CN110785429A - 增加蛋白质半衰期的方法 - Google Patents
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Abstract
本发明涉及通过取代存在于蛋白质的氨基酸序列的一个以上的赖氨酸残基来增加蛋白质的半衰期的方法或半衰期得到增加的蛋白质,本发明的赖氨酸残基被取代的蛋白质长时间残留于人体内,且治疗效果优秀。本发明的蛋白质为表皮细胞生长因子、血小板衍生生长因子A及血小板衍生生长因子B、粒细胞‑巨噬细胞集落刺激因子、卵泡刺激素α、卵泡刺激素β及血管生成素1。
Description
技术领域
本发明涉及通过取代蛋白质或多肽的一个以上的氨基酸残基来增加蛋白质或多肽的半衰期的方法。并且,涉及通过这种方法制备的半衰期得到增加的蛋白质或多肽。
背景技术
细胞内蛋白质分解通过借助溶酶体(lysosome)和蛋白酶体(proteasome)的两种通路进行。分解蛋白质的10~20%的溶酶体通路没有底物特异性及精准的时间调节性。即,如通过内吞作用(endocytosis)向细胞内陷入的细胞表面蛋白质在溶酶体被分解,大部分为分解细胞外或膜蛋白质的过程。但是,为了在真核细胞中选择性地分解蛋白质,需通过如下的过程,即,通过泛素(ubiquitin)结合酶使目标蛋白质与泛素结合后形成聚泛素链,且聚泛素链被蛋白酶体认知并分解的过程,即,泛素-蛋白酶体通路(ubiquitin-proteasomepathway,UPP)。真核细胞蛋白质中的80~90%以上通过上述过程分解,泛素-蛋白酶体通路调节存在于真核细胞内的大部分的蛋白质分解,从而负责蛋白质的转换和稳态。
泛素为由很好地保存的76个氨基酸构成的蛋白质,几乎存在于所有真核细胞,其中,第6、11、27、29、33、48、63个氨基酸残基为赖氨酸(Lysine,Lys,K),在第48和63个氨基酸残基形成聚泛素链的过程中起到重要作用。一系列酶类E1、E2、E3参与泛素标记于蛋白质的过程(泛素化(ubiquitination)),标记的蛋白质通过作为腺嘌呤核苷三磷酸(ATP)-依赖性蛋白质分解酶复合物的26S蛋白酶体分解。泛素-蛋白酶体通路包括独立的两个连续过程,其中,第一个为通过共价键在底物标记多个泛素分子的过程,第二个为通过泛素标记的蛋白质被26S蛋白酶体复合物分解的过程。泛素与底物的结合通过底物分子的赖氨酸残基与泛素的C-末端的甘氨酸之间的异肽键(isopeptide bond)进行,通过泛素活化酶E1、泛素结合酶E2、泛素连接酶E3在泛素与酶之间形成硫酯进行。其中,E1(泛素活化酶(ubiquitin-activating enzyme))通过腺嘌呤核苷三磷酸依赖性反应使泛素活化。E2(泛素结合酶(ubiquitin-conjugating enzyme))在泛素结合域内的半胱氨酸(cysteine)残基接收从E1活化的泛素并向E3连接酶(ligase)传递或向底蛋白质直接传递。E3酶也催化底物蛋白质的赖氨酸残基与泛素的甘氨酸残基之间的稳定异肽键。与底物蛋白质结合的泛素的C-末端赖氨酸残基可与另一泛素连接,若重复这种过程来在底物蛋白质以多个泛素分子分叉的形状连接来形成聚泛素链,则其蛋白质被26S蛋白酶体识别并选择性地分解。
另一方面,众所周知,在生物体内具有治疗效果的多种种类的蛋白质及多肽。如上所述,在生物体内具有治疗效果的蛋白质或多肽包括生长激素释放激素(growth hormonereleasing hormone,GHRH)、生长激素释放肽(growth hormone releasing peptid)、干扰素(interferons,interferon-αor interferon-β)、干扰素受体(interferon receptors)、集落刺激因子(colony stimulating factors,CSFs)、胰高血糖素样肽(glucagon-likepeptides)、白介素(interleukins)、白介素受体(interleukin receptors)、酶(enzymes)、白介素结合蛋白(interleukin binding proteins)、细胞因子结合蛋白(cytokinebinding proteins)、G蛋白偶联受体(G-protein-coupled receptor)、人类生长激素(human growth hormone,hGH)、巨噬细胞活化因子(macrophage activating factor)、巨噬细胞肽(macrophage peptide)、B细胞因子(B cell factor)、T细胞因子(T cellfactor)、蛋白A(protein A)、过敏抑制剂(allergy inhibitor)、细胞坏死糖蛋白(cellnecrosis glycoproteins)、G蛋白偶联受体(G-protein-coupled receptor)、免疫毒素(immunotoxin)、淋巴毒素(lymphotoxin)、肿瘤坏死因子(tumor necrosis factor)、抑癌基因(tumor suppressors)、转移生长因子(metastasis growth factor)、α-1抗胰蛋白酶(alpha-1antitrypsin)、白蛋白(albumin)、α-乳清白蛋白(alpha-lactalbumin)、载脂蛋白-E(apolipoprotein-E)、促红细胞生成素(erythropoietin)、高糖基化促红细胞生成素(highly glycosylated erythropoietin)、血管生成素(angiopoietins)、血红蛋白(hemoglobin)、凝血酶(thrombin)、凝血酶受体活化肽(thrombin receptor activatingpeptide)、血栓调节蛋白(thrombomodulin)、因子VII(factor VII)、因子VIIa(factorVIIa)、因子VIII(factor VIII)、因子IX(factor IX)、因子XIII(factor XIII)、纤溶酶原激活因子(plasminogen activating factor)、尿激酶(urokinase)、链激酶(streptokinase)、水蛭素(hirudin)、蛋白C(protein C)、C反应蛋白(C-reactiveprotein)、肾素抑制剂(renin inhibitor)、胶原酶抑制剂(collagenase inhibitor)、超氧化物歧化酶(superoxide dismutase)、瘦素(leptin)、血小板源生长因子(platelet-derived growth factor)、上皮细胞生长因子(epithelial growth factor)、表皮细胞生长因子(epidermal growth factor)、血管抑素(angiostatin)、血管紧张素(angiotensin)、骨生长因子(bone growth factor)、骨刺激蛋白(bone stimulatingprotein)、降血钙素(calcitonin)、胰岛素(insulin)、心房肽(atriopeptin)、软骨诱导因子(cartilage inducing factor)、纤维蛋白结合肽(fibrin-binding peptide)、依降钙素(elcatonin)、结缔组织激活因子(connective tissue activating factor)、组织因子途径抑制物(tissue factor pathway inhibitor)、卵泡刺激素(follicle stimulatinghormone)、促黄体激素(luteinizing hormone)、促黄体激素释放激素(luteinizinghormone releasing hormone)、神经生长因子(nerve growth factors)、甲状旁腺激素(parathyroid hormone)、松弛素(relaxin)、分泌素(secretin)、生长调节素(somatomedin)、胰岛素样生长因子(insulin-like growth factor)、肾上腺皮质激素(adrenocortical hormone)、胰高血糖素(glucagon)、胆囊收缩素(cholecystokinin)、胰多肽(pancreatic polypeptide)、胃泌素释放肽(gastrin releasing peptide)、促肾上腺皮质激素释放因子(corticotropin releasing factor)、促甲状腺激素(thyroidstimulating hormone)、自体趋化因子(autotaxin)、乳铁蛋白(lactoferrin)、肌肉抑制素(myostatin)、受体(receptors)、受体拮抗剂(receptor antagonists)、细胞表面抗原(cell surface antigens)、病毒衍生疫苗抗原(virus derived vaccine antigens)、单克隆抗体(monoclonal antibodies)、多克隆抗体(polyclonal antibodies)及抗体片段。
表皮细胞生长因子(EGF,Epidermal growth factor)与表皮生长因子受体(EGFR)结合来促进细胞生长、增殖、分化,人类表皮细胞生长因子(EGF)由53个氨基酸形成(ExpCell Res.,284(1):2-13,2003)。并且,据报告,如上所述的表皮细胞生长因子在皮肤及头发的再生起到重要作用(J Dermatol Sci.,72(2):81-86,2013)。
血小板源生长因子(PDGF,Platelet-derived growth factor)为生长因子中的一种,用于调节细胞生长和分裂,参与血管新生,形成血小板衍生生长因子A(PDGFA,Platelet-derived growth factor subunit A)和血小板衍生生长因子B(PDGFB,Platelet-derived growth factor subunit B)具有功能的异二聚体(hetero-dimers)(Biochim.Biophys.Acta.,989(1):110,1989;EMBO J.,11(12):42514259,1992)。血小板源生长因子(PDGF)被合成,存储于血小板的α颗粒(alpha granules),若血小板活化,则被分泌,还在肌肉细胞、活化巨噬细胞和表皮细胞等的细胞中生成(Curr Pharm Des.,19(19):3384-3390,2013)。
粒细胞-巨噬细胞集落刺激因子(GM-CSF,Granulocyte-macrophage colony-stimulating factor)为通过巨噬细胞、T细胞、肥大细胞、自然杀伤细胞、内皮细胞及纤维亚细胞分泌的蛋白质,为具有白细胞生长因子功能的细胞因子。并且,刺激干细胞来使干细胞生成粒细胞(中性粒细胞、嗜碱性粒细胞、嗜酸性粒细胞)和单核细胞,急剧增加巨噬细胞的数量来对抗感染反应,因此,作用于免疫/感染反应(Med Oncol.,31(1):774,2014;Blood,77(6):1131-1145,1991)。据报告重组粒细胞-巨噬细胞集落刺激因子(GM-CSF)可用作人类免疫缺陷病毒(HIV)感染患者的疫苗助剂(Hum Vaccin Immunother.,8(11):16541658,2012;Vaccines(Basel).,2(1):160178,2014)。并且,当非霍金斯淋巴瘤、淋巴瘤白血病或霍金斯患者接受骨髓移植治疗时,可有效增加白细胞数值,但在类风湿性关节炎患者的关节中以高数值表达,因此,据报告,若粒细胞-巨噬细胞集落刺激因子减少,则可减少验证或损伤(Expert Rev Neurother.,13(3):313-335,2013)。
卵泡刺激素(FSH,Follicle-stimulating hormone)为以35.5kDa的糖蛋白多肽(glycoprotein polypeptide)的形态作为两个多肽(polypeptide)的α(alpha)和β(beta)形成异二聚体(heterodimer)的促性腺激素(gonadotrophin)中的一种,促进并维持女性卵泡生长和男性精子发育,在垂体前叶性腺细胞合成并分泌,调节身体的生殖过程、发育、生长和青春期成熟(Annu Rev Biochem.,50:465-495,1981;Proc Natl Acad Sci USA.,109(31):12491-12496,2012)。通常,在作为不孕治疗的体外受精(IVF)时,卵泡刺激素用于诱导促排卵。并且,在实体癌的情况下,据报告卵泡刺激素(FSH)的受体在肿瘤血管内皮中具有高表达,参与新生血管的再生,因此,在研发卵泡刺激素和受体拮抗剂(antagonist)的情况下,还可用于抗癌治疗(N Engl J Med.,363(17):1621-1630,2010)。
血管生成素(Angiopoietin)为血管生长因子,直接参与血管生成,通过血管周围的肌肉细胞的信号传递调节微血管通透性(microvascular permeability)、血管舒张(vasodilation)及血管收缩(vasoconstriction)(BMC Infect Dis.,10:143,2010;CancerLett.,328(1):18-26,2013)。目前已知4种血管生成素——血管生成素1、血管生成素2、血管生成素3、血管生成素4(Proc Natl Acad Sci U S A.,96(5):1904-1909,1999)。其中,血管生成素1(Angiopoietin-1)为在血管生长和血管形成中起到重要作用的蛋白质,通过血管生成素1基因加密。所有血管生成素与内皮细胞特异性酪氨酸蛋白激酶受体(tyrosine-protein kinase receptor)结合,在介导内皮细胞与周围底物及间质之间的相互作用时发挥重要作用。并且,有助于血管成熟和稳定性,参与心脏的早期发育(Cell Res.,13(5):309-317,2003)。
发明内容
技术问题
本发明的目的在于,提供增加蛋白质的半衰期的方法。
并且,本发明的目的在于,提供作为存在于氨基酸序列的一个以上的赖氨酸残基被取代的蛋白质,具有增加的半衰期的蛋白质。
并且,本发明的目的在于,提供包含具有增加的半衰期的蛋白质的药学组合物。
解决问题的手段
为实现上述目的,本发明提供包括取代存在于蛋白质的氨基酸序列的一个以上的赖氨酸残基的增加蛋白质的半衰期的方法。
在本发明中,蛋白质的赖氨酸残基可被保守氨基酸取代。在本发明中,“保守氨基酸取代”意味着氨基酸残基被相似的如具有电荷或疏水性等化学特性且具有侧链的其他氨基酸残基取代。通常,蛋白质的功能特性不会通过保守氨基酸取代而具有实质性变化。具有相似化学特性的具有侧链氨基酸基的例包括:1)脂肪族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸及异亮氨酸;2)脂肪族羟基侧链:丝氨酸及苏氨酸;3)含酰胺侧链:天冬酰胺及谷氨酰胺;4)芳香族侧链:苯丙氨酸、酪氨酸及色氨酸;5)碱基侧链:赖氨酸、精氨酸及组氨酸;6)酸性侧链:天冬氨酸及谷氨酸;7)含硫侧链:半胱氨酸及蛋氨。
在本发明中,蛋白质的赖氨酸残基可被包括碱基侧链的精氨酸或组氨酸取代,优选地,被精氨酸残基取代。
发明的效果
根据本发明,利用精氨酸取代存在于蛋白质的氨基酸序列的一个以上的赖氨酸残基的蛋白质的半衰期增加,可长时间残留于体内。
附图说明
图1示出表皮细胞生长因子表达载体的结构。
图2示出表皮细胞生长因子基因大小和聚合酶链式反应(PCR)产物。
图3示出在HEK-293T细胞中通过表皮细胞生长因子质粒表达蛋白质。
图4提出通过泛素化分析的表皮细胞生长因子的分解通路。
图5示出与野生型进行比较的赖氨酸残基被精氨酸取代的表皮细胞生长因子取代基的泛素化程度。
图6示出利用蛋白合成抑制剂环己酰亚胺(cycloheximide,CHX)处理后的表皮细胞生长因子的半衰期变化。
图7示出与如JAK-STAT、胞内磷脂酰肌醇激酶(PI3K)-蛋白激酶B及丝裂原活化蛋白激酶(MAPK)/细胞外信号调节激酶(ERK)信号诱导的效果有关的结果。
图8示出血小板衍生生长因子A和血小板衍生生长因子B表达载体的结构。
图9示出血小板衍生生长因子A和血小板衍生生长因子B基因大小和聚合酶链式反应产物。
图10示出在HEK-293T细胞中的通过血小板衍生生长因子A和血小板衍生生长因子B的质粒的蛋白质表达。
图11提出通过泛素化分析的血小板衍生生长因子A和血小板衍生生长因子B的分解通路。
图12示出与野生型进行比较的赖氨酸残基被精氨酸取代的血小板衍生生长因子A和血小板衍生生长因子B取代基的泛素化程度。
图13、图14及图15示出利用蛋白合成抑制剂环己酰亚胺处理之后的血小板衍生生长因子A和血小板衍生生长因子B的半衰期变化。
图16示出与如JAK-STAT、胞内磷脂酰肌醇激酶-蛋白激酶B及丝裂原活化蛋白激酶/细胞外信号调节激酶信号诱导的效果有关的结果。
图17示出粒细胞-巨噬细胞集落刺激因子表达载体的结构。
图18示出粒细胞-巨噬细胞集落刺激因子基因大小和聚合酶链式反应结果。
图19示出在HEK-293T细胞中的通过粒细胞-巨噬细胞集落刺激因子的质粒的蛋白质表达。
图20提出通过泛素化分析的粒细胞-巨噬细胞集落刺激因子的分解通路。
图21示出与野生型进行比较的赖氨酸残基被精氨酸取代的粒细胞-巨噬细胞集落刺激因子取代基的泛素化程度。
图22及图23示出利用蛋白合成抑制剂环己酰亚胺处理之后的粒细胞-巨噬细胞集落刺激因子的半衰期变化。
图24示出与如JAK-STAT、胞内磷脂酰肌醇激酶-蛋白激酶B及丝裂原活化蛋白激酶/细胞外信号调节激酶信号诱导的效果有关的结果。
图25示出卵泡刺激素α(FSH-α)和卵泡刺激素β(FSH-β)表达载体的结构。
图26示出卵泡刺激素α和卵泡刺激素β基因大小和聚合酶链式反应结果。
图27示出在HEK-293T细胞中的通过卵泡刺激素α和卵泡刺激素β的质粒的蛋白质表达。
图28提出通过泛素化分析的卵泡刺激素α和卵泡刺激素β的分解通路。
图29示出与野生型进行比较的赖氨酸残基被精氨酸取代的卵泡刺激素α和卵泡刺激素β取代基的泛素化程度。
图30、图31及图32示出利用蛋白合成抑制剂环己酰亚胺处理之后的卵泡刺激素α和卵泡刺激素β的半衰期变化。
图33示出与如JAK-STAT、胞内磷脂酰肌醇激酶-蛋白激酶B及丝裂原活化蛋白激酶/细胞外信号调节激酶信号诱导的效果有关的结果。
图34示出血管生成素1(ANGPT-1)表达载体的结构。
图35示出血管生成素1基因大小和聚合酶链式反应结果。
图36示出在HEK-293T细胞中的通过血管生成素1质粒的质粒的蛋白质表达。
图37提出通过泛素化分析的血管生成素1的分解通路。
图38示出与野生型进行比较的赖氨酸残基被精氨酸取代的血管生成素1取代基的泛素化程度。
图39及图40示出利用蛋白合成抑制剂环己酰亚胺处理之后的血管生成素1的半衰期变化。
图41示出与如胞内磷脂酰肌醇激酶-蛋白激酶B及丝裂原活化蛋白激酶/细胞外信号调节激酶信号诱导的效果有关的结果。
具体实施方式
在本发明的一具体例中,蛋白质为表皮细胞生长因子。在由序列1表示的表皮细胞生长因子的氨基酸序列中从N-末端开始第28及48个赖氨酸残基中的一个以上被精氨酸残基取代。结果,提供上述半衰期得到增加的表皮细胞生长因子及包含其的用于细胞生长、皮肤及头发再生和/或治疗的药学和/或美容组合物(Exp Cell Res.,284(1):2-13,2003;JDermatol Sci.,72(2):81-86,2013)。
在本发明的再一具体例中,蛋白质为血小板衍生生长因子A。在由序列6表示的血小板衍生生长因子A的氨基酸序列中从N-末端开始第160、165及206个赖氨酸残基中的一个以上被精氨酸残基取代。并且,在发明的另一具体例中,蛋白质为血小板衍生生长因子B。在由序列7表示的血小板衍生生长因子B的氨基酸序列中从N-末端开始第162、167及179个赖氨酸残基中的一个以上被精氨酸残基取代。因此,提供上述半衰期得到增加的血小板源生长因子及包含其的用于细胞生长、血管生成及慢性溃疡和骨损失恢复的药学和/或美容组合物。
在本发明的还有一具体例中,蛋白质为粒细胞-巨噬细胞集落刺激因子。在由序列20表示的粒细胞-巨噬细胞集落刺激因子的氨基酸序列中从N-末端开始第89、91及102个赖氨酸残基中的一个以上被精氨酸残基取代。因此,提供半衰期得到增加的粒细胞-巨噬细胞集落刺激因子及包含其的用于预防中性粒细胞缺乏症和/或用于预防和/或治疗免疫疾病和/或包括实体癌及血液癌的癌症和/或类风湿性关节炎的药学组合物。
在本发明的又一具体例中,蛋白质为卵泡刺激素。在由序列27表示的卵泡刺激素α氨基酸序列中从N-末端开始第75、99及115个赖氨酸残基中的一个以上被精氨酸残基取代。并且,在本发明的又一具体例中,蛋白质为卵泡刺激素β。在由序列28表示的卵泡刺激素β氨基酸序列中从N-末端开始第67、104及128个赖氨酸残基中的一个以上被精氨酸残基取代。因此,提供半衰期得到增加的卵泡刺激素及包含其的用于诱导促排卵的不孕治疗剂和/或用于治疗实体癌的药学组合物。
在本发明的又一具体例中,蛋白质为血管生成素1。在由序列41表示的血管生成素1氨基酸序列中从N-末端开始第175、216及414的赖氨酸残基中的一个以上被精氨酸残基取代。因此,提供半衰期得到增加的血管生成素1及包含其的用于治疗糖尿病、心脏疾病和/或败血症的药学组合物。
在本发明中,为利用精氨酸(arginine,R)残基取代存在于蛋白质的氨基酸序列的赖氨酸残基,利用了定点突变(site-directed mutagenesis)。此方法通过利用所要诱导特定突变的DNA序列来制备引物后,在特定条件下进行聚合酶链式反应,从而制备取代特定氨基酸残基的质粒DNA。
在本发明中,通过免疫沉淀分析法向细胞株内转染靶蛋白质并沉淀来确认了泛素化程度,利用MG132(蛋白酶体抑制剂)试剂处理的结果,确认通过泛素化程度的增加,靶蛋白质经过借助泛素-蛋白酶体的分解通路。
在本发明中,药学组合物可通过包括口服(oral)、经皮(transcutaneous)、皮下(subcutaneous)、静脉(intravenous)或肌肉给药在内的各种通路向体内传递,能够以注射型制剂给药。并且,本发明的药学组合物可根据普通技术人员所周知的方法制剂化,来根据上述方法给药后迅速释放、延迟释放或逐渐释放。上述制剂包括片剂(tablet)、药丸(pill)、粉末(powder)、袋装药(sachet)、酏剂(elixir)、悬浮剂(suspension)、乳液(emulsion)、溶液(solution)、糖浆(syrup)、气雾剂(aerosol)、软硬明胶胶囊(soft andhard gelatin capsule)、灭菌注射溶液(sterile injectable solution)、灭菌注封装的粉末等。作为适合的载体、赋形剂及稀释剂包括乳糖(lactose)、葡萄糖(dextrose)、蔗糖(sucrose)、甘露醇(mannitol)、木糖醇(xylitol)、赤藓糖醇(erythritol)、麦芽糖醇(maltitol)、碳水化合物(starches)、阿拉伯树胶(gum acacia)、藻酸盐(alginates)、明胶(gelatin)、磷酸钙(calcium phosphate)、硅酸钙(calcium silicate)、纤维素(cellulose)、甲基纤维素(methyl cellulose)、微晶纤维素(microcrystallinecellulose)、聚乙烯吡咯烷酮(polyvinyl pyrrolidone)、水、羟苯甲酸甲酯(methylhydroxybenzoates)、羟基苯甲酸丙酯(propylhydroxybenzoates)、滑石(talc)、硬脂酸镁(magnesium stearate)及矿物油。并且,制剂还可包括填充剂、抗凝集剂(anti-agglutinating agents)、润滑剂(lubricating agents)、湿润剂(wetting agents)、调味剂(flavoring agents)、乳化剂(emulsifiers)、防腐剂(preservative)等。
在本发明中,除非明确地另行记载,否则单数形态包括复数形态。并且,在本发明中,如构成、具有、形成的术语的含义与“包括……”的含义相似。在本发明中,“生理活性多肽或蛋白质”为向包括人类的哺乳动物给药时呈现有用的生物活性的多肽或蛋白质。
发明实施方式
以下,根据实施例更加详细地说明本发明。下述实施例仅用于例示本发明,本发明并不局限于下述实施例。
实施例1:表皮细胞生长因子蛋白质的泛素化分析及半衰期增加确认、细胞内信号传递确认
1.表达载体克隆及蛋白质表达确认
(1)表达载体克隆
为克隆表皮细胞生长因子,利用总RNA提取试剂(Trizol)和氯仿从海拉(HeLa)细胞(ATCC,CRM-CCL-2TM)中提取片剂化的RNA。之后利用第一链cDNA合成系统(SuperScriptTMFirst-Strand cDNA Synthesis System)(Invitrogen,格兰岛(Grand Island),纽约)NY))合成了单链cDNA。利用模板(template)且通过聚合酶链反应将合成的cDNA扩增为表皮细胞生长因子。利用作为限制酶的BamHI和XhoI将表皮细胞生长因子DNA扩增产物和pcDNA3-myc(5.6kb)制备为切片并接合来进行克隆(图1,表皮细胞生长因子氨基酸序列:序列1)利用限制酶进行切断后,通过琼脂糖凝胶电泳确认(图2)。并且,图1的碱基序列中以下划线和粗体表示的部分为为了再次确认克隆的部位而通过聚合酶链反应确认时使用的引物集(primerset),并还通过琼脂糖凝胶电泳确认其结果(图2)。聚合酶链反应条件如下:在94℃的温度条件下进行3分钟的初始改性反应后,将94℃温度条件下的30秒钟的改性(denature)反应、52℃温度条件下的30秒钟的退火(annealing)反应、72℃温度条件下的30秒钟的延伸(extention)反应等反复循环25次来执行,之后,在72℃的温度条件下反应10分钟。为确认通过如上所述的方法制备的DNA是否正确地通过蛋白质表达,利用抗myc(9E10,Santa CruzBiotechnology,sc-40)抗体并通过免疫印迹(Western blot)确认了存在于图1所示的pcDNA3-myc载体的myc的表达。由此,确认了与myc结合的表皮细胞生长因子蛋白质很好地表达,并确认通过利用肌动蛋白(actin)确认的印迹(blot)以定量负载(loading)(图3)。
(2)赖氨酸(Lysine,K)残基的取代
通过定点突变且利用精氨酸取代赖氨酸残基,利用所要诱导特定突变的DNA序列制备引物(表皮细胞生长因子K28R FP 5'-GAAGCATTGGACAGGTATGCATGCAAC-3'(序列2)、RP5'-GTTGCATGCATACCTGTCCAATGCTTC-3'(序列3);表皮细胞生长因子K48R FP 5'-TACCGAGACCTGAGGTGGTGGGAACTG-3'(序列4)、RP 5'-CAGTTCCCACCACCTCAGGTCTCGGTA-3'(序列5))后,执行聚合酶链式反应来制备了取代特定氨基酸残基的质粒DNA。将pcDNA3-myc-表皮细胞生长因子用作模板,来制备了赖氨酸残基被精氨酸取代(K→R)的质粒DNA(表1)。
表1
2.生物体内泛素化分析
利用pcDNA3-myc-表皮细胞生长因子WT和对pMT123-HA-泛素(J Biol Chem.,279(4),2368-2376,2004;Cell Research,22,873885,2012;Oncogene,22,12731280,2003;Cell,78,787-798,1994)进行编码的质粒感染HEK 293T细胞(ATCC,CRL-3216)。为确认泛素化过程,在细胞共转染(co-transfection)3μg的pcDNA3-myc-表皮细胞生长因子WT和1μg的pMT123-HA-泛素DNA,24小时之后利用MG132(蛋白酶体抑制剂,5μg/ml,Sigma Aldrich)处理6小时,并实施免疫沉淀分析(图4)。并且,为比较WT与取代基之间的泛素化程度,分别利用3μg的pcDNA3-myc-表皮细胞生长因子WT、3μg的pcDNA3-myc-表皮细胞生长因子取代基(K28R)及3μg的pcDNA3-myc-表皮细胞生长因子取代基(K48R)和1μg的pMT123-HA-泛素DNA共转染HEK 293T细胞(ATCC,CRL-3216),并在24小时后实施免疫沉淀分析(图5)。
利用溶解缓冲液(1%的Triton X、150mM的NaCl、50mM的Tris-HCl、pH 8及1mM的苯甲基磺酰氟(PMSF,phenylmethanesulfonyl fluoride))溶解为了免疫沉淀而获取的蛋白质样品后,与抗-myc(9E10)一级抗体(Santa Cruz Biotechnology,sc-40)混合并在4℃的温度条件下培养一夜。利用蛋白A/G磁珠(Santa Cruz Biotechnology)在4℃的温度条件下反应2小时来分离了免疫沉淀物。之后,利用溶解缓冲液清洗2次。与2X SDS缓冲液混合后在100℃的温度条件下加热7分钟后,实施聚丙烯酰胺凝胶电泳(SDS-PAGE)来分离蛋白质样品。向聚偏氟乙烯(polyvinylidene difluoride,PVDF)膜(Millipore)移动所分离的蛋白质后,使用以1:1000的重量比包含抗-myc(9E10,Santa Cruz Biotechnology,sc-40)、抗-HA(Santa Cruz Biotechnology,sc-7392)及抗-β-肌动蛋白(Santa Cruz Biotechnology,sc-47778)的封闭液和抗-小鼠(过氧化物酶标记小鼠IgG抗体(Peroxidase-labeledantibody to mouse IgG)(H+L),KPL,074-1806)二级抗体并利用电化学发光(ECL)系统(免疫印迹检测试剂盒(Western blot detection kit),ABfrontier,首尔(Seoul),韩国(Korea))清洗。结果,在利用抗-myc(9E10,sc-40)实施免疫沉淀的情况下,随着pcDNA3-myc-表皮细胞生长因子WT与泛素结合来形成聚泛素化,检测到扩散状(涂抹(smear))泛素并显示出深颜色的带(图4,第三通路和第四通路)。并且,在利用MG132(蛋白酶体抑制剂,5μg/ml)处理6小时的情况下,聚泛素化的形成增加,来以更深的颜色显示检测到泛素的带(图4,第四通路)。这种结果意味着表皮细胞生长因子与泛素结合并通过泛素-蛋白酶体系统聚泛素化。并且,在pcDNA3-myc-表皮细胞生长因子取代基(K28R)的情况下,带比WT浅。这表示泛素未与上述取代基结合,因此检测到较少的泛素(图5,第三通路)。
3.确认通过蛋白质生成抑制剂环己酰亚胺的表皮细胞生长因子的半衰期
将3μg的pcDNA3-myc-表皮细胞生长因子WT、3μg的pcDNA3-myc-表皮细胞生长因子取代基(K28R)、3μg的pcDNA3-myc-表皮细胞生长因子取代基(K48R)及3μg的pcDNA3-myc-表皮细胞生长因子取代基(K28R+K48R)分别向HEK 293T细胞转染(transfection)。转染48小时后,利用蛋白质生成抑制剂环己酰亚胺(Sigma-Aldrich)(100μg/ml)进行处理,并以1小时、2小时、4小时的时间测定半衰期。结果,确认了人表皮细胞生长因子的分解被抑制(图6)。人表皮细胞生长因子的半衰期为2小时以内,相反,人表皮细胞生长因子取代基(K28R)、表皮细胞生长因子取代基(K48R)、表皮细胞生长因子取代基(K28R+K48R)的半衰期为4小时以上,比WT长,并在图表中示出其结果(图6)。
4.确认细胞内的通过表皮细胞生长因子和表皮细胞生长因子取代基的信号传递
表皮细胞生长因子为生长因子,据报告,通过Ras-Raf-MEK1/2-细胞外信号调节激酶信号(signaling)使细胞外信号调节激酶1/2活化(Journal of Cell Science 117,4619-4628,2004)。
在本实施例中,确认了细胞内的通过表皮细胞生长因子和表皮细胞生长因子取代基的信号传递过程。首先,分别利用3μg的pcDNA3-myc-表皮细胞生长因子WT、3μg的pcDNA3-myc-表皮细胞生长因子取代基(K28R)、3μg的pcDNA3-myc-表皮细胞生长因子取代基(K48R)转染海拉细胞。在感染2日后,从细胞提取蛋白质并分别定量,为确认细胞内信号传递过程,执行了免疫印迹。为此,向聚偏氟乙烯膜分别移动从被pcDNA3-myc-表皮细胞生长因子WT、pcDNA3-myc-表皮细胞生长因子取代基(K28R)、pcDNA3-myc-表皮细胞生长因子取代基(K48R)感染的海拉细胞中分离的蛋白质后,使用以1:1000~1:3000的重量比包含抗-myc(9E10,Santa Cruz Biotechnology,sc-40)、抗-信号传递及转录激活因子3(STAT3)(SantaCruz Biotechnology,sc-21876)、抗-磷酸(phospho)-信号传递及转录激活因子3(Y705,cell signaling 9131S)、抗-蛋白激酶B(AKT)(H-136,Santa Cruz Biotechnology,sc-8312)、抗-磷酸-蛋白激酶B(S473,cell signaling 9271S)、抗-细胞外信号调节激酶1/2(9B3,Abfrontier LF-MA0134)、抗-磷酸-细胞外信号调节激酶1/2(Thr202/Tyr204,Abfrontier LF-PA0090)及抗-β-肌动蛋白(Santa Cruz Biotechnology,sc-47778)的封闭液和抗-兔(辣根过氧化物酶标记山羊抗兔IgG(goat anti-rabbit IgG-HRP),Santa CruzBiotechnology,sc-2004)、抗-小鼠(过氧化物酶标记小鼠IgG抗体(H+L),KPL,074-1806)二级抗体并利用电化学发光系统(免疫印迹检测试剂盒,ABfrontier,首尔(Seoul),韩国(Korea))清洗。结果,pcDNA3-myc-表皮细胞生长因子取代基(K28R)、pcDNA3-myc-表皮细胞生长因子取代基(K48R)在海拉细胞内与pcDNA3-myc-表皮细胞生长因子WT相同或呈现得到增加的磷酸-信号传递及转录激活因子3、磷酸-蛋白激酶B和磷酸-细胞外信号调节激酶1/2的信号传递(图7)。
实施例2:血小板源生长因子蛋白质的泛素化分析及半衰期增加确认、细胞内信号传递确认
1.表达载体克隆及蛋白质表达确认
(1)表达载体克隆
利用作为限制酶的BamHI和XhoI将通过聚合酶链式反应的血小板衍生生长因子A和血小板衍生生长因子B的DNA扩增产物和pcDNA3-myc(5.6kb)制备为切片并接合来进行克隆(图8,血小板衍生生长因子A和血小板衍生生长因子B氨基酸序列:序列6和序列7)。利用限制酶进行切断后通过琼脂糖凝胶电泳确认其结果(图9)。并且,图8的碱基序列中以下划线和粗体表示的部分为为了再次确认克隆的部位而通过聚合酶链反应确认时使用的引物集的一部分,通过琼脂糖凝胶电泳确认其结果(图9)。聚合酶链反应条件如下:在94℃的温度条件下进行3分钟的初始改性反应后,将94℃温度条件下的30秒钟的改性反应、60℃温度条件下的30秒钟的退火反应、72℃温度条件下的45秒钟的延伸反应等反复循环25次来进行,之后,在72℃的温度条件下反应10分钟。为确认通过如上所述的方法制备的DNA是否正确地通过蛋白质表达,利用抗myc(9E10,Santa Cruz Biotechnology,sc-40)抗体并通过免疫印迹确认了存在于图8所示的pcDNA3-myc载体的myc。确认了与myc结合的血小板衍生生长因子A和血小板衍生生长因子B蛋白质很好地表达,并示出通过利用肌动蛋白确认的印迹以定量负载(图10)。
(2)赖氨酸残基的取代
通过定点突变且利用精氨酸取代赖氨酸残基,利用所要诱导特定突变的DNA序列制备引物(血小板衍生生长因子A K160R FP 5'-GAATACGTCAGGAGGAAGCCAAAATTA-3'(序列8)、RP 5'-TAATTTTGGCTTCCTCCTGACGTATTC-3'(序列9);血小板衍生生长因子A K165R FP5'-AAGCCAAAATTAAGAGAAGTCCAGGTG-3'(序列10)、RP 5'-CACCTGGACTTCTCTTAATTTTGGCTT-3'(序列11);血小板衍生生长因子A K206R FP 5'-AAACGGAAAAGAAGAAGGTTAAAACCC-3'(序列12)、RP 5'-GGGTTTTAACCTTCTTCTTTTCCGTTT-3'(序列13)、(血小板衍生生长因子B K162RFP 5'-ATTGTGCGGAAGAGGCCAATCTTT-3'(序列14)、RP5'-AAAGATTGGCCTCTTCCGCACAAT-3'(序列15);血小板衍生生长因子B K167R FP 5'-CCAATCTTTAAGAGGGCCACGGTG-3'(序列16)、RP5'-CACCGTGGCCCTCTTAAAGATTGG-3'(序列17);血小板衍生生长因子B K179R FP 5'-CACCTGGCATGCAGGTGTGAGACA-3'(序列18)、RP 5'-TGTCTCACACCTGCATGCCAGGTG-3'(序列19))后,执行聚合酶链式反应来制备了取代特定氨基酸残基的质粒DNA。将pcDNA3-myc-血小板衍生生长因子A用作模板,来制备了赖氨酸残基被精氨酸取代(K→R)的3个质粒DNA(表2)。
表2
2.生物体内泛素化分析
利用pcDNA3-myc-血小板衍生生长因子A WT和对pMT123-HA-泛素(J Biol Chem.,279(4)、2368-2376,2004;Cell Research,22,873885,2012;Oncogene,22,12731280,2003;Cell,78,787-798,1994)进行编码的质粒感染HEK 293T细胞(ATCC,CRL-3216)。为确认泛素化过程,在细胞共转染3μg的pcDNA3-myc-血小板衍生生长因子A WT和1μg的pMT123-HA-泛素DNA,24小时之后,利用MG132(蛋白酶体抑制剂,5μg/ml)处理6小时,并实施免疫沉淀分析(图4)。并且,为比较WT与取代基之间的泛素化程度,分别利用3μg的pcDNA3-myc-血小板衍生生长因子A WT、3μg的pcDNA3-myc-血小板衍生生长因子A取代基(K160R)、3μg的pcDNA3-myc-血小板衍生生长因子A取代基(K165R)及3μg的pcDNA3-myc-血小板衍生生长因子A取代基(K206R)和3μg的pcDNA3-myc-血小板衍生生长因子B WT、3μg的pcDNA3-myc-血小板衍生生长因子B取代基(K162R)、3μg的pcDNA3-myc-血小板衍生生长因子B取代基(K167R)及3μg的pcDNA3-myc-血小板衍生生长因子B取代基(K179R)和1μg的pMT123-HA-泛素DNA共转染HEK 293T细胞(ATCC,CRL-3216),并在24小时后实施免疫沉淀分析(图11)。
利用溶解缓冲液(1%的Triton X、150mM的NaCl、50mM的Tris-HCl、pH 8及1mM的苯甲基磺酰氟)溶解为了免疫沉淀而获取的蛋白质样品后,与抗-myc(9E10)一级抗体(SantaCruz Biotechnology,sc-40)混合并在4℃的温度条件下培养一夜。利用蛋白A/G磁珠(Santa Cruz Biotechnology)在4℃的温度条件下反应2小时来分离了免疫沉淀物。之后,利用溶解缓冲液清洗2次。与2X SDS缓冲液混合后在100℃的温度条件下加热7分钟后,实施聚丙烯酰胺凝胶电泳来分离蛋白质样品。向聚偏氟乙烯膜(Millipore)移动所分离的蛋白质后,使用以1:1000的重量比包含抗-myc(9E10,Santa Cruz Biotechnology,sc-40)、抗-HA(Santa Cruz Biotechnology,sc-7392)及抗-β-肌动蛋白(Santa Cruz Biotechnology,sc-47778)的封闭液和抗-小鼠(过氧化物酶标记小鼠IgG抗体(H+L),KPL,074-1806)二级抗体并利用电化学发光系统(免疫印迹检测试剂盒,ABfrontier,首尔(Seoul),韩国(Korea))清洗。结果,在利用抗-myc(9E10,sc-40)实施免疫沉淀的情况下,随着pcDNA3-myc-血小板衍生生长因子A WT和pcDNA3-myc-血小板衍生生长因子B WT与泛素结合来形成聚泛素化,检测到扩散状泛素并显示出深颜色的带(图4,第三通路、第四通路、第七通路和第八通路)。并且,在利用MG132(蛋白酶体抑制剂,5μg/ml)处理6小时的情况下,聚泛素化的形成增加,来以更深的颜色显示检测到泛素的带(图4,第四通路、第八通路)。这种结果意味着血小板衍生生长因子A和血小板衍生生长因子B与泛素结合并通过泛素-蛋白酶体系统聚泛素化。并且,在pcDNA3-myc-血小板衍生生长因子A取代基(K160R)、pcDNA3-myc-血小板衍生生长因子A取代基(K165R)、pcDNA3-myc-血小板衍生生长因子A取代基(K206R)、pcDNA3-myc-血小板衍生生长因子B取代基(K162R)、pcDNA3-myc-血小板衍生生长因子B取代基(K167R)和pcDNA3-myc-血小板衍生生长因子B取代基(K179R)的情况下,带比WT浅。这表示泛素未与这些取代基结合,因此,检测到较少的泛素(图12,第三通路至第五通路及第八通路至第十通路)。
3.确认通过蛋白质生成抑制剂环己酰亚胺的血小板源生长因子的半衰期
将3μg的pcDNA3-myc-血小板衍生生长因子A WT、3μg的pcDNA3-myc-血小板衍生生长因子A取代基(K160R)、3μg的pcDNA3-myc-血小板衍生生长因子A取代基(K165R)及3μg的pcDNA3-myc-血小板衍生生长因子A取代基(K206R)和3μg的pcDNA3-myc-血小板衍生生长因子B WT、3μg的pcDNA3-myc-血小板衍生生长因子B取代基(K162R)、3μg的pcDNA3-myc-血小板衍生生长因子B取代基(K167R)及3μg的pcDNA3-myc-血小板衍生生长因子B取代基(K179R)分别向HEK 293T细胞转染。转染48小时后,利用蛋白质生成抑制剂环己酰亚胺(Sigma-Aldrich)(100μg/ml)处理,并以30分钟、60分钟及90分钟和15分钟、30分钟及60分钟的时间测定半衰期。结果,经确认,人血小板衍生生长因子A和血小板衍生生长因子B的分解得到抑制(图6)。可知,人血小板衍生生长因子A在60分钟之后分解,相反,人血小板衍生生长因子A取代基(K160R)、血小板衍生生长因子A取代基(K165R)和血小板衍生生长因子A取代基(K206R)在90分钟之后也不会被分解,人血小板衍生生长因子B在30分钟内被分解,相反,人血小板衍生生长因子B取代基(K162R)、血小板衍生生长因子B取代基(K167R)和血小板衍生生长因子B取代基(K179R)在60分钟之后也不会被分解,并在图表中示出其结果(图13、图14及图15)。
4.确认细胞内的通过血小板源生长因子和血小板源生长因子取代基的信号传递
血小板源生长因子为生长因子,据报告通过Ras-Raf-MEK1/2-细胞外信号调节激酶信号传递使细胞外信号调节激酶1/2活化(Journal of Cell Science 117,4619-4628,2004)。
在本实施例中,确认了细胞内的通过血小板源生长因子和血小板源生长因子取代基的信号传递过程。首先,分别利用3μg的pcDNA3-myc-血小板衍生生长因子A WT、3μg的pcDNA3-myc-血小板衍生生长因子A取代基(K160R)、3μg的pcDNA3-myc-血小板衍生生长因子A取代基(K165R)及3μg的pcDNA3-myc-血小板衍生生长因子A取代基(K206R)和3μg的pcDNA3-myc-血小板衍生生长因子B WT、3μg的pcDNA3-myc-血小板衍生生长因子B取代基(K162R)、3μg的pcDNA3-myc-血小板衍生生长因子B取代基(K167R)及3μg的pcDNA3-myc-血小板衍生生长因子B取代基(K179R)转染海拉细胞。在感染2日后,从细胞提取蛋白质并分别定量,为确认细胞内信号传递过程,执行了免疫印迹。为此,向聚偏氟乙烯膜移动从被pcDNA3-myc-血小板衍生生长因子A WT、pcDNA3-myc-血小板衍生生长因子A取代基(K160R)、pcDNA3-myc-血小板衍生生长因子A取代基(K165R)及pcDNA3-myc-血小板衍生生长因子A取代基(K206R)和pcDNA3-myc-血小板衍生生长因子B WT、pcDNA3-myc-血小板衍生生长因子B取代基(K162R)、pcDNA3-myc-血小板衍生生长因子B取代基(K167R)及pcDNA3-myc-血小板衍生生长因子B取代基(K179R)感染的海拉细胞中分离的蛋白质后,使用以1:1000~1:3000的重量比包含抗-myc(9E10,Santa Cruz Biotechnology,sc-40)、抗-信号传递及转录激活因子3(Santa Cruz Biotechnology,sc-21876)、抗-磷酸-信号传递及转录激活因子3(Y705,cell signaling 9131S)、抗-蛋白激酶B(H-136,Santa CruzBiotechnology,sc-8312)、抗-磷酸-蛋白激酶B(S473,cell signaling 9271S)、抗-细胞外信号调节激酶1/2(9B3,Abfrontier LF-MA0134)、抗-磷酸-细胞外信号调节激酶1/2(Thr202/Tyr204,Abfrontier LF-PA0090)及抗-β-肌动蛋白(Santa Cruz Biotechnology,sc-47778)的封闭液和抗-兔(辣根过氧化物酶标记山羊抗兔IgG,Santa CruzBiotechnology,sc-2004)和抗-小鼠(过氧化物酶标记小鼠IgG抗体(H+L),KPL,074-1806)二级抗体并利用电化学发光系统(免疫印迹检测试剂盒,ABfrontier,首尔(Seoul),韩国(Korea))清洗。结果,pcDNA3-myc-血小板衍生生长因子A取代基(K160R)、pcDNA3-myc-血小板衍生生长因子A取代基(K165R)及pcDNA3-myc-血小板衍生生长因子A取代基(K206R)在海拉细胞内与pcDNA3-myc-血小板衍生生长因子A WT相同或呈现得到增加的磷酸-信号传递及转录激活因子3信号传递,pcDNA3-myc-血小板衍生生长因子B取代基(K162R)、pcDNA3-myc-血小板衍生生长因子B取代基(K167R)及pcDNA3-myc-血小板衍生生长因子B取代基(K179R)在海拉细胞内长线磷酸-蛋白激酶B和磷酸-细胞外信号调节激酶1/2信号传递(图16)。
实施例3:粒细胞-巨噬细胞集落刺激因子蛋白质的泛素化分析及半衰期增加确认、细胞内信号传递确认
1.表达载体克隆及蛋白质表达确认
(1)表达载体克隆
利用作为限制酶的BamHI和XhoI将通过聚合酶链式反应的粒细胞-巨噬细胞集落刺激因子DNA扩增产物和pcDNA3-myc(5.6kb)制备为切片并接合来进行克隆(图17,人粒细胞-巨噬细胞集落刺激因子氨基酸序列:序列20),在利用限制酶进行切断后通过琼脂糖凝胶电泳确认其结果(图18)并且,图17的碱基序列中以下划线和粗体表示的部分为为了再次确认克隆的部位而通过聚合酶链反应确认时使用的引物集的一部分,并通过琼脂糖凝胶电泳确认其结果(图18)。聚合酶链反应条件如下:在94℃的温度条件下进行3分钟的初始改性反应后,将94℃温度条件下的30秒钟的改性反应、60℃温度条件下的30秒钟的退火反应、72℃温度条件下的30秒钟的延伸反应等反复循环25次来执行,之后,在72℃的温度条件下反应10分钟。为确认通过如上所述的方法制备的DNA是否正确地通过蛋白质表达,利用抗myc(9E10,sc-40)抗体并通过免疫印迹确认了存在于图17所示的pcDNA3-myc载体的myc表达,由此,确认了与myc结合的粒细胞-巨噬细胞集落刺激因子蛋白质很好地表达,并确认通过利用肌动蛋白确认的印迹以定量负载(图19)。
(2)赖氨酸残基的取代
通过定点突变且利用精氨酸取代赖氨酸残基,利用所要诱导特定突变的DNA序列制备引物(粒细胞-巨噬细胞集落刺激因子K89R FP 5'-GGCAGCCTCACCAGGCTCAAGGGCC-3'(序列21)、RP 5'-GGCCCTTGAGCCTGGTGAGGCTGCC-3'(序列22);粒细胞-巨噬细胞集落刺激因子K91R FP 5'-CTC ACCAAGCTCAGGGGCCCCTTGACC-3'(序列23)、RP 5'-GGTCAAGGGGCCCCTGAGCTTGGTGAG-3'(序列24);粒细胞-巨噬细胞集落刺激因子K102R FP5'-GCTAGCCACTACAGACAGCACTGCCCT-3'(序列25)、RP 5'-AGGGCAGTGCTGTCTGTAGTGGCTAGC-3'(序列26))后,在特定条件下执行聚合酶链式反应来制备了取代特定氨基酸残基的质粒DNA。将pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子用作模板,来制备了赖氨酸残基被精氨酸取代(K→R)的3个质粒DNA(表3)。
表3
2.生物体内泛素化分析
利用pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子WT和对pMT123-HA-泛素DNA进行编码的质粒感染HEK 293T细胞。未确认泛素化过程,在细胞共转染3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子WT和1μg的pMT123-HA-泛素DNA,24小时之后利用MG132(蛋白酶体抑制剂,5μg/ml)处理6小时,并实施免疫沉淀分析(图20)。并且,为比较WT与取代基之间的泛素化程度,分别利用3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子WT、3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K89R)、3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K91R)及3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K102R)和1μg的pMT123-HA-泛素DNA共转染HEK 293T细胞(ATCC,CRL-3216),并在24小时后实施免疫沉淀分析(图21)。
利用溶解缓冲液(1%的Triton X、150mM的NaCl、50mM的Tris-HCl、pH 8及1mM的苯甲基磺酰氟)溶解为了免疫沉淀而获取的样品后,与抗-myc(9E10)一级抗体混合并在4℃的温度条件下培养一夜。利用蛋白A/G磁珠(Santa Cruz Biotechnology)在4℃的温度条件下反应2小时来分离了免疫沉淀物。之后,利用溶解缓冲液清洗2次。在免疫印迹法中,与2XSDS缓冲液混合后在100℃的温度条件下加热7分钟后,实施聚丙烯酰胺凝胶电泳来分离蛋白质样品。向聚偏氟乙烯膜移动所分离的蛋白质后,使用以1:1000的重量比包含抗-myc(9E10,Santa Cruz Biotechnology,sc-40)、抗-HA(Santa Cruz Biotechnology,sc-7392)及抗-β-肌动蛋白(Santa Cruz Biotechnology,sc-47778)的封闭液和抗-小鼠(过氧化物酶标记小鼠IgG抗体(H+L)、KPL,074-1806)二级抗体并利用电化学发光系统(免疫印迹检测试剂盒,ABfrontier,首尔(Seoul),韩国(Korea))清洗。
结果,在利用抗-myc(9E10,sc-40)实施免疫沉淀的情况下,随着pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子WT与泛素结合来形成聚泛素化,检测到扩散状的泛素并显示出深颜色的带(图20,第三通路和第四通路)。并且,在利用MG132(蛋白酶体抑制剂,5μg/ml)处理6小时的情况下,聚泛素化形成增加,来以更深的颜色显示检测到泛素的带(图20,第四通路)。并且,在pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K89R)、pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K91R)、pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K102R)的情况系,带比WT浅,pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子WT、pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K89R)、pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K91R)、pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K102R)未与泛素结合,因此检测到较少的泛素(图21,第三通路、第四通路及第五通路)。以上结果表示粒细胞-巨噬细胞集落刺激因子与泛素结合并通过泛素-蛋白酶体系统聚泛素化来被分解。
3.确认通过蛋白质生成抑制剂环己酰亚胺的粒细胞-巨噬细胞集落刺激因子的半衰期
将3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子WT、3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K89R)、3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K91R)、3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K102R)分别向HEK 293T细胞转染。转染48小时后,利用蛋白质生成抑制剂环己酰亚胺(Sigma-Aldrich)(100μg/ml)进行处理,并以30分钟、60分钟、90分钟的时间测定半衰期,结果确认,人粒细胞-巨噬细胞集落刺激因子的分解被抑制(图22及图23)。人粒细胞-巨噬细胞集落刺激因子的半衰期为30分钟以内,相反,人pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K91R)、pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K102R)的半衰期为60分钟及90分钟以上,比WT长,并在图表中示出其结果(图22及23)。
4.确认细胞内的通过粒细胞-巨噬细胞集落刺激因子和粒细胞-巨噬细胞集落刺激因子取代基的信号传递
据报告,通过粒细胞-巨噬细胞集落刺激因子的细胞内作用通过JAK/STAT、丝裂原活化蛋白激酶及胞内磷脂酰肌醇激酶/蛋白激酶B信号传递作用(Blood,119(15):3383-3393,2012)。
在本实施例中,确认了细胞内的通过粒细胞-巨噬细胞集落刺激因子和粒细胞-巨噬细胞集落刺激因子取代基的信号传递过程。分别利用3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K89R)、3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K91R)、3μg的pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K102R)感染海拉细胞的2日后,从感染的细胞提取蛋白质并分别定量,为确认细胞内信号传递过程,执行了免疫印迹。在此过程中,向聚偏氟乙烯膜分别移动从被pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K89R)、pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K91R)、pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K102R)感染的海拉细胞中分离的蛋白质后,使用以1:1000~1:3000的重量比包含抗-myc(9E10,Santa Cruz Biotechnology,sc-40)、抗-信号传递及转录激活因子3(Santa Cruz Biotechnology,sc-21876)、抗-磷酸-信号传递及转录激活因子3(Y705,cell signaling 9131S)、抗-蛋白激酶B(H-136,Santa CruzBiotechnology,sc-8312)、抗-磷酸-蛋白激酶B(S473,cell signaling 9271S)、抗-细胞外信号调节激酶1/2(9B3,Abfrontier LF-MA0134)、抗-磷酸-细胞外信号调节激酶1/2(Thr202/Tyr204,Abfrontier LF-PA0090)及抗-β-肌动蛋白(Santa Cruz Biotechnology,sc-47778)的封闭液和抗-兔(辣根过氧化物酶标记山羊抗兔IgG,Santa CruzBiotechnology,sc-2004)和抗-小鼠(过氧化物酶标记小鼠IgG抗体(H+L),KPL,074-1806)二级抗体并利用电化学发光系统(免疫印迹检测试剂盒,ABfrontier,Seoul,Korea)清洗。结果,pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K89R)、pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K91R)、pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子取代基(K102R)在海拉细胞内与pcDNA3-myc-粒细胞-巨噬细胞集落刺激因子WT相同或呈现得到增加的磷酸-信号传递及转录激活因子3和磷酸-蛋白激酶B信号传递(图24)。
实施例4:卵泡刺激素蛋白质的泛素化分析及半衰期增加确认、细胞内信号传递确认
1.表达载体克隆及蛋白质表达确认
(1)表达载体克隆
利用作为限制酶的BamHI和XhoI将通过聚合酶链式反应的卵泡刺激素α和卵泡刺激素βDNA扩增产物、pcDNA3-myc(5.6kb)制备为切片并接合来进行克隆(图25,卵泡刺激素α氨基酸序列:序列27及卵泡刺激素β氨基酸序列:序列28),利用限制酶进行切断后,通过琼脂糖凝胶电泳确认其结果(图26)。并且,图25的碱基序列中以下划线和粗体表示的部分为为了再次确认克隆的部位而通过聚合酶链反应确认时使用的引物集的一部分,并通过琼脂糖凝胶电泳确认其结果(图26)。聚合酶链反应条件如下:在94℃的温度条件下进行3分钟的初始改性反应后,将94℃温度条件下的30秒钟的改性反应、56℃温度条件下的30秒钟的退火反应、72℃温度条件下的1分钟的延伸反应等反复循环25次来执行,之后,在72℃的温度条件下反应10分钟。为确认通过如上所述的方法制备的DNA是否正确地通过蛋白质表达,利用抗myc(9E10,Santa Cruz Biotechnology,sc-40)抗体并通过免疫印迹确认了存在于图29所示的pcDNA3-myc载体的myc的表达。确认了与myc结合的卵泡刺激素α和卵泡刺激素β蛋白质很好地表达,并确认通过利用肌动蛋白确认的印迹以定量负载(图27)。
(2)赖氨酸残基的取代
通过定点突变且利用精氨酸取代赖氨酸残基,利用所要诱导特定突变的DNA序列制备引物(卵泡刺激素αK75R FP 5'-ATGTTGGTCCAAAGGAACGTCACC-3'(序列29)、RP 5'-GGTGACGTTCCTTTGGACCAACAT-3'(序列30)、卵泡刺激素αK99R FP 5'-ATGGGGGGTTTCAGAGTGGAGAAC-3'(序列31)、RP 5'-GTTCTCCACTCTGAAACCCCCCAT-3'(序列32)、卵泡刺激素αK115R FP 5'-TGTTATTATCACAGATCTTAACTCGAG-3'(序列33)、RP 5'-CTCGAGTTAAGATCTGTGATAATAACA-3'(序列34)、卵泡刺激素βK67R FP 5'-GGCCCAAAATCCAGAGAACATGTACCTT-3'(序列35)、RP 5'-AAGGTACATGTTCTCTGGATTTTGGGCC-3'(序列36)、卵泡刺激素βK104R FP 5'-GTCACTGTGGCAGGTGTGACAGCGA-3'(序列37)、RP5'-TCGCTGTCACACCTGCCACAGTGAC-3'(序列38)、卵泡刺激素βK128R FP 5'-GGTGAAATGAGAGAAACGCGTACGCGG-3'(序列39)、RP 5'-CCGCGTACGCGTTTCTCTCATTTCACC-3'(序列40))后,在特定条件下执行聚合酶链式反应来制备了取代特定氨基酸残基的质粒DNA。将pcDNA3-myc-卵泡刺激素α和pcDNA3-myc-卵泡刺激素β用作模板,来制备了赖氨酸残基被精氨酸取代(K→R)的3个质粒DNA(表4)。
表4
2.生物体内泛素化分析
利用pcDNA3-myc-卵泡刺激素αWT和对pMT123-HA-泛素DNA进行编码的质粒感染HEK293T细胞。为确认泛素化过程,在细胞共转染3μg的pcDNA3-myc-卵泡刺激素αWT及3μg的pcDNA3-myc-卵泡刺激素βWT和1μg的pMT123-HA-泛素DNA,24小时之后利用MG132(蛋白酶体抑制剂,5μg/ml)处理6小时,并实施免疫沉淀分析(图28)。并且,为比较WT与取代基之间的泛素化程度,分别利用3μg的pcDNA3-myc-卵泡刺激素αWT、3μg的pcDNA3-myc-卵泡刺激素α取代基(K75R)、3μg的pcDNA3-myc-卵泡刺激素α取代基(K99R)及3μg的pcDNA3-myc-卵泡刺激素α取代基(K115R)和3μg的pcDNA3-myc-卵泡刺激素β取代基(K67R)、3μg的pcDNA3-myc-卵泡刺激素β取代基(K104R)、3μg的pcDNA3-myc-卵泡刺激素β取代基(K128R)和1μg的pMT123-HA-泛素DNA共转染HEK 293T细胞(ATCC,CRL-3216),并在24小时后实施免疫沉淀分析(图28)。
利用溶解缓冲液(1%的Triton X、150mM的NaCl、50mM的Tris-HCl、pH 8及1mM的苯甲基磺酰氟)溶解为了免疫沉淀而获取的样品后,与抗-myc(9E10)一级抗体混合并在4℃的温度条件下培养一夜。利用蛋白A/G磁珠(Santa Cruz Biotechnology)在4℃的温度条件下反应2小时来分离了免疫沉淀物。之后,利用溶解缓冲液清洗2次。在免疫印迹中,与2X SDS缓冲液混合后在100℃的温度条件下加热7分钟后,实施聚丙烯酰胺凝胶电泳来分离蛋白质样品。向聚偏氟乙烯膜移动所分离的蛋白质后,使用以1:1000的重量比包含抗-myc(9E10,Santa Cruz Biotechnology,sc-40)、抗-HA(Santa Cruz Biotechnology,sc-7392)及抗-β-肌动蛋白(Santa Cruz Biotechnology,sc-47778)的封闭液和抗-小鼠(过氧化物酶标记小鼠IgG抗体(H+L),KPL,074-1806)二级抗体并利用电化学发光系统(免疫印迹检测试剂盒,ABfrontier,首尔(Seoul),韩国(Korea))清洗。
结果,在利用抗-myc(9E10,Santa Cruz Biotechnology,sc-40)实施免疫沉淀的情况下,随着pcDNA3-myc-卵泡刺激素αWT及pcDNA3-myc-卵泡刺激素βWT与泛素结合来形成聚泛素化,检测到扩散状泛素并显示出深颜色的带(图28,第三通路、第四通路及第七通路、第八通路)。并且,在利用MG132(蛋白酶体抑制剂,5μg/ml)处理6小时的情况下,聚泛素化的形成增加,来以更深的颜色显示检测到泛素的带(图28,第四通路及第八通路)。并且,在pcDNA3-myc-卵泡刺激素α取代基(K99R)、pcDNA3-myc-卵泡刺激素β取代基(K67R)、pcDNA3-myc-卵泡刺激素β取代基(K104R)、pcDNA3-myc-卵泡刺激素β取代基(K128R)的情况下,带比WT浅,pcDNA3-myc-卵泡刺激素α取代基(K99R)、pcDNA3-myc-卵泡刺激素β取代基(K67R)、pcDNA3-myc-卵泡刺激素β取代基(K104R)、pcDNA3-myc-卵泡刺激素β取代基(K128R)未与泛素结合,因此检测到较少的泛素(图29,第四通路及第八通路至第十通路)。以上结果表示,卵泡刺激素与泛素结合并通过泛素-蛋白酶体系统聚泛素化来被分解。
3.确认通过蛋白质生成抑制剂环己酰亚胺的卵泡刺激素α及卵泡刺激素β的半衰期
将3μg的pcDNA3-myc-卵泡刺激素αWT、3μg的pcDNA3-myc-卵泡刺激素α取代基(K75R)、3μg的pcDNA3-myc-卵泡刺激素α取代基(K99R)、3μg的pcDNA3-myc-卵泡刺激素α取代基(K115R)及3μg的pcDNA3-myc-卵泡刺激素βWT、3μg的pcDNA3-myc-卵泡刺激素β取代基(K67R)、3μg的pcDNA3-myc-卵泡刺激素β取代基(K104R)、3μg的pcDNA3-myc-卵泡刺激素β取代基(K128R)分别向海拉细胞转染。转染48小时后,利用蛋白质生成抑制剂环己酰亚胺(Sigma-Aldrich)(100μg/ml)进行处理,并以30分钟、60分钟、90分钟的时间测定半衰期。结果,确认了人卵泡刺激素的分解被抑制(图27)。人卵泡刺激素α的半衰期为45分钟,相反,人pcDNA3-myc-卵泡刺激素α取代基(K99R)的半衰期为90分钟以上,比WT长,人卵泡刺激素β的半衰期为30分钟以内,相反,人pcDNA3-myc-卵泡刺激素β取代基(K104R)的半衰期为60分钟以上,pcDNA3-myc-卵泡刺激素β取代基(K67R)、pcDNA3-myc-卵泡刺激素β取代基(K128R)的半衰期为90分钟以上,比WT长,并在图表中示出其结果(图30、图31及图32)。
4.确认细胞内的通过卵泡刺激素和卵泡刺激素取代基的信号传递
卵泡刺激素信号传递增加细胞内环磷酸腺苷(cAMP),由此,若蛋白激酶A(PKA)活化,则调节如反应元件结合蛋白(CREBP)的转录因子的磷酸化,并且,与细胞外信号调节激酶、胞内磷脂酰肌醇激酶/蛋白激酶B的信号传递相关(Front Endocrinol(Lausanne)、6:142,2015;Biochem J.,473(11):1483-1501,2016)。
在本实施例中,确认了细胞内的通过卵泡刺激素α和卵泡刺激素α取代基及卵泡刺激素β和卵泡刺激素β取代基的信号传递过程。分别利用3μg的pcDNA3-myc-卵泡刺激素αWT、3μg的pcDNA3-myc-卵泡刺激素α取代基(K75R)、3μg的pcDNA3-myc-卵泡刺激素α取代基(K99R)、3μg的pcDNA3-myc-卵泡刺激素α取代基(K115R)及3μg的pcDNA3-myc-卵泡刺激素βWT、3μg的pcDNA3-myc-卵泡刺激素β取代基(K67R)、3μg的pcDNA3-myc-卵泡刺激素β取代基(K104R)、3μg的pcDNA3-myc-卵泡刺激素β取代基(K128R)感染海拉细胞。在感染2日后,从细胞提取蛋白质并分别定量,为确认细胞内信号传递过程,执行了免疫印迹。在此过程中,向聚偏氟乙烯膜分别移动从被pcDNA3-myc-卵泡刺激素α取代基(K75R)、pcDNA3-myc-卵泡刺激素α取代基(K99R)、pcDNA3-myc-卵泡刺激素α取代基(K115R)感染的海拉细胞中分离的蛋白质后,使用以1:1000~1:3000的重量比包含抗-myc(9E10,Santa Cruz Biotechnology,sc-40)、抗-信号传递及转录激活因子3(Santa Cruz Biotechnology,sc-21876)、抗-磷酸-信号传递及转录激活因子3(Y705,cell signaling 9131S)、抗-蛋白激酶B(H-136,SantaCruz Biotechnology,sc-8312)、抗-磷酸-蛋白激酶B(S473,cell signaling 9271S)、抗-细胞外信号调节激酶1/2(9B3,Abfrontier LF-MA0134)、抗-磷酸-细胞外信号调节激酶1/2(Thr202/Tyr204,Abfrontier LF-PA0090)及抗-β-肌动蛋白(Santa Cruz Biotechnology,sc-47778)的封闭液和抗-兔(辣根过氧化物酶标记山羊抗兔IgG,Santa CruzBiotechnology,sc-2004)、抗-小鼠(过氧化物酶标记小鼠IgG抗体(H+L)、KPL,074-1806)二级抗体并利用电化学发光系统(免疫印迹检测试剂盒,ABfrontier首尔(Seoul),韩国(Korea))清洗。结果,pcDNA3-myc-卵泡刺激素α取代基(K75R)、pcDNA3-myc-卵泡刺激素α取代基(K99R)、pcDNA3-myc-卵泡刺激素α取代基(K115R)在海拉细胞内与pcDNA3-myc-卵泡刺激素αWT相同或呈现得到增加的磷酸-蛋白激酶B信号传递,pcDNA3-myc-卵泡刺激素β取代基(K67R)、pcDNA3-myc-卵泡刺激素β取代基(K104R)、pcDNA3-myc-卵泡刺激素β取代基(K128R)在海拉细胞内与pcDNA3-myc-卵泡刺激素βWT相同或呈现得到增加的磷酸-信号传递及转录激活因子3、磷酸-蛋白激酶B及磷酸-细胞外信号调节激酶1/2的信号传递(图33)。
实施例5:血管生成素1蛋白质的泛素化分析及半衰期增加确认、细胞内信号传递确认
1.表达载体克隆及蛋白质表达
(1)表达载体克隆
利用作为限制酶的BamHI和XhoI将通过聚合酶链式反应的血管生成素1DNA扩增产物和pcDNA3-myc(5.6kb)制备为切片并接合来进行克隆(图34,血管生成素1氨基酸序列:序列41),利用限制酶进行切断后,通过琼脂糖凝胶电泳确认其结果(图35)。并且,图34的碱基序列中以下划线和粗体表示的部分为为了再次确认克隆的部位而通过聚合酶链反应确认时使用的引物集的一部分,通过琼脂糖凝胶电泳确认其结果(图35)。聚合酶链反应条件如下:在94℃的温度条件下进行3分钟的初始改性反应后,将94℃温度条件下的30秒钟的改性反应、60℃温度条件下的30秒钟的退火反应、72℃温度条件下的1分30秒钟的延伸反应反复循环25次来执行,之后,在72℃的温度条件下反应10分钟。为确认通过如上所述的方法制备的DNA是否正确地通过蛋白质表达,利用抗myc(9E10,Santa Cruz Biotechnology,sc-40)抗体并通过免疫印迹确认了存在于图34所示的pcDNA3-myc载体的myc的表达。确认了与myc结合的血管生成素1蛋白质很好地表达,并确认通过利用肌动蛋白确认的印迹以定量负载(图36)。
(2)赖氨酸残基的取代
通过定点突变且利用精氨酸取代赖氨酸残基,利用所要诱导特定突变的DNA序列制备引物(血管生成素1K175R FP 5'-ACCTACAAGCTAGAGAGGCAACTTCTTCAA-3'(序列42)、RP5'-TTGAAGAAGTTGCCTCTCTAGCTTGTAGGT-3'(序列43)、血管生成素1K216R FP 5'-ACCTTAAAGGAAGAGAGAGAGAACCTTCAA-3'(序列44)、RP 5'-TTGAAGGTTCTCTCTCTCTTCCTTTAAGGT-3'(序列45)、血管生成素1K414R FP 5'-GGGACAGCAGGAAGACAGAGCAGC-3'(序列46)、RP 5'-GCTGCTCTGTCTTCCTGCTGTCCC-3'(序列47)后,在特定条件下,
执行聚合酶链式反应来制备了取代特定氨基酸残基的质粒DNA。将pcDNA3-myc-血管生成素1用作模板,来制备了赖氨酸残基被精氨酸取代(K→R)的3个质粒DNA(表5)。
表5
赖氨酸残基位置 | 赖氨酸被精氨酸取代的血管生成素1制备物 |
175 | pcDNA3-myc-血管生成素1(K175R) |
216 | pcDNA3-myc-血管生成素1(K216R) |
414 | pcDNA3-myc-血管生成素1(K414R) |
2.生物体内泛素化分析
利用pcDNA3-myc-血管生成素1WT和对pMT123-HA-泛素DNA进行编码的质粒感染HEK 293T细胞。为确认泛素化过程,在细胞共转染3μg的pcDNA3-myc-血管生成素1WT和1μg的pMT123-HA-泛素DNA,24小时之后利用MG132(蛋白酶体抑制剂,5μg/ml)处理6小时,并实时免疫沉淀分析(图37)。并且,为比较WT与取代基之间的泛素化程度,分别利用3μg的pcDNA3-myc-血管生成素1WT、3μg的pcDNA3-myc-血管生成素1取代基(K175R)、3μg的pcDNA3-myc-血管生成素1取代基(K216R)及3μg的pcDNA3-myc-血管生成素1取代基(K414R)和1μg的pMT123-HA-泛素DNA共转染HEK 293T细胞(ATCC,CRL-3216),并在24小时后实施免疫沉淀分析(图38)。
利用溶解缓冲液(1%的Triton X、150mM的NaCl、50mM的Tris-HCl、pH 8及1mM的苯甲基磺酰氟)溶解为了免疫沉淀而获取的样品后,与抗-myc(9E10)一级抗体混合并在4℃的温度条件下培养一夜。利用蛋白A/G磁珠(Santa Cruz Biotechnology)在4℃的温度条件下反应2小时来分离了免疫沉淀物。之后,利用溶解缓冲液清洗2次。在免疫印迹中,与2X SDS缓冲液混合后在100℃的温度条件下加热7分钟后,实施聚丙烯酰胺凝胶电泳来分离蛋白质样品。向聚偏氟乙烯膜移动所分离的蛋白质后,使用以1:1000的重量比包含抗-myc(9E10,Santa Cruz Biotechnology,sc-40)、抗-HA(Santa Cruz Biotechnology,sc-7392)及抗-β-肌动蛋白(Santa Cruz Biotechnology,sc-47778)封闭液和抗-小鼠(过氧化物酶标记小鼠IgG抗体(H+L),KPL,074-1806)二级抗体并利用电化学发光系统(免疫印迹检测试剂盒,ABfrontier,首尔(Seoul),韩国(Korea))清洗。
结果,在利用抗-myc(9E10,Santa Cruz Biotechnology,sc-40)实施免疫沉淀的情况下,随着pcDNA3-myc-血管生成素1WT与泛素结合来形成聚泛素化,检测到扩散状泛素并显示出深颜色的带(图37,第三通路和第四通路)。并且,在利用MG132(蛋白酶体抑制剂,5μg/ml)处理6小时的情况下,聚泛素化的形成增加,来以更深的颜色显示检测到泛素的带(图37,第四通路)。并且,在pcDNA3-myc-血管生成素1取代基(K175R)、pcDNA3-myc-血管生成素1取代基(K216R)、pcDNA3-myc-血管生成素1取代基(K414R)的情况下,带比WT浅,pcDNA3-myc-血管生成素1取代基(K175R)、pcDNA3-myc-血管生成素1取代基(K216R)、pcDNA3-myc-血管生成素1取代基(K414R)未与泛素结合,因此检测到较少的泛素(图38,第三通路至第五通路)。以上结果表示血管生成素1与泛素结合并通过泛素-蛋白酶体系统聚泛素化来被分解。
3.确认通过蛋白质生成抑制剂环己酰亚胺的血管生成素1的半衰期
将3μg的pcDNA3-myc-血管生成素1WT、3μg的pcDNA3-myc-血管生成素1取代基(K175R)、3μg的pcDNA3-myc-血管生成素1取代基(K216R)、3μg的pcDNA3-myc-血管生成素1取代基(K414R)分别向HEK 293T细胞转染。转染48小时后,利用蛋白质生成抑制剂环己酰亚胺(Sigma-Aldrich)(100μg/ml)进行处理,并以30分钟、60分钟及90分钟的时间测定半衰期。结果,确认了人血管生成素1的分解被抑制(图39及40)。人血管生成素1的半衰期为20分钟以内,相反,人pcDNA3-myc-血管生成素1取代基(K216R)的半衰期为30分钟以上,比WT长,并在图表中示出其结果(图39及图40)。
4.确认细胞内的通过血管生成素1和血管生成素1取代基的信号传递
据报告,血管生成素1通过细胞内ANGPTTIE信号通路(signalling pathways)使丝裂原活化蛋白激酶及PI3K/蛋白激酶B的信号传递活化,之后,参与内皮细胞间的相互作用及细胞生长(Nat Rev Cancer,10(8):575-585,2010)。
在本实施例中,确认了细胞内的通过血管生成素1和血管生成素1取代基的信号传递过程。分别利用5μg的pcDNA3-myc-血管生成素1取代基(K175R)、5μg的pcDNA3-myc-血管生成素1取代基(K216R)、5μg的pcDNA3-myc-血管生成素1取代基(K414R)感染海拉细胞。在感染2日后,从细胞提取蛋白质并分别定量,为确认细胞内信号传递过程,执行了免疫印迹。在此过程中,向聚偏氟乙烯膜分别移动从被pcDNA3-myc-血管生成素1取代基(K175R)、pcDNA3-myc-血管生成素1取代基(K216R)、pcDNA3-myc-血管生成素1取代基(K414R)感染的海拉细胞中分离的蛋白质后,使用以1:1000~1:3000的重量比包含抗-myc(9E10,SantaCruz Biotechnology,sc-40)、抗-信号传递及转录激活因子3(Santa CruzBiotechnology,sc-21876)、抗-磷酸-信号传递及转录激活因子3(Y705,cell signaling9131S)、抗-蛋白激酶B(H-136,Santa Cruz Biotechnology,sc-8312)、抗-磷酸-蛋白激酶B(S473,cell signaling 9271S)、抗-细胞外信号调节激酶1/2(9B3,Abfrontier LF-MA0134)、抗-磷酸-细胞外信号调节激酶1/2(Thr202/Tyr204,Abfrontier LF-PA0090)及抗-β-肌动蛋白(Santa Cruz Biotechnology,sc-47778)的封闭液和抗-兔(辣根过氧化物酶标记山羊抗兔IgG,Santa Cruz Biotechnology,sc-2004)、抗-小鼠(过氧化物酶标记小鼠IgG抗体(H+L),KPL,074-1806)二级抗体并利用电化学发光系统(免疫印迹检测试剂盒,ABfrontier,首尔(Seoul),韩国(Korea))清洗,结果,pcDNA3-myc-血管生成素1取代基(K175R)、pcDNA3-myc-血管生成素1取代基(K216R)、pcDNA3-myc-血管生成素1取代基(K414R)在海拉细胞内与pcDNA3-myc-血管生成素1WT相同或呈现得到增加的磷酸-蛋白激酶B及磷酸-细胞外信号调节激酶1/2的信号传递(图41)。
产业上的可利用性
根据本发明,提供半衰期得到增加的蛋白质或多肽。因此,本发明涉及可用作治疗剂的蛋白质或多肽,可利用于制药产业及美容产业。
序列表
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Ala
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Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile
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Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His
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Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp
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Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe
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Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys
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Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met
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Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser
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Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys
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Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
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Met Asp Tyr Tyr Arg Lys Tyr Ala Ala Ile Phe Leu Val Thr Leu Ser
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Tyr His Lys Ser
115
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Met Lys Thr Leu Gln Phe Phe Phe Leu Phe Cys Cys Trp Lys Ala Ile
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Glu Glu Cys Arg Phe Cys Ile Ser Ile Asn Thr Thr Trp Cys Ala Gly
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<212> PRT
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<400> 41
Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu Thr His
1 5 10 15
Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg
20 25 30
Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro
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Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr
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Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Ser
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Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp
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Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met
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Ala Gln Ile Gln Gln Asn Ala Val Gln Asn His Thr Ala Thr Met Leu
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Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys
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Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu
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Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln
165 170 175
Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser
180 185 190
Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu
195 200 205
Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr
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Arg Gln Thr Tyr Ile Ile Gln Glu Leu Glu Lys Gln Leu Asn Arg Ala
225 230 235 240
Thr Thr Asn Asn Ser Val Leu Gln Lys Gln Gln Leu Glu Leu Met Asp
245 250 255
Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Gly Val Leu Leu
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Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp
275 280 285
Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile
290 295 300
Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn
305 310 315 320
Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp
325 330 335
Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser
340 345 350
Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln
355 360 365
Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg
370 375 380
Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn
385 390 395 400
Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser
405 410 415
Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn
420 425 430
Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp
435 440 445
Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala
450 455 460
Gly Gln Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys
465 470 475 480
Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu
485 490 495
Asp Phe
<210> 42
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<212> DNA
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<220>
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acctacaagc tagagaggca acttcttcaa 30
<210> 43
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<212> DNA
<213> 人工序列
<220>
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ttgaagaagt tgcctctcta gcttgtaggt 30
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<211> 30
<212> DNA
<213> 人工序列
<220>
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<212> DNA
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<220>
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<212> DNA
<213> 人工序列
<220>
<223> 引物
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gggacagcag gaagacagag cagc 24
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<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 引物
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gctgctctgt cttcctgctg tccc 24
Claims (31)
1.一种蛋白质或多肽的半衰期增加方法,其特征在于,在蛋白质或多肽中,利用精氨酸取代与泛素的C-末端的甘氨酸结合的赖氨酸中的一个以上。
2.根据权利要求1所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述蛋白质为表皮细胞生长因子。
3.根据权利要求2所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述表皮细胞生长因子具有序列1的氨基酸序列,利用精氨酸取代从它的N-末端开始第28及48位置的赖氨酸残基中的一个以上。
4.根据权利要求1所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述蛋白质为血小板衍生生长因子A。
5.根据权利要求4所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述血小板衍生生长因子A具有序列6的氨基酸序列,利用精氨酸取代从它的N-末端开始第160、165及206位置的赖氨酸残基中的一个以上。
6.根据权利要求1所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述蛋白质为血小板衍生生长因子B。
7.根据权利要求6所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述血小板衍生生长因子B具有序列7的氨基酸序列,利用精氨酸取代从它的N-末端开始第162、167及179位置的赖氨酸残基中的一个以上。
8.根据权利要求1所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述蛋白质为粒细胞-巨噬细胞集落刺激因子。
9.根据权利要求8所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述粒细胞-巨噬细胞集落刺激因子具有序列20的氨基酸序列,利用精氨酸取代从它的N-末端开始第89、91及102位置的赖氨酸残基中的一个以上。
10.根据权利要求1所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述蛋白质为卵泡刺激素α。
11.根据权利要求10所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述卵泡刺激素α具有序列27的氨基酸序列,利用精氨酸取代从它的N-末端开始第75、99及115位置的赖氨酸残基中的一个以上。
12.根据权利要求1所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述蛋白质为卵泡刺激素β。
13.根据权利要求12所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述卵泡刺激素β具有序列28的氨基酸序列,利用精氨酸取代从它的N-末端开始第67、104及128位置的赖氨酸残基中的一个以上。
14.根据权利要求1所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述蛋白质为血管生成素1。
15.根据权利要求14所述的蛋白质或多肽的半衰期增加方法,其特征在于,上述血管生成素1具有序列41的氨基酸序列,利用精氨酸取代从它的N-末端开始第175、216及414位置的赖氨酸残基中的一个以上。
16.一种具有增加的半衰期的蛋白质,其特征在于,作为具有增加的半衰期的蛋白质,上述蛋白质的赖氨酸残基中的一个以上被精氨酸取代,上述被取代的赖氨酸残基与泛素的C-末端甘氨酸结合。
17.根据权利要求16所述的具有增加的半衰期的蛋白质,其特征在于,上述具有增加的半衰期的蛋白质为生长激素释放激素、生长激素释放肽、干扰素、干扰素受体、集落刺激因子、胰高血糖素样肽、白介素、白介素受体、酶、白介素结合蛋白、细胞因子结合蛋白、G蛋白偶联受体、人类生长激素、巨噬细胞活化因子、巨噬细胞肽、B细胞因子、T细胞因子、蛋白A、过敏抑制剂、细胞坏死糖蛋白、G蛋白偶联受体、免疫毒素、淋巴毒素、肿瘤坏死因子、抑癌基因、转移生长因子、α-1抗胰蛋白酶、白蛋白、α-乳清白蛋白、载脂蛋白-E、促红细胞生成素、高糖基化促红细胞生成素、血管生成素、血红蛋白、凝血酶、凝血酶受体活化肽、血栓调节蛋白、因子VII、因子VIIa、因子VIII、因子IX、因子XIII、纤溶酶原激活因子、尿激酶、链激酶、水蛭素、蛋白C、C反应蛋白、肾素抑制剂、胶原酶抑制剂、超氧化物歧化酶、瘦素、血小板源生长因子、上皮细胞生长因子、表皮细胞生长因子、血管抑素、血管紧张素、骨生长因子、骨刺激蛋白、降血钙素、胰岛素、心房肽、软骨诱导因子、纤维蛋白结合肽、依降钙素、结缔组织激活因子、组织因子途径抑制物、卵泡刺激素、促黄体激素、促黄体激素释放激素、神经生长因子、甲状旁腺激素、松弛素、分泌素、生长调节素、胰岛素样生长因子、肾上腺皮质激素、胰高血糖素、胆囊收缩素、胰多肽、胃泌素释放肽、促肾上腺皮质激素释放因子、促甲状腺激素、自体趋化因子、乳铁蛋白、肌肉抑制素、受体、受体拮抗剂、细胞表面抗原、病毒衍生疫苗抗原、单克隆抗体、多克隆抗体或抗体片段。
18.根据权利要求16所述的具有增加的半衰期的蛋白质,其特征在于,上述蛋白质为具有序列1的表皮细胞生长因子,利用精氨酸取代从它的N-末端开始第28及48位置的赖氨酸残基中的一个以上。
19.根据权利要求16所述的具有增加的半衰期的蛋白质,其特征在于,上述蛋白质为具有序列6的血小板衍生生长因子A,利用精氨酸取代从它的N-末端开始第160、165及206位置的赖氨酸残基中的一个以上。
20.根据权利要求16所述的具有增加的半衰期的蛋白质,其特征在于,上述蛋白质为具有序列7的血小板衍生生长因子B,利用精氨酸取代从它的N-末端开始第162、167及179位置的赖氨酸残基中的一个以上。
21.根据权利要求16所述的具有增加的半衰期的蛋白质,其特征在于,上述蛋白质为具有序列20的粒细胞-巨噬细胞集落刺激因子,利用精氨酸取代从它的N-末端开始第89、91及102位置的赖氨酸残基中的一个以上。
22.根据权利要求16所述的具有增加的半衰期的蛋白质,其特征在于,上述蛋白质为具有序列27的卵泡刺激素α,利用精氨酸取代从它的N-末端开始第75、99及115位置的赖氨酸残基中的一个以上。
23.根据权利要求16所述的具有增加的半衰期的蛋白质,其特征在于,上述蛋白质为具有序列28的卵泡刺激素β,利用精氨酸取代从它的N-末端开始第67、104及128位置的赖氨酸残基中的一个以上。
24.根据权利要求16所述的具有增加的半衰期的蛋白质,其特征在于,上述蛋白质为具有序列41的血管生成素1,利用精氨酸取代从它的N-末端开始第175、216及414位置的赖氨酸残基中的一个以上。
25.一种药学和/或美容组合物,其特征在于,包含权利要求18所述的表皮细胞生长因子及赋形剂,用于细胞生长、皮肤及头发再生和/或治疗。
26.一种药学和/或美容组合物,其特征在于,包含权利要求19所述的血小板衍生生长因子A或权利要求20所述的血小板衍生生长因子B及赋形剂,用于细胞生长、血管生成及慢性溃疡和骨损失恢复。
27.一种药学组合物,其特征在于,包含权利要求21所述的粒细胞-巨噬细胞集落刺激因子及药剂学上可接受的赋形剂,用于预防中性粒细胞缺乏症和/或用于预防和/或治疗免疫疾病和/或包括实体癌及血液癌的癌症和/或类风湿性关节炎。
28.一种药学组合物,其特征在于,包含权利要求22所述的卵泡刺激素α或权利要求23所述的卵泡刺激素β及药剂学上可接受的赋形剂,用于诱导促排卵的不孕治疗剂和/或用于治疗实体癌。
29.一种药学组合物,其特征在于,包含权利要求24所述的血管生成素1及药剂学上可接受的赋形剂,用于治疗糖尿病、心脏疾病和/或败血症。
30.一种表达载体,包含:(a)启动子;(b)碱基序列,对权利要求16至24中任一项所述的蛋白质进行编码;以及任意连接体,上述表达载体的特征在于,上述启动子与碱基序列可操作地连接。
31.一种宿主细胞,其特征在于,包含权利要求30所述的表达载体。
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