号、4,501,728号、4,837,028号和5,019,369号中所述,这些都通过引用结合到本文中。
可以采用静脉内、局部、表面等途径给予包含本发明组合物的脂质体悬浮液,给药剂量尤其根据给药方式、所传送的本发明组合物和所治疗的疾病的阶段而变。
对于固体组合物来说,可以使用常规的无毒固相载体,包括如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖、碳酸镁等等。对于口服给药,通过加入任何一种通常使用的赋形剂,如前面所列出的那些载体,以及通常是10-95%、更优选是25%-75%的浓度的活性成分,即一种或多种本发明的组合物,可以制成药学上可接受的无毒组合物。
对于气雾剂给药,最好将本发明的组合物以良好分散的形式并与一种表面活性物质以及抛射剂一起提供。本发明的组合物的一般百分比是0.01%-20%(重量),最好是1%-10%。当然,所述表面活性剂必须是无毒的,并且最好可溶于抛射剂中。这样的介质的代表是包含6到22个碳原子的脂肪酸(如己酸、辛酸、月桂酸、棕榈酸、硬脂酸、亚油酸、亚麻酸、olesteric acid和油酸)与一种脂肪族多元醇或其环酐形成的酯或部分酯。可以使用混合酯,如混合的或天然的甘油酯。所述表面活性剂可以构成组合物的0.1%-20%(重量),最好是0.25-5%。组合物的剩余部分通常是抛射剂。可以按照需要再包括一种载体,如包括卵磷脂以进行鼻内传递。
此外,可以使用本领域内广为人知的技术,在贮存型***、胶囊化形式或植入物中传递本发明的组合物。同样,可以通过一个泵将所述构成物传递给目的组织。
在本发明的一些实施方案中,将本发明的组合物离体给予从患者移出的细胞或组织,然后将所述细胞或组织移植回患者。基因治疗构成物离体给予的例子包括Arteaga等人,
Cancer Research 56(5):1098-1103(1996);Nolta等人,
Proc.Natl.Acad.Sci.USA 93(6):2414-9(1996);Koc等人,
Seminars in Oncology 23(1):46-65(1996);Raper等人,
Annals of Surgery 223(2):116-26(1996);Dalesandro等人,
J.Thorac.Cardi.Surg.11(2):416-22(1996);和Makarov等人,
Proc.Natl.Acad.Sci.USA 93(1):402-6(1996)。
在本发明的一些实施方案中,在气囊血管成形术之后将本发明的构成物给予心脏动脉,以防止或减弱再狭窄的严重性。本发明的构成物可以用于包被血管成形术所使用的装置(例如,参见Willart等人,Circulation 89:2190-2197(1994);French等人,
Circulation 90:2402-2413(1995))。在其它实施方案中,可以以相同方法使用本发明的融合多肽。
下面的实施例以举例说明的目的包括入本文中,并且不应该被认为是限制本发明。
实施例
实施例I
E2F-RB融合体
A.介绍
在这个实施例中,构建了编码与RB56多肽融合的E2F的不同区段的表达质粒。RB56是全长的RB的一种亚片段,包含对于生长抑制所必需的“袋”域(Hiebert等人,
MCB 13:3384-3391(1993);Qin等人,
Genes and Rev.6:953-964(1992))。E2F194包含E2F氨基酸95-194。这个片段仅包含E2F的DNA结合域。E2F286包含DNA结合域和DP-1异二聚化域。这两种E2F片段都缺失N末端细胞周期蛋白A-激酶结合域,而这个域似乎向下调节E2F的DNA结合活性(Krek等人,
Cell 83:1149-1158(1995);Krek等人,
Cell 78:161-172(1994))。
B.载体的构建
质粒pCTM包含一个CMV启动子、一段侧翼为T7启动子和SP6启动子的三联腺病毒前导序列、一个多克隆位点,并且在多克隆位点下游还有一个牛生长激素(BGH)多腺苷酸化位点和一个SV40多腺苷酸化位点。图3提供了pCTM的一个图示。图4提供了pCTM的DNA序列。
用Xho I和Not I消化pCTM并从一个pCTM-β-gal载体(Clonetech)亚克隆一个180bp的内含子Xho I-Not I片段,从pCTM构建pCTMI。图5提供了pCTMI的一个图示。图6提供了pCTMI的DNA序列。
在一个聚合酶链反应中从SV40病毒DNA扩增SV40增强子,构建pCTMIE。将扩增产物用Bgl II消化,***用BamH I消化的pCTMI,并在BamH I的存在下进行连接。图7图解描述了该质粒。图8提供了pCTMIE的DNA序列。
如下制备pCTM-RB。将pETRBc(Huang等人,
Nature 350:160-162(1991))的一段3.2KB的包含全长人RB cDNA的Xba I-Cla I片段与用Xba I-Cla I消化的pCTM连接。将消化过的pCTM连接到一个1.7KB的包含RB56编码序列的Xba I-Cla I片段上,制备pCTM-RB56。使用同样方法构建PCTMI-RB、pCTMIE-RB、pCTMI-RB56(氨基酸381-928)和pCTMIE-RB56(氨基酸381-928)。
C.RB-E2F融合构成物
图9描述了在这些研究中使用的融合构成物。这些E2F构成物起始于氨基酸95并且缺少部分细胞周期蛋白A结合域。E2F437包含DNA结合域(黑)、异二聚化域(白)和反式激活域(条纹)。E2F194仅包含DNA结合域。E2F286包含DNA结合域和DP-1异二聚化域。RB56-5s是指一种在氨基酸残基606、612、788、807和811具有丙氨酸取代的RB变异体。在E2F194-RB56-5s和E2F286-RB56-5s中,E2F片段符合读框地融合到RB-5s的密码子379上。RB56-C706F包含一个致失活点突变(Kaye等人,Proc.Natl.Acad.Sci.U.S.A.87:6922-6926(1990))。
如下所述构建pCMV-E2F194和pCMV-E2F437。在一个聚合酶链反应中扩增编码E2F的氨基酸95-194(包含DNA结合域)或氨基酸95-437的DNA,用Hind II消化,然后连接进用Sma I/Hind II消化的pCMV-RB56载体。将pCMV-E2F437用Afl II消化,用DNA聚合酶I(克列诺片段)处理末端并在Afl II的存在下重新连接,从而构建pCMVE2F286。平端连接在287位产生了一个终止密码子。将Afl II(平端)/Hind III消化的pE2F437与一个包含RB56-5s编码序列的Sal I(平端)-Hind III片段连接,构建pCMV-E2F286-5s。通过将EcoR I-EcoR V消化的pCTMIE(4.2KB)连接到从pCMV-E2F194-RB5s或pCMV-E2F286-RB5s得到的Hind III(平端)/EcoR I片段上,构建pCTMIE-E2F194-5s和pCTMIE-E2F286-RB5s。
D.启动子阻抑
为衡量E2F-RB融合蛋白的效应,用等量的E2F194-RB56或E2FRB56与一个E2-CAT报道质粒转染***细胞系C33A(ATCC #HTB-31)(参见,如Weintraub等人,
Nature 358:259-261(1992))。
在C33A分析中,在6孔组织培养板的每个孔中接种250,000个C33A细胞并使其粘附过夜。每孔分别用5μg的pCMV-RB56、pCMV-E2FRB56或pCMV-E2F质粒与5μg指示的报道基因构成物(E2-CAT或SVCAT)以及2.5μgβ-gal质粒(pCMV-β,Clonetech)共转染(磷酸钙法,MBS转染试剂盒,Stratagene),并进行双份实验。转染后72小时收获细胞并制备提取物。
在5637分析中,如上所述每孔接种250,000个5637细胞。使用脂质转染试剂(BRL,Bethesda,Maryland)按照厂家的介绍,用RB或E2F-RB融合体质粒、E2-CAT或SV-CAT报道质粒以及pCMV-β-半乳糖苷酶各1μg共转染细胞。
使用20μl(C33A)或50μl(5637)细胞提取物进行CAT分析(Gorman等人,
Mol.Cell.Biol.2:1044(1982))。在一台Phosphoimager SF(Molecular Dynamics)上分析TLC。用根据每种提取物中β-半乳糖苷酶活性,对于转染效率将CAT活性归一化。如Rosenthal等人(
Meth.Enzym.152:704(1987))所述分析提取物的β-半乳糖苷酶活性。
这些研究的结果如下所示。单独E2-CAT报道质粒的转染,或在无功能的对照RB56-H209突变体的存在下E2F-CAT的转染,产生了相对高的CAT活性。与野生型RB56或变异体RB56-5s的共转染导致CAT活性10到12倍的阻抑,这表明RB56或RB56-5s都能有效阻抑依赖于E2F的转录。E2F194-RB5s和E2F286-RB5s大约50倍地阻抑转录。由于E2F194和E2F286的表达并不介导转录阻抑,因此转录阻抑需要融合蛋白的RB56成分和E2F成分。使用E2F-RB构成物进行实验时并不发生对SV40-CAT转录的阻抑,这就显示了E2FRB针对E2启动子的转录阻抑的特异性。图10图解描绘了这些结果。
E.细胞周期的停滞
已经探索了E2F-RB融合多肽在Saos-2(RB-/-细胞)(ATCC #HTB-85)和C33A细胞中导致G1停滞的能力。以前的研究已经显示,RB介导的启动子阻抑和G1停滞在Saos-2细胞中是相关的,但是在C33A(RB突变)细胞中是无关的(Xu等人,
PNAS 92:1357-1361(1992))。在PBS中冲洗细胞并在1ml-20℃ 70%乙醇中固定30分钟。离心收集细胞,重悬浮于0.5ml含10μg/ml RNase A的2%血清中,于37℃温育30分钟。在每个样品中加入0.5ml含碘化丙锭(100μg/ml)的PBS,混合,然后用一个FACS管帽过滤器(tube capstrainer)过滤细胞。在一台FACS-Scan(Becton-Dickenson)中使用双峰鉴别(doublet discrimination)进行FACS分析。分析5,000-10,000个CD20+细胞。使用Modfit模造软件确定处于G0/G1、S1和G2/M的细胞的百分比。
这个实验的结果如下所示。全长的RB110和被截短的RB110,即RB56,在Saos-2细胞中导致G1停滞,但对照突变体RB-H209并不显示这种活性(表1)。相似地,RB56-5s、E2F-194-RB56-5s和E2F286-RB56-5s都能使细胞停滞在G0/G1期。DNA结合域,即E2F194的转染在Saos-2中并不阻断细胞进入S期,如以前针对啮齿类细胞所述(Dobrowolski等人,
Oncogene 9:2605-2612(1994))。与此相比,RB110、RB56和E2F-RB融合蛋白并不能使C33A细胞系停滞,这表明在这些细胞中观察到的转录阻抑并不能说明G1停滞。
也已经探索了E2F-RB融合蛋白使5637细胞停滞的能力(表2)。RB56和RB56-5s都有效地使细胞停滞在G0/G1期(大约90%的细胞处于G0-G1期),而E2F194-RB56-5s和E2F286-RB56-5s在促进G0/G1停滞上效果稍差一些(大约80%的细胞处于G0/G1)。由于没有被任何一种理论限制,E2F-RB融合蛋白对Saos-2细胞和5637细胞的有效性稍差一些的阻滞作用看来是由于在这些细胞中产生的稳态蛋白水平低(图11,板b和板c)。
表1:RB和E2F-RB在RB融合蛋白阴性细胞中的细胞周期调节
%细胞 | |||
CD20+G0/G1 | G2/M | S期 | |
H209 | 52.1 | 27.1 | 20.8 |
p56RB | 78.8 | 14.2 | 7.0 |
p110RB | 70.9 | 14.3 | 14.8 |
p56RB-5s | 84.8 | 13.2 | 2.0 |
p56RB-p5 | 81.3 | 11.5 | 7.3 |
E2F-194-5s | 77.8 | 14.9 | 7.3 |
E2F-286-5s | 72.2 | 15.0 | 12.8 |
E2F-194 | 49.9 | 28.0 | 22.1 |
表2:RB和E2F-RB融合蛋白导致5637膀胱细胞的生长抑制
5637/CD20+ | %细胞 | ||
G0/G1 | S | G2/M | |
CD20 | 59.7 | 16.9 | 20.6 |
RB56-C706F | 57.4 | 16.3 | 24.3 |
RB56WT | 90.7 | 4.12 | 4.88 |
RB56-5s | 89.91 | 3.51 | 6.1 |
E2F194-5s | 80.1 | 1.31 | 0 |
E2F-286-5s | 79.21 | 8.1 | 0 |
F.在有功能的RB背景中融合蛋白的活性
然后测定在一个包含有功能的RB的细胞背景中E2F-RB融合蛋白的活性。用RB56或E2F-RB56融合体转染NIH-3T3细胞,然后用抗RB的单克隆抗体3C8染色(Wen等人,
J.Immuno.Meth.169:231-240(1994))。对这些表达RB的细胞进行FACS分析。图12显示了结果。非门控群体(non-gated population)(g)显示了NIH-3T3细胞的特征性细胞周期分布(60%G0期,28%S期,10%G2/M期)。与此相比,在用RB56(a,b)或E2F-RB融合蛋白(c-f)转染的细胞中,多于90%的表达RB的细胞被停滞在G0/G1期。这些数据表明,RB和E2F-RB56融合体使细胞停滞在G0/G1期的能力并不限于RB阴性肿瘤细胞。还探索了在被转染的NIH-3T3细胞中表达的蛋白的相对水平。RB110在这些细胞中并不能有效地表达。
因此,这些数据表明,E2F-RB融合蛋白是比单独的pRB或RB56更有效的转录阻抑物,并且RB能通过保持结合E2F、而不是直接阻断E2F的反式激活域而阻抑转录。这些数据支持在RB+细胞和RB阴性或RB突变细胞中使用E2F-RB融合体作为RB激动剂。
实施例II
E2F-RB融合体的组织特异性表达
A.重组腺病毒的构建
在这个实验中,产生了重组腺病毒,所述重组腺病毒包含处于一个CMV启动子或平滑肌α-肌动蛋白启动子控制之下的RB多肽。
通过PCR从一个基因组文库中分离平滑肌α-肌动蛋白启动子(碱基-670到+5,Reddy等人,“人平滑肌α-肌动蛋白基因的结构”
J.Biol. Chem.265:1683-1687(1990),Nakano等人,“人平滑肌(主动脉型)α-肌动蛋白编码基因5’上游的转录调节元件和第一个内含子”
Gene99:285-289(1991)),并为克隆目的加入5′Xho I和Avr II和3′Xha I、Cla I和Hind III限制酶位点。将所述片段作为一个Xho I、Hind III片段亚克隆进一个质粒,进行测序以证实其碱基组成。一个融合构成物286-56作为Xha I、Cla I片段亚克隆进平滑肌α-肌动蛋白启动子的直接下游,将该表达盒消化出来,作为一个Xba I到Avr II和Cla I片段克隆进质粒pAd/ITR/IX-,产生质粒pASN286-56,其中所述融合构成物286-56包含连接到p56(全长RB的氨基酸379-928)上的E2F-1的DNA结合域和异二聚化域(氨基酸95-286)。这个质粒包含处于pBR322背景中的腺病毒5型的末端反向重复(ITR)、包装信号和Ela增强子,其后是人类平滑肌α-肌动蛋白启动子和286-56盒,然后是Ad 2序列4021-10462(包含Elb/蛋白IX polyA信号)。使用标准程序产生重组腺病毒。
将质粒pASN286-56用Ngo MI线性化,并与用Cla I消化rAd34得到的大片段共转染进293细胞,其中所述用Cla I消化rAd34得到的大片段在腺病毒5型的E3和E4区都有缺失。Ad34是血清型5的一种衍生型,含有早期区3的一个1.9KB缺失和早期区4的一个1.4KB缺失,其中所述1.9KB缺失是由于Xba I限制片段的缺失所致,其坐标从Ad5的28593延伸到30470,所述1.4KB缺失是由于E4的一个TaqI片段(坐标为33055-35573)被一个包含E4 ORF6和6/7的cDNA置换所致。
分离用同源重组产生的重组腺病毒,并用限制酶消化分析进行鉴定,进一步地用有限稀释法进行纯化。其它对照重组腺病毒在别处描述,并且包含对照病毒ACN(CMV启动子,Wills等人,“肝细胞癌的基因治疗:HSV-1胸苷激酶基因的腺病毒介导的转移赋予的化学敏感性”
Cancer Gene Therapy 2:191-197(1995))和ACN56(处于一个CMV启动子控制下表达的RB)。
如下所述制备ACN56。用从质粒pET 9a-RB56(Antelman等人,Oncogene 10:697-704(1995))中分离到的包含p56 cDNA的1.7KBXbaI-BamHI片段,置换质粒ACNP53(Wills等人,
Human Gene Therapy5:1079-1088(1994))中的p53 cDNA,构建一个包含p56 cDNA的质粒。得到的质粒包含p56的氨基酸381-928、Ad5的末端反向重复、病毒包装信号和Ela增强子,其后是驱动p56表达的人类巨细胞病毒立即早期启动子(CMV)和Ad 2三联前导序列cDNA。p56 cDNA之后是处于pBR322背景中的Ad 2序列4021-10462。将这个质粒用EcoR I线性化,并与bsp106消化DL327得到的大片段(缺失E3;Thimmappaaya等人,
Cell31:543-551(1982))或h5ile4(缺失E4;Hemstrom等人,
J.Virol.62:3258-3264(1988))共转染细胞。进一步用有限稀释法纯化重组病毒。
B.细胞增殖
在这个实验中,用重组腺病毒RB构成物感染培养物中的细胞系,以确定所述RB多肽的相对表达和对细胞增殖的效应。
将H358(ATCC #Crl 5807)细胞和MDA-MB468(ATCC #HTB132,乳腺癌)细胞以5,000细胞/孔的细胞平板接种在96孔微量滴定板(Costar)的正常生长培养基中,在37℃,7%CO2条件下培育过夜。在生长培养基中连续稀释病毒,并以指定剂量用病毒感染细胞48小时。在这个时刻加入3H-胸苷(Amersham,0.5μCi/孔),并将细胞在收获前在37℃下再培育3小时。将A7r5(ATCC CRL1444,大鼠平滑肌)细胞和A10(ATCC CRL 1476,大鼠平滑肌)细胞都以3,000细胞/孔的细胞平板分别接种到DME+0.5%FCS或DME+20%FCS中。在接种培养基中连续稀释病毒,并以图中指示剂量用病毒感染细胞。对A10细胞的感染和标记程序与H358和MDA-MB468细胞同,但使用2μCi/孔的标记物。在接种后48小时才用病毒感染A7r5细胞。感染后48小时,将血清浓度提高到10%FCS,并加入2μCi/孔的3H-胸苷,在收获前继续培育3小时。从孔中吸出培养基,胰蛋白酶消化细胞,并使用带有一个Packard Top计数细胞收集器的96孔GF/C滤器进行收获,从而收获全部细胞。结果在图13和图14中以培养基处理的对照增殖的平均百分比(+/-SD)对病毒剂量作图。
这样,图13就描述了腺病毒p56构成物对肌细胞A10和A7R5细胞的效应的比较。CMV驱动的p56(ACN 56)病毒大约与肌动蛋白启动子驱动的E2F-融合构成物(ASN586-56 #25,26)同等程度地抑制A10生长。图14描述了腺病毒构成物抑制乳腺癌细胞系MDA MB468和非小细胞性肺癌细胞系H358的效应。在这些实验中,对于抑制非平滑肌细胞的生长,肌动蛋白启动子驱动的E2F-p56是无效的,而CMV启动子驱动的p56是有效的。
为确定非平滑肌细胞是否比所使用的平滑肌细胞系更易受腺病毒感染,用一种表达β-半乳糖苷酶的腺病毒(AcβGL;Wills等人,
Human Gene Terapy 5:1079-1088(1994))以MOI 5感染四个细胞系H358、MB468、A7R5和A10,并检测β-gal染色的程度。如图15(上)所示,非平滑肌细胞系显著地比平滑肌细胞系更易被感染。在另一个实验中,用ACN56以更高的感染复数(50,100,250,500)感染细胞,然后用放射自显影检测被感染细胞中存在的p56的量。如在图15(下)中可参见,非肌细胞系中显著地有更多的p56存在,这是由于它们有更大的感染性,被感染的细胞具有更大的病毒负载,也就有更多的由非组织特异性CMV启动子驱动的p56模板的拷贝。
在另一个实验中,确定了针对平滑肌肉组织的肌动蛋白平滑肌启动子的特异性。在这个实验中,测量了用不同启动子驱动的β-gal构成物感染的细胞中β-gal表达的水平。如在图19中可参见,尽管对这些平滑肌细胞的感染性较低,但只有使用平滑肌α-肌动蛋白启动子在这些细胞中的表达是明显的。
图21描述了一个CMV驱动的p56重组腺病毒(ACN56E4)、一个人类平滑肌α-肌动蛋白启动子驱动的E2F-p56融合构成物(ASN286-56)、一个对照腺病毒构成物的效应的比较,其中所述对照腺病毒构成物具有不含下游转基因的CMV启动子或平滑肌α-肌动蛋白启动子(分别为显示的ACNE3或ASBE3-2分离物)。分析是在一种平滑肌细胞系(A7R5)或一种非肌细胞系(MDA-MB468,乳腺癌)中进行的3H-胸苷摄入分析。结果显示了使用平滑肌α-肌动蛋白启动子的肌肉组织特异性以及p56和E2F-p56转基因相对于它们各自的对照的特异性抑制。
C.对再狭窄的抑制
气囊损伤模型基于如Clowes等人(Clowes,
Lab.Invest.49:327-333(1983))所述模型。腹膜内注射戊巴比妥钠(45mg/kg.Abbot Laboratories,North Chicago,Illnois),麻醉重400-500g的雄性Sprague-Dawley大鼠。通过中线切开暴露左侧颈总动脉杈并临时结扎左侧颈总动脉、颈内动脉和颈外动脉。将一根2F栓子切除术导管(Baxter Edwards HealthcareCrop.,Irvine,CA)引入颈外动脉并前进至颈总动脉的远侧结扎处。用盐水灌注气囊并将气囊朝动脉切开术位点牵引3次以产生一个膨胀性去内皮愈合损伤。然后取出导管。把一根插管在颈动脉杈附近***动脉的临时分离的区段。10μl腺病毒(1×109pfu的Ad-RB(ACNRb)或Ad-p56(ACN56))用15%(重量/体积)Poloxamer 407(BASF,Parsippany,N.J.)稀释成100μl,将所述腺病毒或Ad-β-gal(1×109pfu,如上稀释)通过所述插管注射进去。将腺病毒溶液温育20分钟后,抽出病毒输注液并取出导管。然后结扎近端颈外动脉并通过解开结扎恢复颈总动脉的血流。实验方案经过机构动物管理及使用委员会(Institutional Animal Care andUse Committee)批准并且符合“实验动物护理(eare)和使用指南”(NIHPublication No.86-23,1985修订)。
腹膜内注射戊巴比妥(100mg/kg)处理14天后,处死大鼠。用盐水灌注从肩胛舌骨肌近端缘到颈动脉杈的左侧颈总动脉的最初气囊损伤区段,并剖离周围的组织。将该组织在100%甲醇中固定并包埋在石蜡中。从每个组织标本切下几个4-μm切片。将每个标本中的一个切片用苏木精和伊红染色,另一个切片进行Richardson’s组合弹性三色(elastic-trichrome)染色的常规光学显微分析。
将苏木精和伊红染色的横截面切片或弹性三色染色的动脉切片的组织学影像投影到一台数字化板(Summagraphics)上,通过一个计算机化的绘图程序(MACMEASURE,1.9版,National Institute of MentalHealth)进行定量形态测量学分析,测量内膜面积、中层面积和腔面积。
结果表示为平均值±S.E.M.。不同群体之间的差异用不配对双尾Student’s t检验进行分析。当一个零效应(null effect)的概率<0.05时,就假设有统计学的显著性。
结果如图17和18所示。在图17中图解描绘了对新内膜形成的相对抑制,证明了p56和RB抑制新内膜形成的能力。图18提供了存在p56时新内膜惊人减少的照片证据。
在气囊损伤和感染2天后,从大鼠中收获腺病毒处理的颈动脉。将组织在磷酸缓冲***中固定并包埋在石蜡中。将组织切成4μm横截面切片,并通过二甲苯和梯度乙醇脱蜡。用1%过氧化氢处理30分钟,猝灭内源过氧化物酶。在10mM柠檬酸钠缓冲液,pH6.0中95℃下处理10分钟,进行抗原提取。加入含10μg/ml一种单克隆抗体(AB-5,Oncogene Sciences,Uniondale,New York)的PBS,在一个潮湿的室中4℃处理24小时。按照厂家的介绍使用Unitect小鼠免疫组化试剂盒(Oncogene Sciences,Uniondale,New York)中的二级抗体。使用3,3’-二氨基联苯胺(DAB,Vector Laboratories,Burlingame,CA)显色抗体复合物。将载玻片用苏木精薄层复染(thin counterstain)并封固。结果如图20所描述。
为所有目的,本文提到的所有参考资料都通过引用完整地结合到本文中。
序列表
(1)一般信息:
(i)申请人:
(A)NAME:Canji,Inc.
(B)STREET:3030 Science Park Road
(C)CITY:San Diego
(D)STATE:California
(E)COUNTRY:USA
(F)POSTAL CODE(ZIP):92121
(G)TELEPHONE:(619)597-0177
(H)TELEFAX:(619)597-0237
(I)TELEX:
(i)申请人:
(A)NAME:Antelman,Douglas
(B)STREET:1716 Swallowtail Road
(C)CITY:Encinitas
(D)STATE:California
(E)COUNTRY:USA
(F)POSTAL CODE(ZIP):92024
(G)TELEPHONE:
(H)TELEFAX:
(I)TELEX:
(i)申请人:
(A)NAME:Gregory,Richard J.
(B)STREET:2 Wintergreen Lane
(C)CITY:Westford
(D)STATE:Massachusetts
(E)COUNTRY:USA
(F)POSTAL CODE(ZIP):01886
(G)TELEPHONE:
(H)TELEFAX:
(I)TELEX:
(i)申请人:
(A)NAME:Wills,Kenneth N.
(B)STREET:821 Bluffcrest Lane
(C)CITY:Encinitas
(D)STATE:California
(E)COUNTRY:USA
(F)POSTAL CODE(ZIP):92024
(G)TELEPHONE:
(H)TELEFAX:
(I)TELEX:
(ii)发明名称:成视网膜细胞瘤蛋白的组织特异性表达
(iii)序列数:17
(iv)联系地址:
(A)ADDRESSEE:Townsend and Townsend and Crew LLP
(B)STREET:Two Embarcadero Center,Eighth Floor
(C)CITY:San Francisco
(D)STATE:California
(E)COUNTRY:USA
(F)ZIP:94111-3834
(v)COMPUTER READABLE FORM:
(A)MEDIUM TYPE:Floppy disk
(B)COMPUTER:IBM PC compatible
(C)OPERATING SYSTEM:PC-DOS/MS-DOS
(D)SOFTWARE:PatentIn Release #1.0,Version #1.30
(vi)CURRENT APPLICATION DATA:
(A)APPLICATION NUMBER:WO PCT/US97/21821
(B)FILING DATE:13-NOV-1997
(C)CLASSIFICATION:
(vii)PRIOR APPLICATION DATA:
(A)APPLICATION NUMBER:US 08/751,517
(B)FILING DATE:15-NOV-1996
(vii)PRIOR APPLICATION DATA:
(A)APPLICATION NUMBER:US 08/801,092
(B)FILING DATE:14-FEB-1997
(viii)ATTORNEY/AGENT INFORMATION:
(A)NAME:Smith,Timothy L.
(B)REGISTRATION NUMBER:35,367
(C)REFERENCE/DOCKET NUMBER:16930-10-2PC
(ix)TELECOMMUNICATION INFORMATION:
(A)TELEPHONE:(415)576-0200
(B)TELEFAX:(415)576-0300
(2)SEQ ID NO:1信息:
(i)序列特征:
(A)长度:437个氨基酸
(B)类型:氨基酸
(C)链型:
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(ix)特征:
(A)名称/关键:蛋白质
(B)位置:1..437
(D)其它信息:/注意=″转录因子E2F″
(xi)序列描述:SEQ ID NO:1:
Met Ala Leu Ala Gly Ala Pro Ala Gly Gly Pro Cys Ala Pro Ala Leu
1 5 10 15
Glu Ala Leu Leu Gly Ala Gly Ala Leu Arg Leu Leu Asp Ser Ser Gln
20 25 30
Ile Val Ile Ile Ser Ala Ala Gln Asp Ala Ser Ala Pro Pro Ala Pro
35 40 45
Thr Gly Pro Ala Ala Pro Ala Ala Gly Pro Cys Asp Pro Asp Leu Leu
50 55 60
Leu Phe Ala Thr Pro Gln Ala Pro Arg Pro Thr Pro Ser Ala Pro Arg
65 70 75 80
Pro Ala Leu Gly Arg Pro Pro Val Lys Arg Arg Leu Asp Leu Glu Thr
85 90 95
Asp His Gln Tyr Leu Ala Glu Ser Ser Gly Pro Ala Arg Gly Arg Gly
100 105 110
Arg His Pro Gly Lys Gly Val Lys Ser Pro Gly Glu Lys Ser Arg Tyr
115 120 125
Glu Thr Ser Leu Asn Leu Thr Thr Lys Arg Phe Leu Glu Leu Leu Ser
130 135 140
His Ser Ala Asp Gly Val Val Asp Leu Asn Trp Ala Ala Glu Val Leu
145 150 155 160
Lys Val Gln Lys Arg Arg Ile Tyr Asp Ile Thr Asn Val Leu Glu Gly
165 170 175
Ile Gln Leu Ile Ala Lys Lys Ser Lys Asn His Ile Gln Trp Leu Gly
180 185 190
Ser His Thr Thr Val Gly Val Gly Gly Arg Leu Glu Gly Leu Thr Gln
195 200 205
Asp Leu Arg Gln Leu Gln Glu Ser Glu Gln Gln Leu Asp His Leu Met
210 215 220
Asn Ile Cys Thr Thr Gln Leu Arg Leu Leu Ser Glu Asp Thr Asp Ser
225 230 235 240
Gln Arg Leu Ala Tyr Val Thr Cys Gln Asp Leu Arg Ser Ile Ala Asp
245 250 255
Pro Ala Glu Gln Met Val Met Val Ile Lys Ala Pro Pro Glu Thr Gln
260 265 270
Leu Gln Ala Val Asp Ser Ser Glu Asn Phe Gln Ile Ser Leu Lys Ser
275 280 285
Lys Gln Gly Pro Ile Asp Val Phe Leu Cys Pro Glu Glu Thr Val Gly
290 295 300
Gly Ile Ser Pro Gly Lys Thr Pro Ser Gln Glu Val Thr Ser Glu Glu
305 310 315 320
Glu Asn Arg Ala Thr Asp Ser Ala Thr Ile Val Ser Pro Pro Pro Ser
325 330 335
Ser Pro Pro Ser Ser Leu Thr Thr Asp Pro Ser Gln Ser Leu Leu Ser
340 345 350
Leu Glu Gln Glu Pro Leu Leu Ser Arg Met Gly Ser Leu Arg Ala Pro
355 360 365
Val Asp Glu Asp Arg Leu Ser Pro Leu Val Ala Ala Asp Ser Leu Leu
370 375 380
Glu His Val Arg Glu Asp Phe Ser Gly Leu Leu Pro Glu Glu Phe Ile
385 390 395 400
Ser Leu Ser Pro Pro His Glu Ala Leu Asp Tyr His Phe Gly Leu Glu
405 410 415
Glu Gly Glu Gly Ile Arg Asp Leu Phe Asp Cys Asp Phe Gly Asp Leu
420 425 430
Thr Pro Leu Asp Phe
435
(2)SEQ ID NO:2信息:
(i)序列特征:
(A)长度:2517个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线性
(ii)分子类型:DNA
(ix)特征:
(A)名称/关键:-
(B)位置:1..2517
(D)其它信息:/注意=″转录因子E2F″
(xi)序列描述:SEQ ID NO:2:
GGAATTCCGT GGCCGGGACT TTGCAGGCAG CGGCGGCCGG GGGCGGAGCG GGATCGAGCC 60
CTCGCCGAGG CCTGCCGCCA TGGGCCCGCG CCGCCGCCGC CGCCTGTCAC CCGGGCCGCG 120
CGGGCCGTGA GCGTCATGGC CTTGGCCGGG GCCCCTGCGG GCGGCCCATG CGCGCCGGCG 180
CTGGAGGCCC TGCTCGGGGC CGGCGCGCTG CGGCTGCTCG ACTCCTCGCA GATCGTCATC 240
ATCTCCGCCG CGCAGGACGC CAGCGCCCCG CCGGCTCCCA CCGGCCCCGC GGCGCCCGCC 300
GCCGGCCCCT GCGACCCTGA CCTGCTGCTC TTCGCCACAC CGCAGGCGCC CCGGCCCACA 360
CCCAGTGCGC CGCGGCCCGC GCTCGGCCGC CCGCCGGTGA AGCGGAGGCT GGACCTGGAA 420
ACTGACCATC AGTACCTGGC CGAGAGCAGT GGGCCAGCTC GGGGCAGAGG CCGCCATCCA 480
GGAAAAGGTG TGAAATCCCC GGGGGAGAAG TCACGCTATG AGACCTCACT GAATCTGACC 540
ACCAAGCGCT TCCTGGAGCT GCTGAGCCAC TCGGCTGACG GTGTCGTCGA CCTGAACTGG 600
GCTGCCGAGG TGCTGAAGGT GCAGAAGCGG CGCATCTATG ACATCACCAA CGTCCTTGAG 660
GGCATCCAGC TCATTGCCAA GAAGTCCAAG AACCACATCC AGTGGCTGGG CAGCCACACC 720
ACAGTGGGCG TCGGCGGACG GCTTGAGGGG TTGACCCAGG ACCTCCGACA GCTGCAGGAG 780
AGCGAGCAGC AGCTGGACCA CCTGATGAAT ATCTGTACTA CGCAGCTGCG CCTGCTCTCC 840
GAGGACACTG ACAGCCAGCG CCTGGCCTAC GTGACGTGTC AGGACCTTCG TAGCATTGCA 900
GACCCTGCAG AGCAGATGGT TATGGTGATC AAAGCCCCTC CTGAGACCCA GCTCCAAGCC 960
GTGGACTCTT CGGAGAACTT TCAGATCTCC CTTAAGAGCA AACAAGGCCC GATCGATGTT 1020
TTCCTGTGCC CTGAGGAGAC CGTAGGTGGG ATCAGCCCTG GGAAGACCCC ATCCCAGGAG 1080
GTCACTTCTG AGGAGGAGAA CAGGGCCACT GACTCTGCCA CCATAGTGTC ACCACCACCA 1140
TCATCTCCCC CCTCATCCCT CACCACAGAT CCCAGCCAGT CTCTACTCAG CCTGGAGCAA 1200
GAACCGCTGT TGTCCCGGAT GGGCAGCCTG CGGGCTCCCG TGGACGAGGA CCGCCTGTCC 1260
CCGCTGGTGG CGGCCGACTC GCTCCTGGAG CATGTGCGGG AGGACTTCTC CGGCCTCCTC 1320
CCTGAGGAGT TCATCAGCCT TTCCCCACCC CACGAGGCCC TCGACTACCA CTTCGGCCTC 1380
GAGGAGGGCG AGGGCATCAG AGACCTCTTC GACTGTGACT TTGGGGACCT CACCCCCCTG 1440
GATTTCTGAC AGGGCTTGGA GGGACCAGGG TTTCCAGAGT AGCTCACCTT GTCTCTGCAG 1500
CCCTGGAGCC CCCTGTCCCT GGCCGTCCTC CCAGCCTGTT TGGAAACATT TAATTTATAC 1560
CCCTCTCCTC TGTCTCCAGA AGCTTCTAGC TCTGGGGTCT GGCTACCGCT AGGAGGCTGA 1620
GCAAGCCAGG AAGGGAAGGA GTCTGTGTGG TGTGTATGTG CATGCAGCCT ACACCCACAC 1680
GTGTGTACCG GGGGTGAATG TGTGTGAGCA TGTGTGTGTG CATGTACCGG GGAATGAAGG 1740
TGAACATACA CCTCTGTGTG TGCACTGCAG ACACGCCCCA GTGTGTCCAC ATGTGTGTGC 1800
ATGAGTCCAT CTCTGCGCGT GGGGGGGCTC TAACTGCACT TTCGGCCCTT TTGCTCGTGG 1860
GGTCCCACAA GGCCCAGGGC AGTGCCTGCT CCCAGAATCT GGTGCTCTGA CCAGGCCAGG 1920
TGGGGAGGCT TTGGCTGGCT GGGCGTGTAG GACGGTGAGA GCACTTCTGT CTTAAAGGTT 1980
TTTTCTGATT GAAGCTTTAA TGGAGCGTTA TTTATTTATC GAGGCCTCTT TGGTGAGCCT 2040
GGGGAATCAG CAAAAGGGGA GGAGGGGTGT GGGGTTGATA CCCCAACTCC CTCTACCCTT 2100
GAGCAAGGGC AGGGGTCCCT GAGCTGTTCT TCTGCCCCAT ACTGAAGGAA CTGAGGCCTG 2160
GGTGATTTAT TTATTGGGAA AGTGAGGGAG GGAGACAGAC TGACTGACAG CCATGGGTGG 2220
TCAGATGGTG GGGTGGGCCC TCTCCAGGGG GCCAGTTCAG GGCCCAGCTG CCCCCCAGGA 2280
TGGATATGAG ATGGGAGAGG TGAGTGGGGG ACCTTCACTG ATGTGGGCAG GAGGGGTGGT 2340
GAAGGCCTCC CCCAGCCCAG ACCCTGTGGT CCCTCCTGCA GTGTCTGAAG CGCCTGCCTC 2400
CCCACTGCTC TGCCCCACCC TCCAATCTGC ACTTTGATTT GCTTCCTAAC AGCTCTGTTC 2460
CCTCCTGCTT TGGTTTTAAT AAATATTTTG ATGACGTTAA AAAAAGGAAT TCGATAT 2517
(2)SEQ ID NO:3信息:
(i)序列特征:
(A)长度:2994个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线性
(ii)分子类型:DNA
(ix)特征:
(A)名称/关键:-
(B)位置:1..2994
(D)其它信息:/注意=″pRB″
(xi)序列描述:SEQ ID NO:3:
TTCCGGTTTT TCTCAGGGGA CGTTGAAATT ATTTTTGTAA CGGGAGTCGG GAGAGGACGG 60
GGCGTGCCCC GCGTGCGCGC GCGTCGTCCT CCCCGGCGCT CCTCCACAGC TCGCTGGCTC 120
CCGCCGCGGA AAGGCGTCAT GCCGCCCAAA ACCCCCCGAA AAACGGCCGC CACCGCCGCC 180
GCTGCCGCCG CGGAACCCCC GGCACCGCCG CCGCCGCCCC CTCCTGAGGA GGACCCAGAG 240
CAGGACAGCG GCCCGGAGGA CCTGCCTCTC GTCAGGCTTG AGTTTGAAGA AACAGAAGAA 300
CCTGATTTTA CTGCATTATG TCAGAAATTA AAGATACCAG ATCATGTCAG AGAGAGAGCT 360
TGGTTAACTT GGGAGAAAGT TTCATCTGTG GATGGAGTAT TGGGAGGTTA TATTCAAAAG 420
AAAAAGGAAC TGTGGGGAAT CTGTATCTTT ATTGCAGCAG TTGACCTAGA TGAGATGTCG 480
TTCACTTTTA CTGAGCTACA GAAAAACATA GAAATCAGTG TCCATAAATT CTTTAACTTA 540
CTAAAAGAAA TTGATACCAG TACCAAAGTT GATAATGCTA TGTCAAGACT GTTGAAGAAG 600
TATGATGTAT TGTTTGCACT CTTCAGCAAA TTGGAAAGGA CATGTGAACT TATATATTTG 660
ACACAACCCA GCAGTTCGAT ATCTACTGAA ATAAATTCTG CATTGGTGCT AAAAGTTTCT 720
TGGATCACAT TTTTATTAGC TAAAGGGGAA GTATTACAAA TGGAAGATGA TCTGGTGATT 780
TCATTTCAGT TAATGCTATG TGTCCTTGAC TATTTTATTA AACTCTCACC TCCCATGTTG 840
CTCAAAGAAC CATATAAAAC AGCTGTTATA CCCATTAATG GTTCACCTCG AACACCCAGG 900
CGAGGTCAGA ACAGGAGTGC ACGGATAGCA AAACAACTAG AAAATGATAC AAGAATTATT 960
GAAGTTCTCT GTAAAGAACA TGAATGTAAT ATAGATGAGG TGAAAAATGT TTATTTCAAA 1020
AATTTTATAC CTTTTATGAA TTCTCTTGGA CTTGTAACAT CTAATGGACT TCCAGAGGTT 1080
GAAAATCTTT CTAAACGATA CGAAGAAATT TATCTTAAAA ATAAAGATCT AGATGCAAGA 1140
TTATTTTTGG ATCATGATAA AACTCTTCAG ACTGATTCTA TAGACAGTTT TGAAACACAG 1200
AGAACACCAC GAAAAAGTAA CCTTGATGAA GAGGTGAATG TAATTCCTCC ACACACTCCA 1260
GTTAGGACTG TTATGAACAC TATCCAACAA TTAATGATGA TTTTAAATTC AGCAAGTGAT 1320
CAACCTTCAG AAAATCTGAT TTCCTATTTT AACAACTGCA CAGTGAATCC AAAAGAAAGT 1380
ATACTGAAAA GAGTGAAGGA TATAGGATAC ATCTTTAAAG AGAAATTTGC TAAAGCTGTG 1440
GGACAGGGTT GTGTCGAAAT TGGATCACAG CGATACAAAC TTGGAGTTCG CTTGTATTAC 1500
CGAGTAATGG AATCCATGCT TAAATCAGAA GAAGAACGAT TATCCATTCA AAATTTTAGC 1560
AAACTTCTGA ATGACAACAT TTTTCATATG TCTTTATTGG CGTGCGCTCT TGAGGTTGTA 1620
ATGGCCACAT ATAGCAGAAG TACATCTCAG AATCTTGATT CTGGAACAGA TTTGTCTTTC 1680
CCATGGATTC TGAATGTGCT TAATTTAAAA GCCTTTGATT TTTACAAAGT GATCGAAAGT 1740
TTTATCAAAG CAGAAGGCAA CTTGACAAGA GAAATGATAA AACATTTAGA ACGATGTGAA 1800
CATCGAATCA TGGAATCCCT TGCATGGCTC TCAGATTCAC CTTTATTTGA TCTTATTAAA 1860
CAATCAAAGG ACCGAGAAGG ACCAACTGAT CACCTTGAAT CTGCTTGTCC TCTTAATCTT 1920
CCTCTCCAGA ATAATCACAC TGCAGCAGAT ATGTATCTTT CTCCTGTAAG ATCTCCAAAG 1980
AAAAAAGGTT CAACTACGCG TGTAAATTCT ACTGCAAATG CAGAGACACA AGCAACCTCA 2040
GCCTTCCAGA CCCAGAAGCC ATTGAAATCT ACCTCTCTTT CACTGTTTTA TAAAAAAGTG 2100
TATCGGCTAG CCTATCTCCG GCTAAATACA CTTTGTGAAC GCCTTCTGTC TGAGCACCCA 2160
GAATTAGAAC ATATCATCTG GACCCTTTTC CAGCACACCC TGCAGAATGA GTATGAACTC 2220
ATGAGAGACA GGCATTTGGA CCAAATTATG ATGTGTTCCA TGTATGGCAT ATGCAAAGTG 2280
AAGAATATAG ACCTTAAATT CAAAATCATT GTAACAGCAT ACAAGGATCT TCCTCATGCT 2340
GTTCAGGAGA CATTCAAACG TGTTTTGATC AAAGAAGAGG AGTATGATTC TATTATAGTA 2400
TTCTATAACT CGGTCTTCAT GCAGAGACTG AAAACAAATA TTTTGCAGTA TGCTTCCACC 2460
AGGCCCCCTA CCTTGTCACC AATACCTCAC ATTCCTCGAA GCCCTTACAA GTTTCCTAGT 2520
TCACCCTTAC GGATTCCTGG AGGGAACATC TATATTTCAC CCCTGAAGAG TCCATATAAA 2580
ATTTCAGAAG GTCTGCCAAC ACCAACAAAA ATGACTCCAA GATCAAGAAT CTTAGTATCA 2640
ATTGGTGAAT CATTCGGGAC TTCTGAGAAG TTCCAGAAAA TAAATCAGAT GGTATGTAAC 2700
AGCGACCGTG TGCTCAAAAG AAGTGCTGAA GGAAGCAACC CTCCTAAACC ACTGAAAAAA 2760
CTACGCTTTG ATATTGAAGG ATCAGATGAA GCAGATGGAA GTAAACATCT CCCAGGAGAG 2820
TCCAAATTTC AGCAGAAACT GGCAGAAATG ACTTCTACTC GAACACGAAT GCAAAAGCAG 2880
AAAATGAATG ATAGCATGGA TACCTCAAAC AAGGAAGAGA AATGAGGATC TCAGGACCTT 2940
GGTGGACACT GTGTACACCT CTGGATTCAT TGTCTCTCAC AGATGTGACT GTAT 2994
(2)SEQ ID NO:4信息:
(i)序列特征:
(A)长度:928个氨基酸
(B)类型:氨基酸
(C)链型:
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(ix)特征:
(A)名称/关键:蛋白质
(B)位置:1..928
(D)其它信息:/注意=″pRB″
(xi)序列描述:SEQ ID NO:4:
Met Pro Pro Lys Thr Pro Arg Lys Thr Ala Ala Thr Ala Ala Ala Ala
1 5 10 15
Ala Ala Glu Pro Pro Ala Pro Pro Pro Pro Pro Pro Pro Glu Glu Asp
20 25 30
Pro Glu Gln Asp Ser Gly Pro Glu Asp Leu Pro Leu Val Arg Leu Glu
35 40 45
Phe Glu Glu Thr Glu Glu Pro Asp Phe Thr Ala Leu Cys Gln Lys Leu
50 55 60
Lys Ile Pro Asp His Val Arg Glu Arg Ala Trp Leu Thr Trp Glu Lys
65 70 75 80
Val Ser Ser Val Asp Gly Val Leu Gly Gly Tyr Ile Gln Lys Lys Lys
85 90 95
Glu Leu Trp Gly Ile Cys Ile Phe Ile Ala Ala Val Asp Leu Asp Glu
100 105 110
Met Ser Phe Thr Phe Thr Glu Leu Gln Lys Asn Ile Glu Ile Ser Val
115 120 125
His Lys Phe Phe Asn Leu Leu Lys Glu Ile Asp Thr Ser Thr Lys Val
130 135 140
Asp Asn Ala Met Ser Arg Leu Leu Lys Lys Tyr Asp Val Leu Phe Ala
145 150 155 160
Leu Phe Ser Lys Leu Glu Arg Thr Cys Glu Leu Ile Tyr Leu Thr Gln
165 170 175
Pro Ser Ser Ser Ile Ser Thr Glu Ile Asn Ser Ala Leu Val Leu Lys
180 185 190
Val Ser Trp Ile Thr Phe Leu Leu Ala Lys Gly Glu Val Leu Gln Met
195 200 205
Glu Asp Asp Leu Val Ile Ser Phe Gln Leu Met Leu Cys Val Leu Asp
210 215 220
Tyr Phe Ile Lys Leu Ser Pro Pro Met Leu Leu Lys Glu Pro Tyr Lys
225 230 235 240
Thr Ala Val Ile Pro Ile Asn Gly Ser Pro Arg Thr Pro Arg Arg Gly
245 250 255
Gln Asn Arg Ser Ala Arg Ile Ala Lys Gln Leu Glu Asn Asp Thr Arg
260 265 270
Ile Ile Glu Val Leu Cys Lys Glu His Glu Cys Asn Ile Asp Glu Val
275 280 285
Lys Asn Val Tyr Phe Lys Asn Phe Ile Pro Phe Met Asn Ser Leu Gly
290 295 300
Leu Val Thr Ser Asn Gly Leu Pro Glu Val Glu Asn Leu Ser Lys Arg
305 310 315 320
Tyr Glu Glu Ile Tyr Leu Lys Asn Lys Asp Leu Asp Ala Arg Leu Phe
325 330 335
Leu Asp His Asp Lys Thr Leu Gln Thr Asp Ser Ile Asp Ser Phe Glu
340 345 350
Thr Gln Arg Thr Pro Arg Lys Ser Asn Leu Asp Glu Glu Val Asn Val
355 360 365
Ile Pro Pro His Thr Pro Val Arg Thr Val Met Asn Thr Ile Gln Gln
370 375 380
Leu Met Met Ile Leu Asn Ser Ala Ser Asp Gln Pro Ser Glu Asn Leu
385 390 395 400
Ile Ser Tyr Phe Asn Asn Cys Thr Val Asn Pro Lys Glu Ser Ile Leu
405 410 415
Lys Arg Val Lys Asp Ile Gly Tyr Ile Phe Lys Glu Lys Phe Ala Lys
420 425 430
Ala Val Gly Gln Gly Cys Val Glu Ile Gly Ser Gln Arg Tyr Lys Leu
435 440 445
Gly Val Arg Leu Tyr Tyr Arg Val Met Glu Ser Met Leu Lys Ser Glu
450 455 460
Glu Glu Arg Leu Ser Ile Gln Asn Phe Ser Lys Leu Leu Asn Asp Asn
465 470 475 480
Ile Phe His Met Ser Leu Leu Ala Cys Ala Leu Glu Val Val Met Ala
485 490 495
Thr Tyr Ser Arg Ser Thr Ser Gln Asn Leu Asp Ser Gly Thr Asp Leu
500 505 510
Ser Phe Pro Trp Ile Leu Asn Val Leu Asn Leu Lys Ala Phe Asp Phe
515 520 525
Tyr Lys Val Ile Glu Ser Phe Ile Lys Ala Glu Gly Asn Leu Thr Arg
530 535 540
Glu Met Ile Lys His Leu Glu Arg Cys Glu His Arg Ile Met Glu Ser
545 550 555 560
Leu Ala Trp Leu Ser Asp Ser Pro Leu Phe Asp Leu Ile Lys Gln Ser
565 570 575
Lys Asp Arg Glu Gly Pro Thr Asp His Leu Glu Ser Ala Cys Pro Leu
580 585 590
Asn Leu Pro Leu Gln Asn Asn His Thr Ala Ala Asp Met Tyr Leu Ser
595 600 605
Pro Val Arg Ser Pro Lys Lys Lys Gly Ser Thr Thr Arg Val Asn Ser
610 615 620
Thr Ala Asn Ala Glu Thr Gln Ala Thr Ser Ala Phe Gln Thr Gln Lys
625 630 635 640
Pro Leu Lys Ser Thr Ser Leu Ser Leu Phe Tyr Lys Lys Val Tyr Arg
645 650 655
Leu Ala Tyr Leu Arg Leu Asn Thr Leu Cys Glu Arg Leu Leu Ser Glu
660 665 670
His Pro Glu Leu Glu His Ile Ile Trp Thr Leu Phe Gln His Thr Leu
675 680 685
Gln Asn Glu Tyr Glu Leu Met Arg Asp Arg His Leu Asp Gln Ile Met
690 695 700
Met Cys Ser Met Tyr Gly Ile Cys Lys Val Lys Asn Ile Asp Leu Lys
705 710 715 720
Phe Lys Ile Ile Val Thr Ala Tyr Lys Asp Leu Pro His Ala Val Gln
725 730 735
Glu Thr Phe Lys Arg Val Leu Ile Lys Glu Glu Glu Tyr Asp Ser Ile
740 745 750
Ile Val Phe Tyr Asn Ser Val Phe Met Gln Arg Leu Lys Thr Asn Ile
755 760 765
Leu Gln Tyr Ala Ser Thr Arg Pro Pro Thr Leu Ser Pro Ile Pro His
770 775 780
Ile Pro Arg Ser Pro Tyr Lys Phe Pro Ser Ser Pro Leu Arg Ile Pro
785 790 795 800
Gly Gly Asn Ile Tyr Ile Ser Pro Leu Lys Ser Pro Tyr Lys Ile Ser
805 810 815
Glu Gly Leu Pro Thr Pro Thr Lys Met Thr Pro Arg Ser Arg Ile Leu
820 825 830
Val Ser Ile Gly Glu Ser Phe Gly Thr Ser Glu Lys Phe Gln Lys Ile
835 840 845
Asn Gln Met Val Cys Asn Ser Asp Arg Val Leu Lys Arg Ser Ala Glu
850 855 860
Gly Ser Asn Pro Pro Lys Pro Leu Lys Lys Leu Arg Phe Asp Ile Glu
865 870 875 880
Gly Ser Asp Glu Ala Asp Gly Ser Lys His Leu Pro Gly Glu Ser Lys
885 890 895
Phe Gln Gln Lys Leu Ala Glu Met Thr Ser Thr Arg Thr Arg Met Gln
900 905 910
Lys Gln Lys Met Asn Asp Ser Met Asp Thr Ser Asn Lys Glu Glu Lys
915 920 925
(2)SEQ ID NO:5信息:
(i)序列特征:
(A)长度:3853个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线性
(ii)分子类型:DNA
(ix)特征:
(A)名称/关键:-
(B)位置:1..3853
(D)其它信息:/注意=″质粒pCTM″
(ix)特征:
(A)名称/关键:CDS
(B)位置:209..862
(xi)序列描述:SEQ ID NO:5:
GACGGATCGG GAGATCTCCC GATCCCCTAT GGTCGACTCT CAGTACAATC TGCTCTGATG 60
CCGCATAGTT AAGCCAGTAT CTGCTCCCTG CTTGTGTGTT GGAGGTCGCT GAGTAGTGCG 120
CGAGCAAAAT TTAAGCTACA ACAAGGCAAG GCTTGACCGA CAATTGCATG AAGAATCTGC 180
TTAGGGTTAG GCGTTTTGCG CTGCTTCG CGA TGT ACG GGC CAG ATA TAC GCG 232
Arg Cys Thr Gly Gln Ile Tyr Ala
1 5
TTG ACA TTG ATT ATT GAC TAG TTA TTA ATA GTA ATC AAT TAC GGG GTC 280
Leu Thr Leu Ile Ile Asp Leu Leu Ile Val Ile Asn Tyr Gly Val
10 15 20
ATT AGT TCA TAG CCC ATA TAT GGA GTT CCG CGT TAC ATA ACT TAC GGT 328
Ile Ser Ser Pro Ile Tyr Gly Val Pro Arg Tyr Ile Thr Tyr Gly
25 30 35 40
AAA TGG CCC GCC TGG CTG ACC GCC CAA CGA CCC CCG CCC ATT GAC GTC 376
Lys Trp Pro Ala Trp Leu Thr Ala Gln Arg Pro Pro Pro Ile Asp Val
45 50 55
AAT AAT GAC GTA TGT TCC CAT AGT AAC GCC AAT AGG GAC TTT CCA TTG 424
Asn Asn Asp Val Cys Ser His Ser Asn Ala Asn Arg Asp Phe Pro Leu
60 65 70
ACG TCA ATG GGT GGA CTA TTT ACG GTA AAC TGC CCA CTT GGC AGT ACA 472
Thr Ser Met Gly Gly Leu Phe Thr Val Asn Cys Pro Leu Gly Ser Thr
75 80 85
TCA AGT GTA TCA TAT GCC AAG TAC GCC CCC TAT TGA CGT CAA TGA CGG 520
Ser Ser Val Ser Tyr Ala Lys Tyr Ala Pro Tyr Arg Gln Arg
90 95 100
TAA ATG GCC CGC CTG GCA TTA TGC CCA GTA CAT GAC CTT ATG GGA CTT 568
Met Ala Arg Leu Ala Leu Cys Pro Val His Asp Leu Met Gly Leu
105 110 115 120
TCC TAC TTG GCA GTA CAT CTA CGT ATT AGT CAT CGC TAT TAC CAT GGT 616
Ser Tyr Leu Ala Val His Leu Arg Ile Ser His Arg Tyr Tyr His Gly
125 130 135
GAT GCG GTT TTG GCA GTA CAT CAA TGG GCG TGG ATA GCG GTT TGA CTC 664
Asp Ala Val Leu Ala Val His Gln Trp Ala Trp Ile Ala Val Leu
140 145 150
ACG GGG ATT TCC AAG TCT CCA CCC CAT TGA CGT CAA TGG GAG TTT GTT 712
Thr Gly Ile Ser Lys Ser Pro Pro His Arg Gln Trp Glu Phe Val
155 160 165
TTG GCA CCA AAA TCA ACG GGA CTT TCC AAA ATG TCG TAA CAA CTC CGC 760
Leu Ala Pro Lys Ser Thr Gly Leu Ser Lys Met Ser Gln Leu Arg
170 175 180
CCC ATT GAC GCA AAT GGG CGG TAG GCG TGT ACG GTG GGA GGT CTA TAT 808
Pro Ile Asp Ala Asn Gly Arg Ala Cys Thr Val Gly Gly Leu Tyr
185 190 195 200
AAG CAG AGC TCT CTG GCT AAC TAG AGA ACC CAC TGC TTA CTG GCT TAT 856
Lys Gln Ser Ser Leu Ala Asn Arg Thr His Cys Leu Leu Ala Tyr
205 210 215
CGA AAT TAATACGACT CACTATAGGG AGACCCAAGC TTCGCGCGGG TACCACTCTC 912
Arg Asn
TTCCGCATCG CTGTCTGCGA GGGCCAGCTG TTGGGCTCGC GGTTGAGGAC AAACTCTTCG 972
CGGTCTTTCC AGTACTCTTG GATCGGAAAC CCGTCGGCCT CCGAACGGTA CTCCGCCACC 1032
GAGGGACCTG AGCGAGTCCG CATCGACCGG ATCGGAAAAC CTCTCGAGGC GGCCGCTGCA 1092
GTCTAGACGA ATTCGCGTAC GATATCGATG GGCCCTATT CTA TAG TGT CAC CTA 1146
Leu Cys His Leu
220
AAT GCTAGAGCTC GCTGATCAGC CTCGACTGTG CCTTCTAGTT GCCAGCCATC 1199
Asn
TGTTGTTTGC CCCTCCCCCG TGCCTTCCTT GACCCTGGAA GGTGCCACTC CCACTGTCCT 1259
TTCCTAATAA AATGAGGAAA TTGCATCGCA TTGTCTGAGT AGGTGTCATT CTATTCTGGG 1319
GGGTGGGGTG GGGCAGGACA GCAAGGGGGA GGATTGGGAA GACAATAGCC GAAATGACCG 1379
ACCAAGCGAC GCCCAACCTG CCATCACGAG ATTTCGATTC CACCGCCGCC TTCTATGAAA 1439
GGTTGGGCTT CGGAATCGTT TTCCGGGACG CCGGCTGGAT GATCCTCCAG CGCGGGGATC 1499
TCATGCTGGA GTTCTTCGCC CACCCCAACT TGTTTATTGC AGCTTATAAT GGTTACAAAT 1559
AAAGCAATAG CATCACAAAT TTCACAAATA AAGCATTTTT TTCACTGCAT TCTAGTTGTG 1619
GTTTGTCCAA ACTCATCAAT GTATCTTATC ATGTCTGTAT ACCGTCGACC TCTAGCTAGA 1679
GCTTGGCGTA ATCATGGTCA TAGCTGTTTC CTGTGTGAAA TTGTTATCCG CTCACAATTC 1739
CACACAACAT ACGAGCCGGA AGCATAAAGT GTAAAGCCTG GGGTGCCTAA TGAGTGAGCT 1799
AACTCACATT AATTGCGTTG CGCTCACTGC CCGCTTTCCA GTCGGGAAAC CTGTCGTGCC 1859
AGCTGCATTA ATGAATCGGC CAACGCGCGG GGAGAGGCGG TTTGCGTATT GGGCGCTCTT 1919
CCGCTTCCTC GCTCACTGAC TCGCTGCGCT CGGTCGTTCG GCTGCGGCGA GCGGTATCAG 1979
CTCACTCAAA GGCGGTAATA CGGTTATCCA CAGAATCAGG GGATAACGCA GGAAAGAACA 2039
TGTGAGCAAA AGGCCAGCAA AAGGCCAGGA ACCGTAAAAA GGCCGCGTTG CTGGCGTTTT 2099
TCCATAGGCT CCGCCCCCCT GACGAGCATC ACAAAAATCG ACGCTCAAGT CAGAGGTGGC 2159
GAAACCCGAC AGGACTATAA AGATACCAGG CGTTTCCCCC TGGAAGCTCC CTCGTGCGCT 2219
CTCCTGTTCC GACCCTGCCG CTTACCGGAT ACCTGTCCGC CTTTCTCCCT TCGGGAAGCG 2279
TGGCGCTTTC TCAATGCTCA CGCTGTAGGT ATCTCAGTTC GGTGTAGGTC GTTCGCTCCA 2339
AGCTGGGCTG TGTGCACGAA CCCCCCGTTC AGCCCGACCG CTGCGCCTTA TCCGGTAACT 2399
ATCGTCTTGA GTCCAACCCG GTAAGACACG ACTTATCGCC ACTGGCAGCA GCCACTGGTA 2459
ACAGGATTAG CAGAGCGAGG TATGTAGGCG GTGCTACAGA GTTCTTGAAG TGGTGGCCTA 2519
ACTACGGCTA CACTAGAAGG ACAGTATTTG GTATCTGCGC TCTGCTGAAG CCAGTTACCT 2579
TCGGAAAAAG AGTTGGTAGC TCTTGATCCG GCAAACAAAC CACCGCTGGT AGCGGTGGTT 2639
TTTTTGTTTG CAAGCAGCAG ATTACGCGCA GAAAAAAAGG ATCTCAAGAA GATCCTTTGA 2699
TCTTTTCTAC GGGGTCTGAC GCTCAGTGGA ACGAAAACTC ACGTTAAGGG ATTTTGGTCA 2759
TGAGATTATC AAAAAGGATC TTCACCTAGA TCCTTTTAAA TTAAAAATGA AGTTTTAAAT 2819
CAATCTAAAG TATATATGAG TAAACTTGGT CTGACAGTTA CCAATGCTTA ATCAGTGAGG 2879
CACCTATCTC AGCGATCTGT CTATTTCGTT CATCCATAGT TGCCTGACTC CCCGTCGTGT 2939
AGATAACTAC GATACGGGAG GGCTTACCAT CTGGCCCCAG TGCTGCAATG ATACCGCGAG 2999
ACCCACGCTC ACCGGCTCCA GATTTATCAG CAATAAACCA GCCAGCCGGA AGGGCCGAGC 3059
GCAGAAGTGG TCCTGCAACT TTATCCGCCT CCATCCAGTC TATTAATTGT TGCCGGGAAG 3119
CTAGAGTAAG TAGTTCGCCA GTTAATAGTT TGCGCAACGT TGTTGCCATT GCTACAGGCA 3179
TCGTGGTGTC ACGCTCGTCG TTTGGTATGG CTTCATTCAG CTCCGGTTCC CAACGATCAA 3239
GGCGAGTTAC ATGATCCCCC ATGTTGTGCA AAAAAGCGGT TAGCTCCTTC GGTCCTCCGA 3299
TCGTTGTCAG AAGTAAGTTG GCCGCAGTGT TATCACTCAT GGTTATGGCA GCACTGCATA 3359
ATTCTCTTAC TGTCATGCCA TCCGTAAGAT GCTTTTCTGT GACTGGTGAG TACTCAACCA 3419
AGTCATTCTG AGAATAGTGT ATGCGGCGAC CGAGTTGCTC TTGCCCGGCG TCAATACGGG 3479
ATAATACCGC GCCACATAGC AGAACTTTAA AAGTGCTCAT CATTGGAAAA CGTTCTTCGG 3539
GGCGAAAACT CTCAAGGATC TTACCGCTGT TGAGATCCAG TTCGATGTAA CCCACTCGTG 3599
CACCCAACTG ATCTTCAGCA TCTTTTACTT TCACCAGCGT TTCTGGGTGA GCAAAAACAG 3659
GAAGGCAAAA TGCCGCAAAA AAGGGAATAA GGGCGACACG GAAATGTTGA ATACTCATAC 3719
TCTTCCTTTT TCAATATTAT TGAAGCATTT ATCAGGGTTA TTGTCTCATG AGCGGATACA 3779
TATTTGAATG TATTTAGAAA AATAAACAAA TAGGGGTTCC GCGCACATTT CCCCGAAAAG 3839
TGCCACCTGA CGTC 3853
(2)SEQ ID NO:6信息:
(i)序列特征:
(A)长度:14个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(xi)序列描述:SEQ ID NO:6:
Arg Cys Thr Gly Gln Ile Tyr Ala Leu Thr Leu Ile Ile Asp
1 5 10
(2)SEQ ID NO:7信息:
(i)序列特征:
(A)长度:12个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(xi)序列描述:SEQ ID NO:7:
Leu Leu Ile Val Ile Asn Tyr Gly Val Ile Ser Ser
1 5 10
(2)SEQ ID NO:8信息:
(i)序列特征:
(A)长度:71个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(xi)序列描述:SEQ ID NO:8:
Pro Ile Tyr Gly Val Pro Arg Tyr Ile Thr Tyr Gly Lys Trp Pro Ala
1 5 10 15
Trp Leu Thr Ala Gln Arg Pro Pro Pro Ile Asp Val Asn Asn Asp Val
20 25 30
Cys Ser His Ser Asn Ala Asn Arg Asp Phe Pro Leu Thr Ser Met Gly
35 40 45
Gly Leu Phe Thr Val Asn Cys Pro Leu Gly Ser Thr Ser Ser Val Ser
50 55 60
Tyr Ala Lys Tyr Ala Pro Tyr
65 70
(2)SEQ ID NO:9信息:
(i)序列特征:
(A)长度:45个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(xi)序列描述:SEQ ID NO:9:
Met Ala Arg Leu Ala Leu Cys Pro Val His Asp Leu Met Gly Leu Ser
1 5 10 15
Tyr Leu Ala Val His Leu Arg Ile Ser His Arg Tyr Tyr His Gly Asp
20 25 30
Ala Val Leu Ala Val His Gln Trp Ala Trp Ile Ala Val
35 40 45
(2)SEQ ID NO:10信息:
(i)序列特征:
(A)长度:10个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(xi)序列描述:SEQ ID NO:10:
Leu Thr Gly Ile Ser Lys Ser Pro Pro His
1 5 10
(2)SEQ ID NO:11信息:
(i)序列特征:
(A)长度:18个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(xi)序列描述:SEQ ID NO:11:
Arg Gln Trp Glu Phe Val Leu Ala Pro Lys Ser Thr Gly Leu Ser Lys
1 5 10 15
Met Ser
(2)SEQ ID NO:12信息:
(i)序列特征:
(A)长度:10个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(xi)序列描述:SEQ ID NO:12:
Gln Leu Arg Pro Ile Asp Ala Asn Gly Arg
1 5 10
(2)SEQ ID NO:13信息:
(i)序列特征:
(A)长度:15个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(xi)序列描述:SEQ ID NO:13:
Ala Cys Thr Val Gly Gly Leu Tyr Lys Gln Ser Ser Leu Ala Asn
1 5 10 15
(2)SEQ ID NO:14信息:
(i)序列特征:
(A)长度:11个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(xi)序列描述:SEQ ID NO:14:
Arg Thr His Cys Leu Leu Ala Tyr Arg Asn Leu
1 5 10
(2)SEQ ID NO:15信息:
(i)序列特征:
(A)长度:4个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(xi)序列描述:SEQ ID NO:15:
Cys His Leu Asn
1
(2)SEQ ID NO:16信息:
(i)序列特征:
(A)长度:4026个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线性
(ii)分子类型:DNA
(ix)特征:
(A)名称/关键:-
(B)位置:1..4026
(D)其它信息:/注意=″质粒pCTMI″
(xi)序列描述:SEQ ID NO:16:
GACGGATCGG GAGATCTCCC GATCCCCTAT GGTCGACTCT CAGTACAATC TGCTCTGATG 60
CCGCATAGTT AAGCCAGTAT CTGCTCCCTG CTTGTGTGTT GGAGGTCGCT GAGTAGTGCG 120
CGAGCAAAAT TTAAGCTACA ACAAGGCAAG GCTTGACCGA CAATTGCATG AAGAATCTGC 180
TTAGGGTTAG GCGTTTTGCG CTGCTTCGCG ATGTACGGGC CAGATATACG CGTTGACATT 240
GATTATTGAC TAGTTATTAA TAGTAATCAA TTACGGGGTC ATTAGTTCAT AGCCCATATA 300
TGGAGTTCCG CCTTACATAA CTTACGGTAA ATGGCCCGCC TGGCTGACCG CCCAACGACC 360
CCCGCCCATT GACGTCAATA ATGACGTATG TTCCCATAGT AACGCCAATA GGGACTTTCC 420
ATTGACGTCA ATGGGTGGAC TATTTACGGT AAACTGCCCA CTTGGCAGTA CATCAAGTGT 480
ATCATATGCC AAGTACGCCC CCTATTGACG TCAATGACGG TAAATGGCCC GCCTGGCATT 540
ATGCCCAGTA CATGACCTTA TGGGACTTTC CTACTTGGCA GTACATCTAC GTATTAGTCA 600
TCGCTATTAC CATGGTGATG CGGTTTTGGC AGTACATCAA TGGGCGTGGA TAGCGGTTTG 660
ACTCACGGGG ATTTCCAAGT CTCCACCCCA TTGACGTCAA TGGGAGTTTG TTTTGGCACC 720
AAAATCAACG GGACTTTCCA AAATGTCGTA ACAACTCCGC CCCATTGACG CAAATGGGCG 780
GTAGGCGTGT ACGGTGGGAG GTCTATATAA GCAGAGCTCT CTGGCTAACT AGAGAACCCA 840
CTGCTTACTG GCTTATCGAA ATTAATACGA CTCACTATAG GGAGACCCAA GCTTCGCGCG 900
GGTACCACTC TCTTCCGCAT CGCTGTCTGC GAGGGCCAGC TGTTGGGCTC GCGGTTGAGG 960
AGAAACTCTT CGCGGTCTTT CCAGTACTCT TGGATCGGAA ACCCGTCGGC CTCCGAACGG 1020
TACTCCGCCA CCGAGGGACC TGAGCGAGTC CGCATCGACC GGATCGGAAA ACCTCTCGAG 1080
GAACTGAAAA ACCAGAAAGT TAACTGGTAA GTTTAGTCTT TTTGTCTTTT TATTTCAGGT 1140
CCCGGATCCG GTGGTGGTGC AAATCAAAGA ACTGCTCCTC AGTGGATGTT GCCTTTACTT 1200
CTAGGCCTGT ACGGAAGTGT TACTTCTGCT CTAAAAGCTG CGGAATTGTA CCCGCGGCCG 1260
CTGCAGTCTA GACGAATTCG CGTACGATAT CGATGGGCCC TATTCTATAG TGTCACCTAA 1320
ATGCTAGAGC TCGCTGATCA GCCTCGACTG TGCCTTCTAG TTGCCAGCCA TCTGTTGTTT 1380
GCCCCTCCCC CGTGCCTTCC TTGACCCTGG AAGGTGCCAC TCCCACTGTC CTTTCCTAAT 1440
AAAATGAGGA AATTGCATCG CATTGTCTGA GTAGGTGTCA TTCTATTCTG GGGGGTGGGG 1500
TGGGGCAGGA CAGCAAGGGG GAGGATTGGG AAGACAATAG CCGAAATGAC CGACCAAGCG 1560
ACGCCCAACC TGCCATCACG AGATTTCGAT TCCACCGCCG CCTTCTATGA AAGGTTGGGC 1620
TTCGGAATCG TTTTCCGGGA CGCCGGCTGG ATGATCCTCC AGCGCCGGGA TCTCATGCTG 1680
GAGTTCTTCG CCCACCCCAA CTTGTTTATT GCAGCTTATA ATGGTTACAA ATAAAGCAAT 1740
AGCATCACAA ATTTCACAAA TAAAGCATTT TTTTCACTGC ATTCTAGTTG TGGTTTGTCC 1800
AAACTCATCA ATGTATCTTA TCATGTCTGT ATACCGTCGA CCTCTAGCTA GAGCTTGGCG 1860
TAATCATGGT CATAGCTGTT TCCTGTGTGA AATTGTTATC CGCTCACAAT TCCACACAAC 1920
ATACGAGCCG GAAGCATAAA GTGTAAAGCC TGGGGTGCCT AATGAGTGAG CTAACTCACA 1980
TTAATTGCGT TGCGCTCACT GCCCGCTTTC CAGTCGGGAA ACCTGTCGTG CCAGCTGCAT 2040
TAATGAATCG GCCAACGCGC GGGGAGAGGC GGTTTGCGTA TTGGGCGCTC TTCCGCTTCC 2100
TCGCTCACTG ACTCGCTGCG CTCGGTCGTT CGGCTGCGGC GAGCGGTATC AGCTCACTCA 2160
AAGGCGGTAA TACGGTTATC CACAGAATCA GGGGATAACG CAGGAAAGAA CATGTGAGCA 2220
AAAGGCCAGC AAAAGGCCAG GAACCGTAAA AAGGCCGCGT TGCTGGCGTT TTTCCATAGG 2280
CTCCGCCCCC CTGACGAGCA TCACAAAAAT CGACGCTCAA GTCAGAGGTG GCGAAACCCG 2340
ACAGGACTAT AAAGATACCA GGCGTTTCCC CCTGGAAGCT CCCTCGTGCG CTCTCCTGTT 2400
CCGACCCTGC CGCTTACCGG ATACCTGTCC GCCTTTCTCC CTTCGGGAAG CGTGGCGCTT 2460
TCTCAATGCT CACGCTGTAG GTATCTCAGT TCGGTGTAGG TCGTTCGCTG CAAGCTGGGC 2520
TGTGTGCACG AACCCCCCGT TCAGCCCGAC CGCTGCGCCT TATCCGGTAA CTATCGTCTT 2580
GAGTCCAACC CGGTAAGACA CGACTTATCG CCACTGGCAG CAGCCACTGG TAACAGGATT 2640
AGCAGAGCGA GGTATGTAGG CGGTGCTACA GAGTTCTTGA AGTGGTGGCC TAACTACGGC 2700
TACACTAGAA GGACAGTATT TGGTATCTGC GCTCTGCTGA AGCCAGTTAC CTTCGGAAAA 2760
AGAGTTGGTA GCTCTTGATC CGGCAAACAA ACCACCGCTG GTAGCGGTGG TTTTTTTGTT 2820
TGCAAGCAGC AGATTACGCG CAGAAAAAAA GGATCTCAAG AAGATCCTTT GATCTTTTCT 2880
ACGGGGTCTG ACGCTCAGTG GAACGAAAAC TCACGTTAAG GGATTTTGGT CATGAGATTA 2940
TCAAAAAGGA TCTTCACCTA GATCCTTTTA AATTAAAAAT GAAGTTTTAA ATCAATCTAA 3000
AGTATATATG AGTAAACTTG GTCTGACAGT TACCAATGCT TAATCAGTGA GGCACCTATC 3060
TCAGCGATCT GTCTATTTCG TTCATCCATA GTTGCCTGAC TCCCCGTCGT GTAGATAACT 3120
ACGATACGGG AGGGCTTACC ATCTGGCCCC AGTGCTGCAA TGATACCGCG AGACCCACGC 3180
TCACCGGCTC CAGATTTATC AGCAATAAAC CAGCCAGCCG GAAGGGCCGA GCGCAGAAGT 3240
GGTCCTGCAA CTTTATCCGC CTCCATCCAG TCTATTAATT GTTGCCGGGA AGCTAGAGTA 3300
AGTAGTTCGC CAGTTAATAG TTTGCGCAAC GTTGTTGCCA TTGCTACAGG CATCGTGGTG 3360
TCACGCTCGT CGTTTGGTAT GGCTTCATTC AGCTCCGGTT CCCAACGATC AAGGCGAGTT 3420
ACATGATCCC CCATGTTGTG CAAAAAAGCG GTTAGCTCCT TCGGTCCTCC GATCGTTGTC 3480
AGAAGTAAGT TGGCCGCAGT GTTATCACTC ATGGTTATGG CAGCACTGCA TAATTCTCTT 3540
ACTGTCATGC CATCCGTAAG ATGCTTTTCT GTGACTGGTG AGTACTCAAC CAAGTCATTC 3600
TGAGAATAGT GTATGCGGCG ACCGAGTTGC TCTTGCCCGG CGTCAATACG GGATAATACC 3660
GCGCCACATA GCAGAACTTT AAAAGTGCTC ATCATTGGAA AACGTTCTTC GGGGCGAAAA 3720
CTCTCAAGGA TCTTACCGCT GTTGAGATCC AGTTCGATGT AACCCACTCG TGCACCCAAC 3780
TGATCTTCAG CATCTTTTAC TTTCACCAGC GTTTCTGGGT GAGCAAAAAC AGGAAGGCAA 3840
AATGCCGCAA AAAAGGGAAT AAGGGCGACA CGGAAATGTT GAATACTCAT ACTCTTCCTT 3900
TTTCAATATT ATTGAAGCAT TTATCAGGGT TATTGTCTCA TGAGCGGATA CATATTTGAA 3960
TGTATTTAGA AAAATAAACA AATAGGGGTT CCGCGCACAT TTCCCCGAAA AGTGCCACCT 4020
GACGTC 4026
(2)SEQ ID NO:17信息:
(i)序列特征:
(A)长度:4249个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线性
(ii)分子类型:DNA
(ix)特征:
(A)名称/关键:-
(B)位置:1..4249
(D)其它信息:/注意=″质粒pCTMIE″
(xi)序列描述:SEQ ID NO:17:
GACGGATCGG GAGATCTCCC GATCCCCTAT GGTCGACTCT CAGTACAATC TGCTCTGATG 60
CCGCATAGTT AAGCCAGTAT CTGCTCCCTG CTTGTGTGTT GGAGGTCGCT GAGTAGTGCG 120
CGAGCAAAAT TTAAGCTACA ACAAGGCAAG GCTTGACCGA CAATTGCATG AAGAATCTGC 180
TTAGGGTTAG GCGTTTTGCG CTGCTTCGCG ATGTACGGGC CAGATATACG CGTTGACATT 240
GATTATTGAC TAGTTATTAA TAGTAATCAA TTACGGGGTC ATTAGTTCAT AGCCCATATA 300
TGGAGTTCCG CGTTACATAA CTTACGGTAA ATGGCCCGCC TGGCTGACCG CCCAACGACC 360
CCCGCCCATT GACGTCAATA ATGACGTATG TTCCCATAGT AACGCCAATA GGGACTTTCC 420
ATTGACGTCA ATGGGTGGAC TATTTACGGT AAACTGCCCA CTTGGCAGTA CATCAAGTGT 480
ATCATATGCC AAGTACGCCC CCTATTGACG TCAATGACGG TAAATGGCCC GCCTGGCATT 540
ATGCCCAGTA CATGACCTTA TGGGACTTTC CTACTTGGCA GTACATCTAC GTATTAGTCA 600
TCGCTATTAC CATGGTGATG CGGTTTTGGC AGTACATCAA TGGGCGTGGA TAGCGGTTTG 660
ACTCACGGGG ATTTCCAAGT CTCCACCCCA TTGACGTCAA TGGGAGTTTG TTTTGGCACC 720
AAAATCAACG GGACTTTCCA AAATGTCGTA ACAACTCCGC CCCATTGACG CAAATGGGCG 780
GTAGGCGTGT ACGGTGGGAG GTCTATATAA GCAGAGCTCT CTGGCTAACT AGAGAACCCA 840
CTGCTTACTG GCTTATCGAA ATTAATACGA CTCACTATAG GGAGACCCAA GCTTCGCGCG 900
GGTACCACTC TCTTCCGCAT CGCTGTCTGC GAGGGCCAGC TGTTGGGCTC GCGGTTGAGG 960
ACAAACTCTT CGCGGTCTTT CCAGTACTCT TGGATCGGAA ACCCGTCGGC CTCCGAACGG 1020
TACTCCGCCA CCGAGGGACC TGAGCGAGTC CGCATCGACC GGATCGGAAA ACCTCTCGAG 1080
GAACTGAAAA ACCAGAAAGT TAACTGGTAA GTTTAGTCTT TTTGTCTTTT TATTTCAGGT 1140
CCCGGATCTG AGTTAGGGCG GGACATGGGC GGAGTTAGGG GCGGGACTAT GGTTGCTGAC 1200
TAATTGAGAT GCATGCTTTG CATACTTCTG CCTGCTGGGG AGCCTGGGGA CTTTCCACAC 1260
CTGGTTGCTG ACTAATTGAG ATGCATGCTT TGCATACTTC TGCCTGCTGG GGAGCCTGGG 1320
GACTTTCCAC ACCCTAACTG ACACACATTC CACAGCTGGT TCTTTCAGAT CCGGTGGTGG 1380
TGCAAATCAA AGAACTGCTC CTCAGTGGAT GTTGCCTTTA CTTCTAGGCC TGTACGGAAG 1440
TGTTACTTCT GCTCTAAAAG CTGCGGAATT GTACCCGCGG CCGCTGCAGT CTAGACGAAT 1500
TCGCGTACGA TATCGATGGG CCCTATTCTA TAGTGTCACC TAAATGCTAG AGCTCGCTGA 1560
TCAGCCTCGA CTGTGCCTTC TAGTTGCCAG CCATCTGTTG TTTGCCCCTC CCCCGTGCCT 1620
TCCTTGACCC TGGAAGGTGC CACTCCCACT GTCCTTTCCT AATAAAATGA GGAAATTGCA 1680
TCGCATTGTC TGAGTAGGTG TCATTCTATT CTGGGGGGTG GGGTGGGGCA GGACAGCAAG 1740
GGGGAGGATT GGGAAGACAA TAGCCGAAAT GACCGACCAA GCGACGCCCA ACCTGCCATC 1800
ACGAGATTTC GATTCCACCG CCGCCTTCTA TGAAAGGTTG GGCTTCGGAA TCGTTTTCCG 1860
GGACGCCGGC TGGATGATCC TCCAGCGCGG GGATCTCATG CTGGAGTTCT TCGCCCACCC 1920
CAACTTGTTT ATTGCAGCTT ATAATGGTTA CAAATAAAGC AATAGCATCA CAAATTTCAC 1980
AAATAAAGCA TTTTTTTCAC TGCATTCTAG TTGTGGTTTG TCCAAACTCA TCAATGTATC 2040
TTATCATGTC TGTATACCGT CGACCTCTAG CTAGAGCTTG GCGTAATCAT GGTCATAGCT 2100
GTTTCCTGTG TGAAATTGTT ATCCGCTCAC AATTCCACAC AACATACGAG CCGGAAGCAT 2160
AAAGTGTAAA GCCTGGGGTG CCTAATGAGT GAGCTAACTC ACATTAATTG CGTTGCGCTC 2220
ACTGCCCGCT TTCCAGTCGG GAAACCTGTC GTGCCAGCTG CATTAATGAA TCGGCCAACG 2280
CGCGGGGAGA GGCGGTTTGC GTATTGGGCG CTCTTCCGCT TCCTCGCTCA CTGACTCGCT 2340
GCGCTCGGTC GTTCGGCTGC GGCGAGCGGT ATCAGCTCAC TCAAAGGCGG TAATACGGTT 2400
ATCCACAGAA TCAGGGGATA ACGCAGGAAA GAACATGTGA GCAAAAGGCC AGCAAAAGGC 2460
CAGGAACCGT AAAAAGGCCG CGTTGCTGGC GTTTTTCCAT AGGCTCCGCC CCCCTGACGA 2520
GCATCACAAA AATCGACGCT CAAGTCAGAG GTGGCGAAAC CCGACAGGAC TATAAAGATA 2580
CCAGGCGTTT CCCCCTGGAA GCTCCCTCGT GCGCTCTCCT GTTCCGACCC TGCCGCTTAC 2640
CGGATACCTG TCCGCCTTTC TCCCTTCGGG AAGCGTGGCG CTTTCTCAAT GCTCACGCTG 2700
TAGGTATCTC AGTTCGGTGT AGGTCGTTCG CTCCAAGCTG GGCTGTGTGC ACGAACCCCC 2760
CGTTCAGCCC GACCGCTGCG CCTTATCCGG TAACTATCGT CTTGAGTCCA ACCCGGTAAG 2820
ACACGACTTA TCGCCACTGG CAGCAGCCAC TGGTAACAGG ATTAGCAGAG CGAGGTATGT 2880
AGGCGGTGCT ACAGAGTTCT TGAAGTGGTG GCCTAACTAC GGCTACACTA GAAGGACAGT 2940
ATTTGGTATC TGCGCTCTGC TGAAGCCAGT TACCTTCGGA AAAAGAGTTG GTAGCTCTTG 3000
ATCCGGCAAA CAAACCACCG CTGGTAGCGG TGGTTTTTTT GTTTGCAAGC AGCAGATTAC 3060
GCGCAGAAAA AAAGGATCTC AAGAAGATCC TTTGATCTTT TCTACGGGGT CTGACGCTCA 3120
GTGGAACGAA AACTCACGTT AAGGGATTTT GGTCATGAGA TTATCAAAAA GGATCTTCAC 3180
CTAGATCCTT TTAAATTAAA AATGAAGTTT TAAATCAATC TAAAGTATAT ATGAGTAAAC 3240
TTGGTCTGAC AGTTACCAAT GCTTAATCAG TGAGGCACCT ATCTCAGCGA TCTGTCTATT 3300
TCGTTCATCC ATAGTTGCCT GACTCCCCGT CGTGTAGATA ACTACGATAC GGGAGGGCTT 3360
ACCATCTGGC CCCAGTGCTG CAATGATACC GCGAGACCCA CGCTCACCGG CTCCAGATTT 3420
ATCAGCAATA AACCAGCCAG CCGGAAGGGC CGAGCGCAGA AGTGGTCCTG CAACTTTATC 3480
CGCCTCCATC CAGTCTATTA ATTGTTGCCG GGAAGCTAGA GTAAGTAGTT CGCCAGTTAA 3540
TAGTTTGCGC AACGTTGTTG CCATTGCTAC AGGCATCGTG GTGTCACGCT CGTCGTTTGG 3600
TATGGCTTCA TTCAGCTCCG GTTCCCAACG ATCAAGGCGA GTTACATGAT CCCCCATGTT 3660
GTGCAAAAAA GCGGTTAGCT CCTTCGGTCC TCCGATCGTT GTCAGAAGTA AGTTGGCCGC 3720
AGTGTTATCA CTCATGGTTA TGGCAGCACT GCATAATTCT CTTACTGTCA TGCCATCCGT 3780
AAGATGCTTT TCTGTGACTG GTGAGTACTC AACCAAGTCA TTCTGAGAAT AGTGTATGCG 3840
GCGACCGAGT TGCTCTTGCC CGGCGTCAAT ACGGGATAAT ACCGCGCCAC ATAGCAGAAC 3900
TTTAAAAGTG CTCATCATTG GAAAACGTTC TTCGGGGCGA AAACTCTCAA GGATCTTACC 3960
GCTGTTGAGA TCCAGTTCGA TGTAACCCAC TCGTGCACCC AACTGATCTT CAGCATCTTT 4020
TACTTTCACC AGCGTTTCTG GGTGAGCAAA AACAGGAAGG CAAAATGCCG CAAAAAAGGG 4080
AATAAGGGCG ACACGGAAAT GTTGAATACT CATACTCTTC CTTTTTCAAT ATTATTGAAG 4140
CATTTATCAG GGTTATTGTC TCATGAGCGG ATACATATTT GAATGTATTT AGAAAAATAA 4200
ACAAATAGGG GTTCCGCGCA CATTTCCCCG AAAAGTGCCA CCTGACGTC 4249
Claims (18)
1.编码一种融合多肽的核酸,所述多肽包含一种E2F转录因子的DNA结合域和一种成视网膜细胞瘤多肽的有功能的生长抑制域的融合体,其中所述融合多肽缺失有功能的E2F转录因子的细胞周期蛋白A激酶结合域。
2.权利要求1的核酸,其中所述核酸***一种腺病毒载体中。
3.一种包含编码一种融合多肽的DNA的表达载体,所述多肽包含一种E2F转录因子的DNA结合域和一种成视网膜细胞瘤多肽的有功能的生长抑制域的融合体,其中所述融合多肽缺失有功能的E2F转录因子的细胞周期蛋白A激酶结合域。
4.权利要求3的表达载体,其包含与编码所述融合体的DNA操作性地连接的组织特异性启动子。
5.权利要求4的表达载体,其中所述组织特异性启动子是一种平滑肌肌动蛋白启动子。
6.权利要求3的表达载体,其中所述载体是一种病毒载体。
7.权利要求6的表达载体,其中所述载体是一种腺病毒载体。
8.权利要求7的表达载体,其中所述腺病毒载体是复制缺陷型腺病毒载体。
9.权利要求3的表达载体,其中所述表达载体是一种质粒。
10.权利要求5的表达载体,其中所述肌动蛋白启动子是一种α-肌动蛋白启动子。
11.一种编码融合多肽的核酸序列,所述融合多肽包含E2F的氨基酸95-194(SEQ ID NO:1)和成视网膜细胞瘤的氨基酸379-928(SEQID NO:4)的融合体。
12.权利要求11的核酸序列,其中所述核酸序列***一种载体中。
13.权利要求12的核酸序列,其中所述载体是一种病毒载体。
14.权利要求13的核酸序列,其中所述病毒载体是一种腺病毒载体。
15.权利要求14的核酸序列,其中所述腺病毒载体是复制缺陷型腺病毒载体。
16.权利要求11的核酸序列,其中所述核酸序列还包含一种组织特异性的启动子,所述融合多肽在所述组织特异性启动子的控制下表达。
17.权利要求16的核酸序列,其中所述组织特异性启动子是一种平滑肌肌动蛋白启动子。
18.权利要求17的核酸序列,其中所述平滑肌启动子是一种α-肌动蛋白启动子。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US75151796A | 1996-11-15 | 1996-11-15 | |
US08/801,092 | 1997-02-14 | ||
US08/801,092 US6074850A (en) | 1996-11-15 | 1997-02-14 | Retinoblastoma fusion polypeptides |
US08/751,517 | 1997-02-14 |
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CN1244870A CN1244870A (zh) | 2000-02-16 |
CN100338219C true CN100338219C (zh) | 2007-09-19 |
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CNB971813175A Expired - Fee Related CN100338219C (zh) | 1996-11-15 | 1997-11-13 | 成视网膜细胞瘤蛋白的组织特异性表达 |
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US (2) | US6379927B1 (zh) |
EP (1) | EP0948520B1 (zh) |
JP (1) | JP4109721B2 (zh) |
KR (1) | KR100336551B1 (zh) |
CN (1) | CN100338219C (zh) |
AT (1) | ATE286908T1 (zh) |
AU (1) | AU723660B2 (zh) |
BR (1) | BR9712767B1 (zh) |
CA (1) | CA2271478C (zh) |
DE (1) | DE69732246T2 (zh) |
ES (1) | ES2234040T3 (zh) |
HK (1) | HK1019751A1 (zh) |
HU (1) | HU226662B1 (zh) |
IL (1) | IL129922A0 (zh) |
NZ (1) | NZ335738A (zh) |
WO (1) | WO1998021228A1 (zh) |
Families Citing this family (9)
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EP1054969A2 (en) * | 1998-02-12 | 2000-11-29 | Curagen Corporation | Retinoblastoma protein complexes and retinoblastoma interacting proteins |
AU6497799A (en) * | 1998-10-15 | 2000-05-01 | Canji, Inc. | Methods and compositions to induce antitumor response |
US6649158B1 (en) | 1998-10-15 | 2003-11-18 | Canji, Inc. | Methods and compositions to induce antitumor response |
TWI262948B (en) * | 1998-10-15 | 2006-10-01 | Canji Inc | Selectively replicating viral vectors |
US7691370B2 (en) | 1998-10-15 | 2010-04-06 | Canji, Inc. | Selectivity replicating viral vector |
WO2002050101A1 (en) * | 2000-12-19 | 2002-06-27 | The Council Of The Queensland Institute Of Medical Research | Retinoblastoma-binding protein |
US6866994B2 (en) * | 2001-05-30 | 2005-03-15 | Neomatrix, Llc | Noninvasive intraductal fluid diagnostic screen |
CN103463646A (zh) * | 2013-09-19 | 2013-12-25 | 浙江大学 | E2f1蛋白在制备诊断和治疗骨肉瘤药物中的应用 |
GB2544843B (en) * | 2015-07-14 | 2022-08-03 | Professional Compounding Centers Of America Pcca | Poloxamer-based intralesional injections for the delivery of chemotherapeutic agents |
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WO1995007708A2 (en) * | 1993-09-13 | 1995-03-23 | The Regents Of The University Of California | Therapeutic use of the retinoblastoma susceptibility gene product |
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US4235871A (en) | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
US4501728A (en) | 1983-01-06 | 1985-02-26 | Technology Unlimited, Inc. | Masking of liposomes from RES recognition |
US5019369A (en) | 1984-10-22 | 1991-05-28 | Vestar, Inc. | Method of targeting tumors in humans |
US4837028A (en) | 1986-12-24 | 1989-06-06 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
AU660629B2 (en) | 1990-10-01 | 1995-07-06 | University Of Connecticut, The | Targeting viruses and cells for selective internalization by cells |
AU3434393A (en) | 1992-01-17 | 1993-08-03 | Regents Of The University Of Michigan, The | Targeted virus |
WO1993019768A1 (en) | 1992-04-03 | 1993-10-14 | The Regents Of The University Of California | Self-assembling polynucleotide delivery system |
EP0633943A4 (en) | 1992-04-03 | 1997-05-02 | Alexander T Young | GENTHERAPY USING TARGETED VIRAL VECTORS. |
WO1994006923A1 (en) | 1992-09-24 | 1994-03-31 | The University Of Connecticut | Modification of a virus to redirect infectivity and enhance targeted delivery of polynucleotides to cells |
US5656609A (en) | 1992-09-24 | 1997-08-12 | University Of Connecticut | Method of enhancing and/or prolonging expression of gene introduced into a cell using colchicine |
US5473056A (en) * | 1993-10-13 | 1995-12-05 | Merck & Co., Inc. | E2F-2, a novel mammalian transcription factor |
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AU723660B2 (en) | 2000-08-31 |
HUP9903864A3 (en) | 2001-09-28 |
IL129922A0 (en) | 2000-02-29 |
US6902731B1 (en) | 2005-06-07 |
WO1998021228A1 (en) | 1998-05-22 |
HUP9903864A2 (hu) | 2001-04-28 |
ATE286908T1 (de) | 2005-01-15 |
KR100336551B1 (ko) | 2002-05-11 |
DE69732246T2 (de) | 2005-12-08 |
EP0948520A4 (en) | 2003-03-12 |
ES2234040T3 (es) | 2005-06-16 |
JP4109721B2 (ja) | 2008-07-02 |
DE69732246D1 (de) | 2005-02-17 |
CN1244870A (zh) | 2000-02-16 |
HK1019751A1 (en) | 2000-02-25 |
NZ335738A (en) | 2001-02-23 |
CA2271478A1 (en) | 1998-05-22 |
BR9712767B1 (pt) | 2010-11-30 |
EP0948520B1 (en) | 2005-01-12 |
BR9712767A (pt) | 1999-10-26 |
US6379927B1 (en) | 2002-04-30 |
CA2271478C (en) | 2003-02-04 |
AU5589998A (en) | 1998-06-03 |
JP2001503638A (ja) | 2001-03-21 |
EP0948520A1 (en) | 1999-10-13 |
KR20000053323A (ko) | 2000-08-25 |
HU226662B1 (en) | 2009-06-29 |
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