组蛋白H4融合蛋白载体用于肿瘤基因治疗的研究
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摘要
作为一类新型的非病毒基因转运工具,蛋白或多肽介导的基因转运越来越表现出强大的基因转运效率。在当前的研究中,一些研究人员发现,组蛋白能有效的介导基因转运(组蛋白转染)。小麦组蛋白H4是构成核小体的核心组蛋白,由103个氨基酸组成,它的基因序列和蛋白的空间结构最初是由Tabata等人1983年发表的。它与人的组蛋白H4及其它真核生物的组蛋白H4有着高度的同源性,基因内部均不含内含子序列。在氨基酸组成上来讲,与人的组蛋白H4氨基酸序列相比,只有第61和78两个位点的氨基酸差异。这个分子量大约在11.0 kDa小分子蛋白,由于它的低毒性和低免疫原性,是一个较好的基因转运工具的候选分子。基于此,我们构建了组蛋白H4融合蛋白基因转运载体。
蛋白跨膜结构转导域(PTDs)是一类能穿越哺乳动物细胞质膜的小分子多肽类物质,这类物质已经被广泛应用于蛋白质治疗的各个领域。研究人员可以通过基因工程的方法将PTDs的基因与细胞毒作用的蛋白进行融合与表达,借此将异源目的蛋白携入细胞内。PTD-tat是研究比较透彻的一个穿膜肽。它是来源于HIV-1病毒的TAT蛋白的一个多肽结构域,由11个氨基酸组成。它的组成序列,YGRKKRRQRRR,由几个强碱性的氨基酸序列组成的,并且是完成穿膜作用的关键肽段。考虑到PTD-tat在药物运输中起到的重要作用,很多人利用此分子作为治疗性分子或粒子进入哺乳动物细胞的重要工具。尽管有报导称,四种核心组蛋白都有蛋白跨膜转运的能力,但是在研究表明,与单纯的组蛋白相比较,引入PTD-tat融合组蛋白作为DNA转运工具,在很大程度上能够提高组蛋白转染细胞的效率。正是因为此多肽能够高效的介导小分子和大分子的细胞内摄,在本研究中,我们将此肽整合进入小麦组蛋白H4的C末端,以保证小麦组蛋白H4能通过PTD-tat的途径高效的将治疗基因携入细胞内。
除此之外,靶向性药物专一地用于治疗癌症有着许多优点,例如可以维持一个较低的给药浓度,就能将药物从血清中运送至靶细胞,还可以减少药物的副作用,并且可以提高抗肿瘤的效率。一个成功的靶向性药物传输系统必须能够获得很高的细胞穿膜效率并能停滞于特异性的细胞类群上。这种特异性是通过将靶向性的基序与药物传输系统相结合,而这些基序也必须能够精确的与癌症细胞表面的受体相结合。这样才能有效的降低药物对正常的健康组织的副作用。促黄体素释放素(LHRH)的受体在人乳腺癌、卵巢和子宫内膜肿瘤以及前列腺癌细胞等肿瘤细胞表面过量表达,而在正常内脏组织细胞表面没有表达,因此,我们利用LHRH作为靶向性的基序转运抗肿瘤药物至特定的癌症细胞,起到了很好的效果。
本研究构建了一个异源性的、有组氨酸标签的重组小麦组蛋白H4,命名为H4TL。在小麦根尖组织中提取了小麦基因组,目标基因H4TL包含小麦组蛋白H4基因,蛋白跨膜转导肽TAT基因以及靶向性配体分子LHRH的基因序列。通过PCR方法在小麦基因组中扩增H4基因,利用重叠延伸PCR方法对基因进行改造。经过6次PCR,每次PCR片段均克隆进pMD18T载体中进行鉴定,鉴定正确后的片段进入下一次延伸反应,最后得到了编码完全正确的基因片段,将此片段插入改造过的原核表达载体pET28a (++)中,得到重组pET28a(++)-H4TL质粒。将鉴定正确的质粒转入大肠杆菌E.coli BL21(DE3)中,利用IPTG诱导表达。此目的蛋白在大肠杆菌中获得高效表达。目的蛋白是一个含有141个氨基酸,分子量为15.5 kDa小分子蛋白。利用抗His标签的单克隆抗体对目的蛋白进行了Western blot鉴定。
将表达阳性的细胞通过摇瓶进行发酵培养,通过改变诱导条件,优化了最佳表达条件,培养基PH为6.8-7.6,诱导剂IPTG浓度范围0.6-1.0mM,诱导温度25-30℃,诱导时间>10h,得到了高效可溶性表达,表达量占菌体总蛋白的35%以上。收集发酵瓶中细胞,用超声波破碎后离心,上清过滤后冷冻保存。
用质量分数为30%的硫酸铵溶液盐析沉淀目的蛋白,随后用6M盐酸胍变性结合亲和层析分离和纯化融合蛋白H4TL,亲和纯化的介质为Ni~+-葡聚糖。100-200mM的咪唑进行梯度洗脱,收集到峰期的洗脱液,用凝胶层析脱盐柱快速脱盐,纯化后的样品经超滤柱或PEG20000进行浓缩,于超净工作台用0.22μm滤膜过滤后冷冻保存。最终建立了一种有效的纯化方法,对重组蛋白进行了高效的分离和纯化,高效液相色谱分析其纯度达到了95%以上。
用SmartSpecTM plus分光光度法测定纯化后蛋白浓度,分别按蛋白/质粒DNA质量比0-8进行凝胶电泳阻滞试验,凝胶电泳阻滞结果证明重组蛋白H4TL可以有效的结合质粒DNA。在凝胶电泳阻滞试验的基础上,我们对结合后的蛋白/DNA复合物进行了降解试验。核酸降解试验结果证明了重组蛋白与DNA形成的复合物有很强的稳定性,并且可以有效的防止DNA酶的降解。更重要的是,此蛋白成功地将报告基因pEGFP/C1转染进入人乳腺癌细胞MCF-7,人卵巢癌细胞HO8910,人前列腺癌细胞LNCap,人肺癌细胞A549以及人宫颈癌细胞HeLa中,转染效率与细胞类型、复合物浓度、蛋白与质粒DNA的配比、细胞密度及Ca~(2+)浓度有关。我们确立的最佳的转染条件为蛋白与质粒DNA质量比4:1,转染前细胞为60-70%丰度,Ca~(2+)浓度为2-4mM。
凋亡素,是一个来源于鸡贫血病毒的小分子蛋白质,之所以受到人们关注,是因为它可以选择性的杀死肿瘤细胞而对正常细胞无毒性作用。凋亡素的亚细胞定位是肿瘤特异性的关键因素,在正常细胞中,它位于细胞质中,而有肿瘤细胞中它可以转运进入细胞核中。凋亡素的这种核定位机制主要是由自身的磷酸化水平控制的。在肿瘤细胞中,凋亡素引起活细胞内包括Akt等激酶物质的核聚集,并且可以被CDK2磷酸化。因此,凋亡素可以间接地在活细胞内传递细胞凋亡信号。此外,凋亡素也会以多聚物的形式与DNA分子相结合,通过与几个核靶分子相互作用,例如与促细胞后期复合物相互作用,导致G2/M期逃逸。这种促凋亡信号由信号分子Nur77经核传递给细胞质,激活非p53依赖的线粒体途径,诱导肿瘤细胞凋亡。
我们利用靶向性的蛋白H4TL作为载体,进行凋亡素基因的转染研究,来评价H4TL的转染效率及其凋亡素转入细胞后的释控及表达,同时检测凋亡素基因对人乳腺癌细胞MCF-7及人卵巢癌HO8910两种肿瘤细胞的凋亡作用。我们构建了凋亡素真核表达载体pcDNA3.1(+)/apoptin,利用重组蛋白H4TL将其转染进入受试细胞中。利用经典的RT-PCR和western blot分析其在受试细胞中的表达情况;MTT法检测了转染凋亡素后细胞的增殖抑制情况,利用Annexin V–FITC /PI双荧光染色法对转染后的细胞进行细胞凋亡的检测,得到了较高凋亡率,对阴性的对照细胞系-正常人肺胚二倍体细胞2BS的凋亡率不超过20%,MCF-7细胞的凋亡率达到了42%(对照组为9.18%); HO8910细胞的凋亡率为44%(对照组为3.31%)。此外,我们利用DNA ladder法检测了凋亡后细胞中的基因组DNA的片段化,利用罗丹明123作为荧光染料检测了处于凋亡状态的细胞的线粒体膜电位的缺失情况,这些试验帮助我们进一步验证了重组蛋白H4TL作为基因转运载体和凋亡素作为治疗基因的有效性。同时,这些结果说明了靶向于肿瘤特异性受体的非病毒载体为基因转运提供了一个廉价的、简单高效的工具。
Protein/peptide-mediated gene delivery has recently emerged as a powerful approach in non-viral gene transfer. In previous studies, several groups found that histones can efficiently mediate gene transfer (histonefection). Wheat histone H4 is a nucleosome core histone whose gene was cloned and structure determined by Tabata et al. It is relatively conservative in eukaryotic core histones. There are only two amino acid differences at sites 61 and 78 between human histone H4 and that of wheat, which allows for a good candidate for gene transfer. For these reasons, we have constructed recombinant wheat histone H4 as a new gene delivery carrier.
Protein transduction domain TAT (PTD-tat) is one of the most well-studied and efficient cell-penetrating peptides. It contains an 11-amino acid peptide of the human immunodeficiency viruses type 1 (HIV-1) Tat Protein. The amino acids of PTD-tat are highly basic, YGRKKRRQRRR, which is crucial for penetrating the plasma membrane. Because of the potential of PTD-tat for mediating cellular uptake of small and large molecules, in this study we genetically incorporated PTD-tat into the C-terminus of wheat histone H4 to allow H4 to enhance penetration of the plasma membrane via the PTD-tat pathway. In addition, a targeted drug delivery system must achieve high cell permeability and retention by the specific cell population. Target cell specificity is achieved by attaching molecular targeting moieties to the drug delivery system that interact precisely with receptors of cancer cell surface. This ensures that adverse side effects on healthy tissues will be minimized. Receptors for the luteinizing hormone-releasing hormone (LHRH) are overexpressed in the plasma membrane of cancer cells, and expression is not detected in normal visceral organs. Therefore, LHRH can potentially be used as the targeting moiety to deliver anticancer drugs specifically to cancer cells and facilitate their cellular uptake.
Here, we report the generation of plasmid constructs that overproduce H4-TAT-LHRH (H4TL) as heterologous, His-tagged fusion proteins. The wheat genome was extracted from wheat root tissue. The putative fusion H4TL gene containing the wheat histone H4 gene with PDT-tat (YGRKKRRQRRR) and LHRH (QHWSYGLRPG) gene sequences was cloned from the Triticum aestivum genome and amplified by overlap extention polymerase chain reaction (OE-PCR). Every PCR fragment was determined by cloning it into pMD18-T vector and sequenced. The sequence of modified wheat histone H4 gene was in alignment with the GenBank sequence. The last amplified sequence was digested using EcoR I-Not I, cloned into pET28a (++), transferred E.coli JM109 cells, and identified by PCR and restriction digest. Correct constructs were identified by sequencing. E.coli BL21(DE3) containing the pET28a(++)-H4TL recombinant plasmid were induced by isopropyl-β-D-thiogalactopyranoside (IPTG) .
The expression positive cells were induced using shake-flask fermentation and collected by centrifugation (7000xg at 4 oC for 15 min), washed twice with PBS and lysed by sonication. The clear supernatant was collected by centrifugation (10000xg at 4oC for 15 min), then obtained by filtration through a 0.22μm Millipore membrane. The supernatant proteins were denaturated by 6 M guanidine hydrochloride and loaded onto a nickel column, (0.7x2.5 mm, GE Healthcare). Chromatography operation was performed on an AKTA~(TM) Explorer Fast Protein Liquid Chromatography system (GE Healthcare). Ni~+ -metal affinity chromatography was used to purify His-tagged H4TL fusion proteins from supernatant proteins by guanidine hydrochloride denaturation.
Purified proteins were desalted using a HiTrap desalt column (GE Healthcare) according to the manufacturer’s instructions, concentrated using an Amicon Ultra-15 Centrifugal Filter Units (Milipore, UK), and buffer-exchanged with 5% dextrose in 20 mM Tris-HCl pH 7.4. The H4TL fraction was freeze-dried and stored at -70oC for further use.
The modified H4TL gene encoded a recombinant protein of 141 amino acids with an approximate molecular weight of 15.5 kDa. Gel electrophoresis mobility shift assays demonstrated that the purified modified H4 protein had high affinity for DNA. Most significantly, complexing plasmid pEGFP/C1 with H4TL was transfected with high efficiency into MCF-7, HO8910, LNCap, A549 and HeLa cells in vitro. The transfection efficiency mediated by histones is dependent on the relative concentration (DNA: histone ratio), type of cells and the incubation time.
The chicken anaemia virus-derived protein apoptin is a tumour-specific cell-killing agent. This 14 kDa protein selectively induces apoptosis in a wide variety of transformed cells but not in primary cells. The cancer-selective toxicity of apoptin correlates with its cellular localization. Apoptin enters the nuclei of cancerous cells, whereas in nontransformed cells it remains in the cytoplasm. The current hypothesis is that nuclear trafficking and tumor specific phosphorylation of apoptin at Thr-108 are essential for the induction of apoptosis. Recently, Rohn and colleagues reported that phosphorylation of apoptin is required for apoptosis, but that abolishing the phosphorylation site of apoptin does not significantly disrupt its nuclear input into tumor cells.
In the present study, we attempted to use H4TL with naked plasmid DNA, which contains a apoptin tumor suppressor gene, to evaluate the transfection efficiency and antitumor activity in human ovarian carcinoma (HO8910) and breast cancer (MCF-7) cells in vitro. We observed that apoptin delivery resulted in a more differential growth inhibition pattern in cancer cells in vitro. In this study, the wild-type apoptin gene was transfected into cancer cells using the H4TL as a vector, and the expression level and the activity of apoptin gene were evaluated in vitro. Gene expression was determined by classic reverse transcriptase-PCR and western blotting analysis. The cellular growth inhibition of H4TL-mediated apoptin transfection were assessed by MTT ([3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrasolium bromide] benzene sulfonic acid hydrate) assay. The apoptosis induced by apoptin were measured by Annexin V–FITC (fluorescein isothiocyanate) /PI staining, DNA ladder and lost of mitochondrial membrane potential. The results showed that remarkable apoptotic characteristics such as nuclear shrinkage appeared in tumor cells, but few apoptotic characteristics were observed in control groups. The apoptosis present were higher than control, the cell cycle were exchanged also detected by FACS. It was suggested that the recombination protein H4TL could mediate apoptin’s transfection and could promote them expression and induce apoptosis in different tested tumor cells effectively. Our data suggest that H4TL can mediate apoptin gene transfer in vitro with high efficiency and is a promising new strategy for apoptin gene therapy. These results demonstrate that the targeting of non-viral vectors to tumor-specific receptors provide a cheap, simple, highly efficient tool for gene delivery.
蛋白跨膜结构转导域(PTDs)是一类能穿越哺乳动物细胞质膜的小分子多肽类物质,这类物质已经被广泛应用于蛋白质治疗的各个领域。研究人员可以通过基因工程的方法将PTDs的基因与细胞毒作用的蛋白进行融合与表达,借此将异源目的蛋白携入细胞内。PTD-tat是研究比较透彻的一个穿膜肽。它是来源于HIV-1病毒的TAT蛋白的一个多肽结构域,由11个氨基酸组成。它的组成序列,YGRKKRRQRRR,由几个强碱性的氨基酸序列组成的,并且是完成穿膜作用的关键肽段。考虑到PTD-tat在药物运输中起到的重要作用,很多人利用此分子作为治疗性分子或粒子进入哺乳动物细胞的重要工具。尽管有报导称,四种核心组蛋白都有蛋白跨膜转运的能力,但是在研究表明,与单纯的组蛋白相比较,引入PTD-tat融合组蛋白作为DNA转运工具,在很大程度上能够提高组蛋白转染细胞的效率。正是因为此多肽能够高效的介导小分子和大分子的细胞内摄,在本研究中,我们将此肽整合进入小麦组蛋白H4的C末端,以保证小麦组蛋白H4能通过PTD-tat的途径高效的将治疗基因携入细胞内。
除此之外,靶向性药物专一地用于治疗癌症有着许多优点,例如可以维持一个较低的给药浓度,就能将药物从血清中运送至靶细胞,还可以减少药物的副作用,并且可以提高抗肿瘤的效率。一个成功的靶向性药物传输系统必须能够获得很高的细胞穿膜效率并能停滞于特异性的细胞类群上。这种特异性是通过将靶向性的基序与药物传输系统相结合,而这些基序也必须能够精确的与癌症细胞表面的受体相结合。这样才能有效的降低药物对正常的健康组织的副作用。促黄体素释放素(LHRH)的受体在人乳腺癌、卵巢和子宫内膜肿瘤以及前列腺癌细胞等肿瘤细胞表面过量表达,而在正常内脏组织细胞表面没有表达,因此,我们利用LHRH作为靶向性的基序转运抗肿瘤药物至特定的癌症细胞,起到了很好的效果。
本研究构建了一个异源性的、有组氨酸标签的重组小麦组蛋白H4,命名为H4TL。在小麦根尖组织中提取了小麦基因组,目标基因H4TL包含小麦组蛋白H4基因,蛋白跨膜转导肽TAT基因以及靶向性配体分子LHRH的基因序列。通过PCR方法在小麦基因组中扩增H4基因,利用重叠延伸PCR方法对基因进行改造。经过6次PCR,每次PCR片段均克隆进pMD18T载体中进行鉴定,鉴定正确后的片段进入下一次延伸反应,最后得到了编码完全正确的基因片段,将此片段插入改造过的原核表达载体pET28a (++)中,得到重组pET28a(++)-H4TL质粒。将鉴定正确的质粒转入大肠杆菌E.coli BL21(DE3)中,利用IPTG诱导表达。此目的蛋白在大肠杆菌中获得高效表达。目的蛋白是一个含有141个氨基酸,分子量为15.5 kDa小分子蛋白。利用抗His标签的单克隆抗体对目的蛋白进行了Western blot鉴定。
将表达阳性的细胞通过摇瓶进行发酵培养,通过改变诱导条件,优化了最佳表达条件,培养基PH为6.8-7.6,诱导剂IPTG浓度范围0.6-1.0mM,诱导温度25-30℃,诱导时间>10h,得到了高效可溶性表达,表达量占菌体总蛋白的35%以上。收集发酵瓶中细胞,用超声波破碎后离心,上清过滤后冷冻保存。
用质量分数为30%的硫酸铵溶液盐析沉淀目的蛋白,随后用6M盐酸胍变性结合亲和层析分离和纯化融合蛋白H4TL,亲和纯化的介质为Ni~+-葡聚糖。100-200mM的咪唑进行梯度洗脱,收集到峰期的洗脱液,用凝胶层析脱盐柱快速脱盐,纯化后的样品经超滤柱或PEG20000进行浓缩,于超净工作台用0.22μm滤膜过滤后冷冻保存。最终建立了一种有效的纯化方法,对重组蛋白进行了高效的分离和纯化,高效液相色谱分析其纯度达到了95%以上。
用SmartSpecTM plus分光光度法测定纯化后蛋白浓度,分别按蛋白/质粒DNA质量比0-8进行凝胶电泳阻滞试验,凝胶电泳阻滞结果证明重组蛋白H4TL可以有效的结合质粒DNA。在凝胶电泳阻滞试验的基础上,我们对结合后的蛋白/DNA复合物进行了降解试验。核酸降解试验结果证明了重组蛋白与DNA形成的复合物有很强的稳定性,并且可以有效的防止DNA酶的降解。更重要的是,此蛋白成功地将报告基因pEGFP/C1转染进入人乳腺癌细胞MCF-7,人卵巢癌细胞HO8910,人前列腺癌细胞LNCap,人肺癌细胞A549以及人宫颈癌细胞HeLa中,转染效率与细胞类型、复合物浓度、蛋白与质粒DNA的配比、细胞密度及Ca~(2+)浓度有关。我们确立的最佳的转染条件为蛋白与质粒DNA质量比4:1,转染前细胞为60-70%丰度,Ca~(2+)浓度为2-4mM。
凋亡素,是一个来源于鸡贫血病毒的小分子蛋白质,之所以受到人们关注,是因为它可以选择性的杀死肿瘤细胞而对正常细胞无毒性作用。凋亡素的亚细胞定位是肿瘤特异性的关键因素,在正常细胞中,它位于细胞质中,而有肿瘤细胞中它可以转运进入细胞核中。凋亡素的这种核定位机制主要是由自身的磷酸化水平控制的。在肿瘤细胞中,凋亡素引起活细胞内包括Akt等激酶物质的核聚集,并且可以被CDK2磷酸化。因此,凋亡素可以间接地在活细胞内传递细胞凋亡信号。此外,凋亡素也会以多聚物的形式与DNA分子相结合,通过与几个核靶分子相互作用,例如与促细胞后期复合物相互作用,导致G2/M期逃逸。这种促凋亡信号由信号分子Nur77经核传递给细胞质,激活非p53依赖的线粒体途径,诱导肿瘤细胞凋亡。
我们利用靶向性的蛋白H4TL作为载体,进行凋亡素基因的转染研究,来评价H4TL的转染效率及其凋亡素转入细胞后的释控及表达,同时检测凋亡素基因对人乳腺癌细胞MCF-7及人卵巢癌HO8910两种肿瘤细胞的凋亡作用。我们构建了凋亡素真核表达载体pcDNA3.1(+)/apoptin,利用重组蛋白H4TL将其转染进入受试细胞中。利用经典的RT-PCR和western blot分析其在受试细胞中的表达情况;MTT法检测了转染凋亡素后细胞的增殖抑制情况,利用Annexin V–FITC /PI双荧光染色法对转染后的细胞进行细胞凋亡的检测,得到了较高凋亡率,对阴性的对照细胞系-正常人肺胚二倍体细胞2BS的凋亡率不超过20%,MCF-7细胞的凋亡率达到了42%(对照组为9.18%); HO8910细胞的凋亡率为44%(对照组为3.31%)。此外,我们利用DNA ladder法检测了凋亡后细胞中的基因组DNA的片段化,利用罗丹明123作为荧光染料检测了处于凋亡状态的细胞的线粒体膜电位的缺失情况,这些试验帮助我们进一步验证了重组蛋白H4TL作为基因转运载体和凋亡素作为治疗基因的有效性。同时,这些结果说明了靶向于肿瘤特异性受体的非病毒载体为基因转运提供了一个廉价的、简单高效的工具。
Protein/peptide-mediated gene delivery has recently emerged as a powerful approach in non-viral gene transfer. In previous studies, several groups found that histones can efficiently mediate gene transfer (histonefection). Wheat histone H4 is a nucleosome core histone whose gene was cloned and structure determined by Tabata et al. It is relatively conservative in eukaryotic core histones. There are only two amino acid differences at sites 61 and 78 between human histone H4 and that of wheat, which allows for a good candidate for gene transfer. For these reasons, we have constructed recombinant wheat histone H4 as a new gene delivery carrier.
Protein transduction domain TAT (PTD-tat) is one of the most well-studied and efficient cell-penetrating peptides. It contains an 11-amino acid peptide of the human immunodeficiency viruses type 1 (HIV-1) Tat Protein. The amino acids of PTD-tat are highly basic, YGRKKRRQRRR, which is crucial for penetrating the plasma membrane. Because of the potential of PTD-tat for mediating cellular uptake of small and large molecules, in this study we genetically incorporated PTD-tat into the C-terminus of wheat histone H4 to allow H4 to enhance penetration of the plasma membrane via the PTD-tat pathway. In addition, a targeted drug delivery system must achieve high cell permeability and retention by the specific cell population. Target cell specificity is achieved by attaching molecular targeting moieties to the drug delivery system that interact precisely with receptors of cancer cell surface. This ensures that adverse side effects on healthy tissues will be minimized. Receptors for the luteinizing hormone-releasing hormone (LHRH) are overexpressed in the plasma membrane of cancer cells, and expression is not detected in normal visceral organs. Therefore, LHRH can potentially be used as the targeting moiety to deliver anticancer drugs specifically to cancer cells and facilitate their cellular uptake.
Here, we report the generation of plasmid constructs that overproduce H4-TAT-LHRH (H4TL) as heterologous, His-tagged fusion proteins. The wheat genome was extracted from wheat root tissue. The putative fusion H4TL gene containing the wheat histone H4 gene with PDT-tat (YGRKKRRQRRR) and LHRH (QHWSYGLRPG) gene sequences was cloned from the Triticum aestivum genome and amplified by overlap extention polymerase chain reaction (OE-PCR). Every PCR fragment was determined by cloning it into pMD18-T vector and sequenced. The sequence of modified wheat histone H4 gene was in alignment with the GenBank sequence. The last amplified sequence was digested using EcoR I-Not I, cloned into pET28a (++), transferred E.coli JM109 cells, and identified by PCR and restriction digest. Correct constructs were identified by sequencing. E.coli BL21(DE3) containing the pET28a(++)-H4TL recombinant plasmid were induced by isopropyl-β-D-thiogalactopyranoside (IPTG) .
The expression positive cells were induced using shake-flask fermentation and collected by centrifugation (7000xg at 4 oC for 15 min), washed twice with PBS and lysed by sonication. The clear supernatant was collected by centrifugation (10000xg at 4oC for 15 min), then obtained by filtration through a 0.22μm Millipore membrane. The supernatant proteins were denaturated by 6 M guanidine hydrochloride and loaded onto a nickel column, (0.7x2.5 mm, GE Healthcare). Chromatography operation was performed on an AKTA~(TM) Explorer Fast Protein Liquid Chromatography system (GE Healthcare). Ni~+ -metal affinity chromatography was used to purify His-tagged H4TL fusion proteins from supernatant proteins by guanidine hydrochloride denaturation.
Purified proteins were desalted using a HiTrap desalt column (GE Healthcare) according to the manufacturer’s instructions, concentrated using an Amicon Ultra-15 Centrifugal Filter Units (Milipore, UK), and buffer-exchanged with 5% dextrose in 20 mM Tris-HCl pH 7.4. The H4TL fraction was freeze-dried and stored at -70oC for further use.
The modified H4TL gene encoded a recombinant protein of 141 amino acids with an approximate molecular weight of 15.5 kDa. Gel electrophoresis mobility shift assays demonstrated that the purified modified H4 protein had high affinity for DNA. Most significantly, complexing plasmid pEGFP/C1 with H4TL was transfected with high efficiency into MCF-7, HO8910, LNCap, A549 and HeLa cells in vitro. The transfection efficiency mediated by histones is dependent on the relative concentration (DNA: histone ratio), type of cells and the incubation time.
The chicken anaemia virus-derived protein apoptin is a tumour-specific cell-killing agent. This 14 kDa protein selectively induces apoptosis in a wide variety of transformed cells but not in primary cells. The cancer-selective toxicity of apoptin correlates with its cellular localization. Apoptin enters the nuclei of cancerous cells, whereas in nontransformed cells it remains in the cytoplasm. The current hypothesis is that nuclear trafficking and tumor specific phosphorylation of apoptin at Thr-108 are essential for the induction of apoptosis. Recently, Rohn and colleagues reported that phosphorylation of apoptin is required for apoptosis, but that abolishing the phosphorylation site of apoptin does not significantly disrupt its nuclear input into tumor cells.
In the present study, we attempted to use H4TL with naked plasmid DNA, which contains a apoptin tumor suppressor gene, to evaluate the transfection efficiency and antitumor activity in human ovarian carcinoma (HO8910) and breast cancer (MCF-7) cells in vitro. We observed that apoptin delivery resulted in a more differential growth inhibition pattern in cancer cells in vitro. In this study, the wild-type apoptin gene was transfected into cancer cells using the H4TL as a vector, and the expression level and the activity of apoptin gene were evaluated in vitro. Gene expression was determined by classic reverse transcriptase-PCR and western blotting analysis. The cellular growth inhibition of H4TL-mediated apoptin transfection were assessed by MTT ([3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrasolium bromide] benzene sulfonic acid hydrate) assay. The apoptosis induced by apoptin were measured by Annexin V–FITC (fluorescein isothiocyanate) /PI staining, DNA ladder and lost of mitochondrial membrane potential. The results showed that remarkable apoptotic characteristics such as nuclear shrinkage appeared in tumor cells, but few apoptotic characteristics were observed in control groups. The apoptosis present were higher than control, the cell cycle were exchanged also detected by FACS. It was suggested that the recombination protein H4TL could mediate apoptin’s transfection and could promote them expression and induce apoptosis in different tested tumor cells effectively. Our data suggest that H4TL can mediate apoptin gene transfer in vitro with high efficiency and is a promising new strategy for apoptin gene therapy. These results demonstrate that the targeting of non-viral vectors to tumor-specific receptors provide a cheap, simple, highly efficient tool for gene delivery.
引文
[1]Breyer B, Jiang W, Cheng H, et al. Adenoviral vector-mediated gene transfer for human gene therapy [J]. Curr Gene Ther, 2001,1:149-162.
[2] Bertram J S. The molecular biology of cancer [J].Mol Aspects Med, 2000, 21:167-223.
[3]Mullen C A. Metabolic suicide genes in gene therapy, Pharmacol Ther, 1994, 63:199–207.
[4]Shi F, Rakhmilevich A L, Heise C P, et al. Intratumoral injection of interleukin-12 plasmid DNA, either naked or in complex with cationic lipid, results in similar tumor regression in a murine model [J]. Mol Cancer Ther, 2002, 1 :949-957.
[5]Barajas M, Mazzolini G, Genove G, et al. Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12 [J]. Hepatology, 2001,33:52-61.
[6]Walther W, Stein U, Fichtner I, et al. Intratumoral low-volume jet-injection for efficient nonviral gene transfer [J]. Mol Biotechnol, 2002, 21:105-115.
[7]Hanke P, Serwe M, Dombrowski F, et al. DNA vaccination with AFP-encoding plasmid DNA prevents growth of subcutaneous AFP-expressing tumors and does not interfere with liver regeneration in mice [J]. Cancer Gene Ther, 2002,9:346-355.
[8]Conry M R, White S A, Fultz P N, et al. Polynucleotide immunization of nonhuman primates against carcinoembryonic antigen [J]. Clin Cancer Res, 1998,4 :2903-2912.
[9]Wei C M, Gibson M, Spear P G, et al.Construction and isolation of a transmissible retrovirus containing the src gene of Harvey murine sarcoma virus and the thymidine kinase gene of herpes simplex virus type 1 [J]. J Virol, 1981,39:935-944.
[10]Shimotohno K, Temin H M. Formation of infectious progeny virus after insertion of herpes simplex thymidine kinase gene into DNA of an avian retrovirus [J]. Cell, 1981,26 :67-77.
[11]Barzon L, Bonaguro R, Castagliuolo I, et al. Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase [J]. Eur J Endocrinol, 2003, 148:73-80.
[12]Saudemont A, Buffenoir G, Denys A, et al. Gene transfer of CD154 and IL12 cDNA induces an anti-leukemic immunity in a murine model of acute leukemia [J]. Leukemia, 2002,16:1637-1644.
[13]Fillat C, Carrio M, Cascante A, et al. Suicide gene therapy mediated by the herpes simplex virus thymidine kinase gene/ganciclovir system: fifteen years of application [J]. Curr GeneTher,2003,3 :13-26.
[14]Lewis P F, Emerman M. Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus [J]. J Virol, 1994, 68:510-516.
[15]Miller D G, Adam M A, Miller A D. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection [J]. Mol Cell Biol, 1994,10: 4239–4242.
[16]Ind raccolo S, Habeler W, Tisato V, et al. Gene transfer in ovarian cancer cells: acomparison between retroviral and lentiviral vectors [J].Cancer Res, 2002,62:6099- 6107.
[17]Pang S, Kang M K, Kung S, et al. Anticancer effect of a lentiviral vector capable of expressing HIV-1 Vpr [J]. Clin Cancer Res, 2001,7:3567-3573.
[18]Solly S K, Trajcevski S, Frisen C, et al. Replicative retroviral vectors for cancer gene therapy [J].Cancer Gene Ther, 2003,10 :30– 39.
[19]Li Q, Kay M A, Finegold M, et al. Assessment of recombinant adenoviral vectors for hepatic gene therapy [J]. Hum Gene Ther, 1993, 4:403-409.
[20]Swisher S G, Roth J A, Komaki R, et al.Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy [J].Clin Cancer Res, 2003,9:93-101.
[21]Roy I, Holle L, Song W, et al. Efficient translocation and apoptosis induction by adenovirus encoded VP22-p53 fusion protein in human tumor cells in vitro [J]. Anticancer Res, 2002, 22 :3185-3189.
[22]Anderson S C, Johnson D E, Engler H, et al. p53 gene therapy in a rat model of hepatocellular carcinoma: intra-arterial delivery of recombinant adenovirus [J]. Clin Cancer Res, 1998,4 :1649-1659.
[23]Bramson J L, Hitt M, Gauldie J, et al. Pre-existing immunity to adenovirus does not prevent tumor regression following intratumoral administration of a vector expressing IL-12 but inhibits virus dissemination [J].Gene Ther, 1997,4 :1069-1076.
[24]Raper S E, Yudkoff M, Chirmule N, et al. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency [J]. Hum Gene Ther, 2002),13:163-175.
[25]Vlachaki M T, Hernandez-Garcia A, Ittmann M, et al.The Impact of preimmunization on adenoviral vector expression and toxicity in a subcutaneous mouse cancer model [J]. Mol Ther, 2002),6:342–348.
[26]Heise C, Hermiston T, Johnson L, et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy [J]. Nat Med, 2000, 6:1134-1139.
[27]Rodriguez R, Schuur E R, Lim H Y, et al. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells [J].Cancer Res, 1997, 57:2559-2563.
[28]Bischoff J R, Kirn D H, Williams A, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells [J]. Science, 1996,274:373-376.
[29]Parker J N, Gillespie G Y, Love C E, et al. Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors [J].Proc Natl Acad Sci USA, 2000,97:2208-2213.
[30]Moriuchi S, Wolfe D, Tamura M, et al. Double suicide gene therapy using a replication defective herpes simplex virus vector reveals reciprocal interference in a malignant glioma model [J]. Gene Ther, 2002, 9:584–591.
[31]Kanazawa T, Mizukami H, Okada T, et al. Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice [J].Gene Ther, 2003,10:51-58.
[32]Ponnazhagan S, Curiel D T, Shaw D R, et al. Adeno-associated virus for cancer gene therapy [J].Cancer Res, 2001, 61:6313-6321.
[33]Su H, Lu R, Chang J C, et al. Tissue-specific expression of herpes simplex virus thymidine kinase gene delivered by adeno-associated virus inhibits the growth of human hepatocellular carcinoma in athymic mice [J]. Proc Natl Acad Sci USA, 1997, 94:13891-13896.
[34]Vermeij J, Zeinoun Z, Neyns B, et al. Transduction of ovarian cancer cells: a recombinant adeno-associated viral vector compared to an adenoviral vector [J]. Br J Cancer, 2001, 85:1592-1599.
[35]Smith G L, Moss B. Infectious poxvirus vectors have capacity for at least 25 000 base pairs of foreign DNA [J]. Gene, 1983, 25:21-28.
[36]Gomella L G, Mastrangelo M J, McCue P A, et al. Phase I study of intravesical vaccinia virus as a vector for gene therapy of bladder cancer [J]. J Urol, 2001,166 :1291–1295.
[37]Kaufman H L, Flanagan K, Lee C S, et al. Insertion of interleukin-2 (IL-2) and interleukin-12 (IL-12) genes into vaccinia virus results in effective antitumor responses without toxicity [J]. Vaccine , 2002,20:1862-1869.
[38]Felgner P L, Gadek T R, Holm M, et al. Lipofection:a highly efficient, lipid-mediated DNA -transfection procedure [J]. Proc Natl Acad Sci USA, 1987, 84: 7413-7417
[39]Andrew M. Gene therapy: the first decade. Tibtech March, 2000, 18: 119-128
[40]Boussif O, Lezoualc’h F, Zanta M A, et al. Versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine [J]. Proc Natl Acad Sci USA , 1995,92 :7297-7301.
[41]Klemm A R, Young D, Lloyd J B. Effects of polyethyleneimine on endocytosis and lysosome stability [J]. Biochem Pharmacol, 1998, 56 41– 46.
[42]Fischer D, Bieber T, Li Y et al. A novel non-viral vector for DNA delivery based on low molecular weight, branched polyethylenimine: effect of molecular weight on transfection efficiency and cytotoxicity [J]. Pharm Res, 1999,16:1273–1279.
[43]Wightman L, Kircheis R, Rossler V, et al. Different behavior of branched and linear polyethylenimine for gene delivery in vitro and in vivo [J]. J Gene Med, 2001,3 362–372.
[44]Chollet P, Favrot M C, Hurbin A, et al. Side-effects of a systemic injection of linear polyethylenimine–DNA complexes [J]. J Gene Med, 2002, 4:84– 91.
[45]Kircheis R, Schuller S, Brunner S, et al. Polycation-based DNA complexes for tumor-targeted gene delivery in vivo [J]. J Gene Med, 1999,1:111-120.
[46]Pouton C W, Lucas P, Thomas B J, et al. Polycation-DNA complexes for gene delivery: a comparison of the biopharmaceutical properties of cationic polypeptides and cationic lipids [J]. J Control Release, 1998, 53:289-299.
[47]Ward C M, Pechar M, Oupicky D, et al. Modification of pLL/DNA complexes with a multivalent hydrophilic polymer permits folate-mediated targeting in vitro and prolonged plasma circulation in vivo [J]. J Gene Med, 2002, 4:536–547.
[48]Lee H, Jeong J H, Park T G. PEG grafted polylysine with fusogenic peptide for gene delivery: high transfection efficiency with low cytotoxicity [J]. J Control Release, 2002,79:283-291.
[49]Wu G Y, Wu C H. Receptor-mediated in vitro gene transformation by a soluble DNA carrier system [J]. J Biol Chem, 1987,262:4429-4432.
[50]Suh W, Chung J K, Park S H, et al. Anti-JL1 antibody-conjugated poly(L-lysine) for targeted gene delivery to leukemia T cells [J]. J Control Release, 2001,72:171-178.
[51]Faraasen S, Voros J, Csucs G, et al. Ligand-specific targeting of microspheres to phagocytes by surface modification with poly(L-lysine)-grafted poly(ethylene glycol) conjugate [J].Pharm Res, 2003,20:237-246.
[52]Pichon C, Goncalve s C, Midoux P. Histidine-rich peptides and polymers for nucleic acids delivery [J]. Adv Drug Deliv Rev, 2001,53:75– 94.
[53]Choi B Y, Chung J W, Park J H, et al.Gene delivery to the rat liver using cationic lipid emulsion/DNA complex: comparison between intra-arterial, intraportal and intravenous administration [J].Korean J Radiol, 2002, 3 :194-198.
[54]Legendre J Y, Trzeciak B, Deuschle U, et al. N-acyl -(α,γ-diaminobutyric acid) n hydrazide as an efficient gene transfer vectorin mammalian cells in culture [J]. Pharm Res, 1997, 14: 619-624
[55]Roy K, Mao HQ, Huang S K, et al. Oral gene delivery with chitosan- DNA nanoparticles generates immunologic protection in a murine model of peanut allergy [J]. Nature Med, 1999, 5: 387-391
[56]Koping-Hoggard M, Mel’nikovaS Y S, Varum K M, et al. Relationship between the physical shape and the efficiency of oligomeric chitosan as a gene delivery system in vitro and in vivo [J]. J Gene Med, 2003,5130– 141.
[57]M. Lee, J.W. Nah, Y. Kwon, J.J. Koh, K.S. Ko, S.W. Kim,Water-soluble and low molecular weight chitosan-based plasmid DNA delivery [J].Pharm. Res, 2001, 18 :427- 431.
[58]Vincent L, Varet J, Pille J Y, et al. Efficacy of dendrimer-mediated angiostatin and TIMP-2 gene delivery on inhibition of tumor growth and angiogenesis:in vitro and in vivo studies [J]. Int J Cancer , 2003,105: 419–429.
[59]Read M L, Bremner K H, Oupick D et al. Vectors based on reducible polycationsfacilitate intracellular release of nucleic acids [J]. J Gene Med, 2003,5 :232-245.
[60]Simon R H, Engelhardt J F, Yang Y, et al. Adenovirus -mediated gene transfer of the CFTR gene to the lung of non - human primates: atosicity study [J]. Hum Gene Tuer, 1993, 4: 771-780
[61]Donahue R E, Kessler S W, Bodine D, et al. Helper virus induced T cell lymphoma in non - human primates after retroviral gene transfer [J]. J Exp Biol, 1992, 176: 1125-1135
[62]Li S, Tseng W C, Stolz D B, et al. Dynamic changes in the characteristics of cationic lipidic vectors after exposure to mouse serum: implications for intravenous lipofection [J]. Gene Therapy, 1999, 6: 585-594
[63]Maitra A . Calcium phosphate nanoparticles: second-generation nonviral vectors in genetherapy [J]. Expert Rev Mol Diagn,2005, 5:893 -905 .
[64]Megeed Z, Haider M, Li D, et al. In vitro and in vivo evaluation of recombinant silkelastinlike hydrogels for cancer gene therapy [J]. J Control Release,2004,94:433 -445 .
[64]Balicki D, Beutler E. Gene therapy of human disease [J]. Medicine, 2002,81:69-86.
[65]Kovesdi I, Brough D E, Bruder J T, et al. Adenoviral vectors for gene transfer [J]. Curr Opin Biotechnol,1997 8:583-589.
[66]Felgner P L, Barenholz Y, Behr J P, et al. Nomenclature for synthetic gene delivery systems [J]. Hum Gene Ther, 1997,8:511-512.
[67]Mahato R I, Smith L C, Rolland A. Pharmaceutical perspectives of nonviral gene therapy [J]. Adv Genet,1999, 41:95-156.
[68]Balicki D, Reisfeld R A, Pertl U, et al. Histone H2Amediated transient cytokine gene delivery induces efficient antitumor responses in murine neuroblastoma [J]. Proc Natl Acad Sci USA, 2000,97 :11500-11504.
[69]Schwartz B, Ivanov M A, Pitard B, et al. Synthetic DNA-compacting peptides derived from human sequence enhance cationic lipid-mediated gene transfer in vitro and in vivo [J]. Gene Ther, 1999, 6: 282-292.
[70]Morris M C, Vidal P, Chaloin L, et al. A new peptide vector for efficient delivery of oligonucleotides into mammalian cells [J]. Nucleic Acids Res, 1997, 25:2730-2736.
[71]Balicki D, Beutler E. Histone H2A significantly enhances in vitro DNA transfection [J]. Mol Med 1997,3 :782-787.
[72]Balicki D, Putnam C D, Scaria P V, et al. Structure and function correlation in histone H2A peptide-mediated gene transfer [J]. Proc Natl Acad Sci USA, 2002,99:7467-7471.
[73]Kornberg R D, Lorch Y L. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome [J]. Cell, 1999,98:285-294.
[74]Palau J, Climent F, Aviles F J, et al. Interactions of histones and histone peptides with DNA. Thermal denaturation and solubility studies [J]. Biochim Biophys Acta 1977, 476:108-121.
[75]Baake M, Doenecke D, Albig W, Characterisation of nuclear localisation signals of the four human core histones [J]. J Cell Biochem, 2001,81:333-346.
[76]Cheung P, Allis CD, Sassone-Corsi P. Signaling to chromatin through histone modifications. Cell [J]2000,103, 263–271 ().
[77]Khan AU, Krishnamurthy S. Histone modifications as key regulators of transcription. Front.Biosci. [J] 2005,10, 866–872 .
[78]Iniguez-Lluhi JA . For a healthy histone code, a little SUMO in the tail keeps the acetyl away. ACS Chem. Biol. [J] 20061: 204–206.
[79]Thompson PR & Fast W. Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock ACS Chem. Biol. [J].2006, 1: 433–441.
[80]Ryser H J, Hancock R. Histones and basic polyamino acids stimulate the uptake of albumin by tumor cells in culture [J]. Science, 1965,150:501-503.
[81]Ryser H J. Uptake of protein by mammalian cells: an underdeveloped area. The penetration of foreign proteins into mammalian cells can be measured and their functions explored[J]. Science, 1968,159:390-396.
[82]Zaitsev S, Buchwalow I, Haberland A, et al. Histone H1-mediated transfection: role of calcium in the cellular uptake and intracellular fate of H1-DNA complexes [J]. Acta Histochem, 2002,104:85-92.
[83]Budker V, Hagstrom J E, Lapina O, et al. Protein/amphipathic polyamine complexes enable highly efficient transfection with minimal toxicity [J]. Biotechniques, 1997,139 :142-147.
[84]Fritz J D, Herweijer H, Zhang G F, et al. Gene transfer into mammalian cells using histone-condensed plasmid DNA [J]. Hum Gene Ther, 1996, 7: 1395-1404.
[85]Haberland A, Dalluge R, Zaitsev S, et al. Ligand-histone H1 conjugates: increased solubility of DNA complexes, but no enhanced transfection activity [J]. Somat Cell Mol Genet, 1999,25:237-245.
[86]Haberland A, Knaus T, Zaitsev S V, et al. Histone H1-mediated transfection: serum inhibition can be overcome by Ca2+ ions [J]. Pharm Res, 2000,17: 229-235.
[87]Hagstrom J E, Sebestyen M G, Budker V, et al.Complexes of non-cationic liposomes and histone H1 mediate efficient transfection of DNA without encapsulation [J]. Biochim Biophys Acta 1996, 1284:47-55.
[88]Kott M, Haberland A, Zaitsev S, et al. A new efficient method for transfection of neonatal cardiomyocytes using histone H1 in combination with DOSPER liposomal transfection reagent [J], Somat Cell Mol Genet, 1998,24: 257-261.
[89]Lucius H, Haberland A, Zaitsev S, et al. Structure of transfection-active histone H1/DNA complexes [J]. Mol Biol Rep,2001,28:157-165.
[90]Zaitsev S V, Haberland A, Otto A, et al. H1 and HMG17 extracted from calf thymus nuclei areefficient DNA carriers in gene transfer [J]. Gene Ther, 1997,4:586-592.
[91]Demirhan I, HasselmayerO, Chandra A, et al. Histone-mediated transfer and expression of the HIV-1 tat gene in Jurkat cells [J], J Hum Virol,1998, 1: 430-440.
[92]Bottger M, Zaitsev S V, Otto A, et al. Acid nuclear extracts as mediators of gene transfer and expression [J]. Biochim Biophys Acta, 1998, 1395: 78-87.
[93]Haberland A, Knaus T, Zaitsev S V, et al. Calcium ions as efficient cofactor of polycationmediated gene transfer [J]. Biochim Biophys Acta, 1999,1445:21-30.
[94]Puebla I, Esseghir S, Mortlock A, et al. A recombinant H1 histone-based system for efficient delivery of nucleic acids [J]. J Biotechnol, 2003,105:215-226.
[95]Moran F, Montero F, Azorin F, et al. Condensation of DNA by the Cterminal domain of histone H-1. A circular-dichroism study [J]. Biophys Chem, 1985, 22:125-129.
[96]Hasselmayer O, Demirhan I, Chandra A, et al. Inhibition of histone-mediated gene transfer in eucaryotic cells by anti-histone IgG [J]. Anticancer Res, 2001, 21:2377-2386.
[97]Weng L, Liu D, Li Y, An archaeal histone-like protein as an efficient DNA carrier in gene transfer [J]. Biochim BiophysActa,2004,1702:209-216.
[98]Esser D, Amanuma H, Yoshiki A, et al. A hyperthermostable bacterial histone-like protein as an efficient mediator for transfection of eukaryotic cells[J]. Nat Biotechnol, 2000,18:1211-1213.
[99]Goodwin G H, Sanders C, Johns E W. A new group of chromatinassociated proteins with a high content of acidic and basic amino acids [J]. Eur J Biochem, 1973,38:14-19.
[100]Kaneda Y, Iwai K, Uchida T. Introduction and expression of the human insulin gene in adult rat liver [J]. J Biol Chem, 1989, 264:12126-12129.
[101]Kato K, Nakanishi M, Kaneda Y, et al. Expression of hepatitis B virus surface antigen in adult rat liver. Co-introduction of DNA and nuclear protein by a simplified liposome method [J], J Biol Chem, 1991,266:3361-3364.
[102]Tomita N, Higaki J, Morishita R, et al. Direct in vivo gene introduction into rat kidney [J]. Biochem Biophys Res Commun, 1992,186:129-134.
[103]Sawa Y, Suzuki K, Bai H Z , et al. Efficiency of in vivo gene transfection into transplanted rat heart by coronary infusion of HVJ liposome [J]. Circulation,1995,92:II479-II482.
[104]Bottger M, Vogel F, Platzer M, et al. Condensation of vector DNA by the chromosomal protein HMG1 results in efficient transfection [J]. Biochim Biophys Acta,1988,950:221-228.
[105]Namiki Y, Takahashi T, Ohno T. Gene transduction for disseminated intraperitoneal tumor using cationic liposomes containing non-histone chromatin proteins: cationic liposomal gene therapy of carcinomatosa [J]. Gene Ther, 1998, 5:240-246.
[106]Mistry A R, Falciola L, Monaco L, et al. Recombinant HMG1 protein produced in Pichia pastoris: a nonviral gene delivery agent [J]. Biotechniques, 1997,22 :718-729.
[107]Haberland A, Bottger M. Nuclear proteins as gene-transfer vectors [J]. Biotechnol Appl Biochem, 2005,42:97-106.
[108]Anwer K, Bailey A, Sullivan S M. Targeted gene delivery: a twopronged approach [J]. Crit Rev Ther Drug Carr Syst, 2000,17:377-424.
[109]Lee T K, Han J S, Fan S T, et al. Gene delivery using a receptor-mediated gene transfer system targeted to hepatocellular carcinoma cells [J]. Int J Cancer,2001,93:393-400.
[110]Liu X, Tian P, Yu Y, et al. Enhanced antitumor effect of EGF R-targeted p21WAF-1 and GM-CSF gene transfer in the established murine hepatoma by peritumoral injection [J]. Cancer Gene Ther, ,2002,9:100-108.
[111]Dai F H, Chen Y, Ren C C, et al. Construction of an EGF receptor-mediated histone H1(0)-based gene delivery system [J]. J Cancer Res Clin Oncol, 2003, 129:456-462.
[112]Chen J, Stickles R J, Daichendt K A. Galactosylated histone-mediated gene-transfer and expression [J]. Hum Gene Ther, 1994,5:429–435.
[113]Junbo H, Li Q, Zaide W, et al. Receptor-mediated interleukin-2 gene transfer into human hepatoma cells [J]. Int J Mol Med, 1999, 3: 601-608.
[114]Scheule R K, George RG, BagleyJ, et al. Basis of pulmonary toxicity associated with cationic lipidmediated gene transfer to the mammalian lung [J]. Hum Gene Ther,1997,8:689-707.
[115]Tousignant J D, Gates A L, Ingram L A, et al. Comprehensive analysis of the acute toxicities induced by systemic administration of cationic lipid:plasmid DNA complexes in mice [J]. Hum Gene Ther, 2000,11: 2493-2513.
[116]Filion M C, Phillips N C. Toxicity and immunomodulatory activity of liposomal vectors formulated with cationic lipids toward immune effector cells [J]. Biochim Biophys Acta, 1997,1329: 345-356.
[117]Filion M C, Phillips N C. Anti-inflammatory activity of cationic lipids [J]. Br Jpharmacol, 1997,122:551-557.
[118]Lappalainen K, Jaaskelainen I, Syrjanen K, et al.Comparison of cell proliferation and toxicity assays using two cationic liposomes [J]. Pharm Res, 1994,11: 1127-1131.
[119]Monestier M. Autoantibodies to nucleosomes and histone-DNA complexes [J]. Methods, 1997,11 :36-43.
[120]Hardin J A, Thomas J O. Antibodies to histones in systemic lupus erythematosus: localization of prominent autoantigens on histones H1 and H2B [J]. Proc Natl Acad Sci USA, 1983, 80 :7410-7414.
[121]Iborra S, Soto M, Carrion J, et al. Vaccination with a plasmid DNA cocktail encoding the nucleosomal histones of Leishmania confers protection against murine cutaneous leishmaniosis [J].Vaccine, 2004, 22 :3865-3876.
[122]Collins L, Asuni A A, Anderton B H, et al. Efficient gene delivery to primary neuron cultures using a synthetic peptide vector system [J]. J Neurosci Methods, 2003, 125 :113-120.
[123]Zhang X, Collins L, Sawyer G J, et al.In vivo gene delivery via portal vein and bile duct to individual lobes of the rat liver using a polylysine-based nonviral DNA vector in combination with chloroquine [J]. Hum Gene Ther, 2001, 12 :2179-2190.
[124]Torchilin V P, Lukyanov A N. Peptide and protein drug delivery to and into tumors: challenges and solutions [J]. Drug Discov Today, 2003,8:259-266.
[125]Plank C, Mechtler K, Szoka F C, et al. Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery [J], Hum Gene Ther, 1996, 7:1437-1446.
[126]Yang J P, Huang L. Overcoming the inhibitory effect of serum on lipofection by increasing the charge ratio of cationic liposome to DNA [J]. Gene Ther, 1997, 4: 950-960.
[127]Mizuguchi H, Nakagawa T, Nakanishi M, et al. Efficient gene transfer into mammalian cells using fusogenic liposome [J]. Biochem Biophys Res Commun, 1996,218: 402-407.
[128]Zhou X H, Klibanov A L, Huang L. Lipophilic polylysines mediate efficient DNA transfection in mammalian cells [J]. Biochim Biophys Acta, 1991,1065:8–14.
[129]Ogris M, Brunner S, Schuller S, et al. PEGylated DNA/transferrin-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery [J]. Gene Ther, 1999, 6: 595-605.
[130]Kaneda Y, Iwai K, Uchida T. Increased expression of DNA cointroduced with nuclear-protein in adult-rat liver [J]. Science, 1989,243 :375-378.
[131]Hagstrom J E, Ludtke J J, Bassik M C, et al. Nuclear import of DNA in digitonin-permeabilized cells [J]. J Cell Sci, 1997,110:2323-2331.
[132]Conary J T, Erdos G, McGuire M, et al. Cationic liposome plasmid DNA complexes: in vitro cell entry and transgene expression augmented by synthetic signal peptides [J]. Eur J Pharm. Biopharm, 1996,42: 277-285.
[133]Zanta M A, Belguise V P, Behr J P. Gene delivery: a single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus [J]. Proc Natl Acad Sci USA, 1999,96:91-96.
[134]Collas P, Alestrom P. Rapid targeting of plasmid DNA to zebrafish embryo nuclei by the nuclear localization signal of SV40 T antigen [J]. Mol Mar Biol Biotechnol, 1997, 6: 48-58.
[135]Mosammaparast N, Jackson K R, Guo Y, et al. Nuclear import of histone H2A and H2B is mediated by a network of karyopherins [J]. J Cell Biol, 2001, 153:251-262.
[136]Mosammaparast N, Guo Y, Shabanowitz J, et al. Pathways mediating the nuclear import of histones H3 and H4 in yeast [J]. J Biol Chem, 2002,277:862-868.
[137]Moreland R B, Langevin G L, Singer R H, et al. Amino-acid-sequences that determine the nuclear-localization of yeast histone-2B [J]. Mol Cell Biol, 1987, 7: 4048-4057.
[138]Wilke M, Fortunati E, vandenBroek M, et al. Efficacy of a peptide-based gene delivery system depends on mitotic activity [J]. Gene Ther, 1996,3: 1133-1142.
[139]Itaka K, Harada A, Yamasaki Y, et al. In situ single cell observation by fluorescence resonance energy transfer reveals fast intra-cytoplasmic delivery and easy release of plasmid DNA complexed with linear polyethylenimine [J]. J Gene Med, 2004, 6 :76-84.
[140]Okuda T, Niidome T, Aoyagi H. Cytosolic soluble proteins induce DNA release from DNA-gene carrier complexes [J]. J Control Release,2004, 98 325-332.
[141]Luger K, Mader A W, Richmond R K, et al. Crystal structure of the nucleosome core particle at 2.8 A resolution [J].Nature, 1997, 389: 251-260.
[142]Zelphati O, Szoka F C. Mechanism of oligonucleotide release from cationic liposomes [J]. Proc Natl Acad Sci USA, 1996,93:11493-11498.
[143]Zelphati O, Szoka F C. Intracellular distribution and mechanism of delivery of oligonucleotides mediated by cationic lipids [J]. Pharm Res, 1996, 13:1367-1372.
[144]Zelphati O, Szoka F C. Liposomes as a carrier for intracellular delivery of antisense oligonucleotides: a real or magic bullet? [J] J Control Release, 1996,41: 99-119.
[145]Sieczkarski S B, Whittaker G R. Dissecting virus entry via endocytosis [J]. J Gen Virol. 2002, 83 :1535-1545.
[146]Bratosin D, Mazurier J, Tissier J P, et al. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review [J], Biochimie, 1998, 80: 173-195.
[147]Cardelli J. Phagocytosis and macropinocytosis in Dictyostelium: phosphoinositide-based processes, biochemically distinct [J]. Traffic, 2001,2: 311-320.
[148]Nichols B J, LippincottS J. Endocytosis without clathrin coats [J]. Trends Cell Biol, 2001,11:406-412.
[149]Schwartz J J, Zhang S G. Peptide-mediated cellular delivery [J]. Curr Opin Mol Ther, 2000, 2 :162-167.
[150]Hariton G E, Rosenbluh J, Graessmann A, et al. Direct translocation of histone molecules across cell membranes [J]. J Cell Sci, 2003, 116: 4577-4586.
[151]Murphy R F, Jorgensen E D, Cantor C R. Kinetics of histone endocytosis in Chinese hamster ovary cells. A flow cytofluorometric analysis [J], J Biol Chem, 1982, 257:1695-1701.
[152]Vives E, Charneau P, Vanrietschoten J, et al. Effects of the Tat basic domain on human-immunodeficiency-virus type-1 transactivation, using chemically synthesized tat protein and tat peptides [J]. J Virol, 1994,68: 3343-3353.
[153]Vives E, Brodin P, Lebleu B. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus [J]. J Biol Chem, 1997,272:16010-16017.
[154]Rosenbluh J, Singh S K, Gafni Y, et al. Nonendocytic penetration of core histones into petunia protoplasts and cultured cells: a novel mechanism for the introduction of macromolecules into plant cells [J]. Biochim Biophys Acta, 2004, 1664:230-240.
[155]Rosenbluh J, Hariton G E, Dagan A, et al.Translocation of histone proteins across lipid bilayers and Mycoplasma membranes [J]. J Mol Biol, 2005, 345:387-400.
[156]Gao X, Huang L. Cationic liposome-mediated gene transfer [J]. Gene Ther, 1995,2: 710-722.
[157]Niidome T, Wakamatsu M, Wada A, et al. Required structure of cationic peptide for oligonucleotide-binding and–delivering into cells [J]. J Pept Sci, 2000, 6 :271-279.
[158]Kopatz I, Remy S J, Behr J P. A model for non-viral gene delivery: through syndecan adhesion molecules and powered by actin [J]. J Gene Med, 2004,6: 769-776.
[159]Lorch Y, LaPointe J W, Kornberg R D. Nucleosomes inhibit the initiation of transcription butallow chain elongation with the displacement of histones [J]. Cell, 1987, 49: 203-210.
[160]Schlissel M S,Brown D D. The transcriptional regulation of Xenopus 5s RNA genes in chromatin: the roles of active stable transcription complexes and histone H1 [J]. Cell, 1984, 37: 903-913.
[161]Wolffe A P. Dominant and specific repression of Xenopus oocyte 5SRNA genes and satellite I DNA by histone H1 [J]. EMBO J, 1989,8 :527-537.
[162]Brown D T, Sittman DB. Identification through overexpression and tagging of the variant type of the mouse H1e and H1c genes [J]. J Biol Chem, 1993,268:713-718.
[163]Brown D T, Alexander B T, Sittman D B. Differential effect of H1 variant overexpression on cell cycle progression and gene expression [J]. Nucleic Acids Res, 1996,24: 486-493.
[164]Brown D T, Gunjan A, Alexander B T, et al. Differential effect of H1 variant overproduction on gene expression is due to differences in the central globular domain [J]. 1997, Nucleic Acids Res, 25 :5003-5009.
[165]Sun J M, Wiaderkiewicz R, Ruiz C A. Histone H5 in the control of DNA synthesis and cell proliferation [J]. Science, 1989,245:68-71.
[166]Johnson L M, FisherA G, Grunstein M. Identification of a nonbasic domain in the histone H4 N-terminus required for repression of the yeast silent mating loci [J].EMBO J, 1992,11:2201-2209.
[167]Megee P C, Morgan B A, Smith M M. Histone H4 and the maintenance of genome integrity [J].Genes Dev, 1995, 9: 1716-1727.
[168]Latner A L, Longstaff E. Transformation of mammalian cells by crude histones [J]. Br J Cancer , 1971,25:280-283.
[169]Latner A L, Turner G A, Cornell C. Increased nuclear size in BHK21 cells after treatment with non-toxic levels of calf thymus histones [J]. Exp Cell Biol, 1979,47:145-154.
[170]Bases R, Mendez F, Mendez L, et al. Stimulation of HeLa cellsurface attachment by histones [J]. Exp Cell Res, 1973, 76 :441-444.
[171]Okabe K J, Honma Y, Hayashi M, et al. Effects of histone fractions on induction of differentiation of cultured mouse myeloid leukemia cells [J]. Cancer Res, 1981, 41:1997-2002.
[172]Butler L M, Agus D B, Sche r H I, et al. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo [J].Cancer Res, 2000,60:5165-5170.
[173]Richon V M, Emiliani S, Verdin E, et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases [J]. Proc Natl Acad Sci USA, 1998,95:3003–3007.
[174]Pearse I, Glick RD, Abramson S J, et al. Hybrid polar histone deacetylase inhibitor induces apoptosis and CD95/CD95 ligand expression in human neuroblastoma [J]. Cancer Res, 1999,59:4392-4399.
[175]Qiu L, Kelso M J, Hansen C, et al. Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate [J]. Br J Cancer,1999, 80 :1252-1258.
[176]Noteborn M H, de Boer G F, van Roozelaar D J, et al. Characterization of cloned chicken anemia virus DNA that contains all elements for the infectious replication cycle [J]. J Virol, 1991, 65:3131-3139.
[177]Natesan S, Kataria J M, Dhama K, et al. Anti-neoplastic effect of chicken anemia virus VP3 protein (apoptin) in Rous sarcoma virus-induced tumours in chicken [J]. J Gen Virol, 2006, 87:2933-2940.
[178]Noteborn M H, Verschueren C A, Zantema A, et al.Identification of the promoter region of chicken anemia virus (CAV) containing a novel enhancer-like element [J].Gene, 1994, 150: 313-318.
[179]Miller M M, Jarosinski K W, Schat K A. Positive and negative regulation of chicken anemia virus transcription [J]. J Virol, 2005, 79:2859-2868.
[180]Noteborn M H, Todd D, Verschueren C A, et al. A single chicken anemia virus protein induces apoptosis [J]. J Virol, 1994,68:346-351.
[181]Phenix K V, Meehan B M, Todd D, et al. Transcriptional analysis and genome expression of chicken anaemia virus [J]. J Gen Virol, 1994, 75:905-909.
[182]Maddika S, Mendoza F J, Hauff K, et al.Cancerselective therapy of the future: apoptin and its mechanism of action [J]. Cancer Biol Ther, 2006,5:10-19.
[183]Noteborn M H. Chicken anemia virus induced apoptosis: underlying molecular mechanisms [J].Vet Microbiol, 2004,98:89-94.
[184]Heilman D W, Teodoro J G, Green M R. Apoptin nucleocytoplasmic shuttling is required for cell type-specific localization, apoptosis, and recruitment of the anaphase-promoting complex/cyclosome to PML bodies [J].J Virol, 2006,80:7535-7545.
[185]Poon I K H, Oro C, Dias M M, et al. Apoptin nuclear accumulation is modulated by a CRM1-recognized nuclear export signal that is active in normal but not in tumor cells [J]. Cancer Res, 2005,65:7059-7064.
[186]Kamada K, Kuroishi A, Kamahora T, et al. Spliced mRNAs detected during the life cycle of chicken anemia virus [J]. J Gen Virol, 2006,87 :2227-2233.
[187]Danen-Van Oorschot A A, Zhang Y H, Leliveld S R, et al. Importance of nuclear localization of apoptin for tumor-specific induction of apoptosis [J]. J Biol Chem, 2003, 278:27729-27736.
[188]Kuusisto H V, Wagstaff K M, Alvisi G, et al. The C-terminus of apoptin represents a unique tumor cell-enhanced nuclear targeting module [J]. Int J Cancer, 2008,2965-2969.
[189]Backendorf C, Visser A E, de Boer A G, et al. Apoptin: therapeutic potential of an early sensor of carcinogenic transformation [J]. Annu Rev Pharmacol Toxicol, 2008,48: 143-169.
[190]Leliveld S R, Zhang Y H, Rohn J L, et al. Apoptin induces tumor-specific apoptosis as a globular multimer [J]. J Biol Chem, 2003,278: 9042-9051.
[191]Leliveld S R, Dame R T, Mommaas M A, et al. Apoptin protein multimers form distinct higher-order nucleoprotein complexes with DNA [J]. Nucleic Acids Res, 2003,31:4805-4813.
[192]Tavassoli M, Guelen L, Luxon B A, et al. Apoptin: specific killer of tumor cells [J]? Apoptosis, 2005,10:717-724.
[193]Danen-Van Oorschot A A, Fischer D F, Grimbergen J M, et al. Apoptin induces apoptosis in human transformed and malignant cells but not in normal cells [J]. Proc Natl Acad Sci USA, 1997,94:5843-5847.
[194]Zhang Y H, Abrahams P J, van der Eb A J, et al.The viral protein Apoptin induces apoptosis in UV-C-irradiated cells from individuals with various hereditary cancer-prone syndromes [J]. Cancer Res, 1999, 59: 3010-3015.
[195]Guelen L, Paterson H, Gaken J, et al. TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells [J]. Oncogene, 2004,23 :1153-1165.
[196]Pietersen A, Erkeland S J, Rutjes S A, et al.Continuous apoptin expression in transgenic mice does not interfere with lymphocyte development and proliferation [J]. J Med Mol Biol,2005,2: 321-330.
[197]Pietersen A M, van der Eb M M, Rademaker H J, et al. Specific tumor-cell killing withadenovirus vectors containing the apoptin gene [J]. Gene Ther, 1999,6 :882-892.
[198]Maddika S, Ande S R, Wiechec E, et al. Los, Aktmediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis [J]. J Cell Sci, 2008,121:979-988.
[199]Olijslagers S J, Zhang Y H, Backendorf C, et al. Additive cytotoxic effect of apoptin and chemotherapeutic agents paclitaxel and etoposide on human tumour cells [J]. Basic Clin Pharmacol Toxicol, 2007,100:127-131.
[200]Zhuang S M, Shvarts A, van Ormondt H, et al. Apoptin, a protein derived from chicken anemia virus, induces p53-independent apoptosis in human osteosarcoma cells [J]. Cancer Res, 1995,55: 486-489.
[201]Los M, Wesselborg S, Schulze-Osthoff K. The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice [J].Immunity, 1999,10:629-639.
[202]Schwerk C, Schulze-Osthoff K. Regulation of apoptosis by alternative pre-mRNA splicing [J].Mol Cell, 2005,19:1-13.
[203]Fischer U, J?nicke R U, Schulze-Osthoff K. Many cuts to ruin: a comprehensive update of caspase substrates [J]. Cell Death Differ, 2003,10 :76-100.
[204]Danen-van Oorschot A A, van Der Eb A J, Noteborn M H. The chicken anemia virus-derived protein apoptin requires activation of caspases for induction of apoptosis in human tumor cells [J]. J Virol, 2000, 74:7072-7078.
[205]Maddika S, Booy E P, Johar D, et al.Cancer-specific toxicity of apoptin is independent of death receptors but involves the loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators by a Nur77-dependent pathway [J]. J Cell Sci, 2005,118:4485-4493.
[206]Burek M, Maddika S, Burek C J, et al. Apoptin induced cell death is modulated by Bcl-2 family members and is Apaf-1dependent [J].Oncogene, 2005, 25: 2213-2222.
[207]Danen-Van Oorschot A A, van der Eb A J, Noteborn M H. BCL-2 stimulates Apoptin-induced apoptosis [J]. Adv Exp Med Biol, 1999,457:245-249.
[208]Danen-Van Oorschot A A, Zhang Y, Erkeland SJ, et al.The effect of Bcl-2 on Apoptin in‘normal’vs transformed human cells [J].Leukemia, 1999,13 (Suppl 1): S75–S77.
[209]Liu X, Elojeimy S, El-Zawahry A M, et al. Modulation of ceramide metabolism enhancesviral protein apoptin's cytotoxicity in prostate cancer [J]. Molec Ther, 2006, 14 :637-646.
[210]Lin B, Kolluri S K, Lin F, et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3 [J].Cell, 2004,116:527-540.
[211]Huo D H, Yi L N, Yang J. Interaction with Ppil3 leads to the cytoplasmic localization of Apoptin in tumor cells [J]. Biochem Biophys Res Commun, 2008,372:14-18.
[212]Cheng C M, Huang S P, Chang Y F, et al.The viral death protein Apoptin interacts with Hippi, the protein interactor of Huntingtin-interacting protein1 [J]. Biochem Biophys Res Commun, 2003, 305 :359-364.
[213]Sun G J, Tong X, Dong Y, et al. Identification of a protein interacting with apoptin from human leucocyte cDNA library by using yeast two-hybrid screening [J]. ShengWu HuaXue Yu ShengWu WuLi XueBao (Shanghai), 2002,34:369-372.
[214]Teodoro J G., Heilman D W, Parker A E, et al.The viral protein Apoptin associates with the anaphase-promoting complex to induce G2/M arrest and apoptosis in the absence of p53 [J]. Genes Dev, 2004,18:1952-1957.
[215]Danen-van Oorschot A A, Voskamp P, Seelen M C, et al. Human death effector domain-associated factor interacts with the viral apoptosis agonist Apoptin and exerts tumor-preferential cell killing[J]. Cell Death Differ, 2004, 11 564-573.
[216]Janssen K, HofmannT G, Jans D A, et al. Apoptin is modified by SUMO conjugation and targeted to promyelocytic leukemia protein nuclear bodies [J]. Oncogene, 2007, 26 :1557-1566.
[217]Krieghoff-Henning E, Hofmann T G. Role of nuclear bodies in apoptosis signalling [J]. Biochim Biophys Acta, 2008, 1783:2185-2194.
[218]Maddika S, Wiechec E, Ande S R, et al. Interaction with PI3-kinase contributes to the cytotoxic activity of apoptin[J]. Oncogene, 2008,27 :3060-3065.
[219]Maddika S, Bay G H, Kroczak T J, et al. Akt is transferred to the nucleus of cells treated with apoptin, and it participates in apoptin-induced cell death [J]. Cell Prolif, 2007, 40 :835-848.
[220]Aki T, Yamaguchi K, Fujimiya T, et al. Phosphoinositide 3-kinase accelerates autophagic cell death during glucose deprivation in the rat cardiomyocyte-derived cell line H9c2 [J]. Oncogene, 2003,22:8529-8535.
[221]Lu B, Wang L, Stehlik C, et al. Phosphatidylinositol 3-kinase/Akt positively regulates Fas (CD95)-mediated apoptosis in epidermal Cl41 cells [J]. J Immunol, 2006,176: 6785-6793.
[222]D. Nimbalkar, M.K. Henry, F.W. Quelle, Cytokine activation of phosphoinositide 3-kinase sensitizes hematopoietic cells to cisplatin-induced death, Cancer Res. 2003,63:1034–1039.
[223]Shack S, Wang X T, Kokkonen G C, et al.Caveolin-induced activation of the phosphatidylinositol 3-kinase/Akt pathway increases arsenite cytotoxicity [J]. Mol Cell Biol, 2003, 23 :2407-2414.
[224]Maddika S, Panigrahi S, Wiechec E, et al. Unscheduled Akt-triggered activation of CDK2 as a key effector mechanism of apoptin's anticancer toxicity [J]. Mol Cell Biol, 2009, 29:1235-1248.
[225]Lei H, Furlong P J, Ra J H, et al. AKT activation and response to interferon-beta in human cancer cells [J]. Cancer Biol Ther, 2005,4:709-715.
[226]Tang D, Okada H, Ruland J, et al. Akt is activated in response to an apoptotic signal [J]. J Biol Chem, 2001, 276: 30461-30466.
[227]van Gorp A G , Pomeranz K M, Birkenkamp K U, et al. Chronic protein kinaseB , (PKB/c-akt) activation leads to apoptosis induced by oxidative stress-mediated Foxo3a transcriptional up-regulation [J]. Cancer Res, 2006,66:10760-10769.
[228]Nogueira V, Park Y, Chen C C, et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis [J]. Cancer Cell, 2008,14: 458-470.
[229]Los M, Maddika S, Erb B, et al. Switching Akt: from survival signaling to deadly response [J]. BioEssays, 2009, 31:492-495.
[230]Poon I K, Oro C, Dias M M, et al. A tumor cell-specific nuclear targeting signal within chicken anemia virus VP3/Apoptin [J]. J Virol, 2005,79:1339-1341.
[231]Rohn J L, Noteborn M H. The viral death effector Apoptin reveals tumor-specific processes [J]. Apoptosis, 2004, 9 :315-322.
[232]Rohn J L, Zhang Y H, Aalbers R I J M, et al. A tumorspecific kinase activity regulates the viral death protein apoptin [J]. J Biol Chem, 2002, 277: 50820-50827.
[233]Lee Y H, Cheng C M, Chang Y F, et al. Apoptin T108 phosphorylation is not required for its tumor-specific nuclear localization but partially affects its apoptotic activity [J]. Biochem Biophys Res Commun, 2007, 354: 391-395.
[234]Leliveld S R, Dame R.T, Rohn J L, et al. Apoptin's functional N- and C-termini independently bind DNA [J]. FEBS Lett, 2004,557:155-158.
[235]Nakayama S, Torikoshi Y, Takahashi T, et al. Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells [J]. Breast Cancer Res, 2009,11:R12.
[236]Gil-Gomez G, Berns A, Brady H J. A link between cell cycle and cell death: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis [J]. EMBO J, 1998,17: 7209-7218.
[237]Liu Q, Fu H, Xing R, et al. Survivin knockdown combined with apoptin overexpression inhibits cell growth significantly [J].Cancer Biol Ther, 2008, 7;1053-1060.
[238]Panigrahi S, Klonisch T, Los M.The art of killing: double stroke with apoptin and survivinas anovelapproachin cancer therapy [J].Cancer Biol Ther, 2008,7:1061-1062.
[239]Lian H, Jin N, Li X, et al. Induction of an effective anti-tumor immune response and tumor regression by combined administration of IL-18 and Apoptin [J]. Cancer Immunol Immunother, 2007,56:181-192.
[240]Li X, Jin N, Mi Z, et al. Antitumor effects of a recombinant fowlpox virus expressing Apoptin in vivo and in vitro [J]. Int J Cancer, 2006,119:2948-2957.
[241]Peng D J, Sun J, Wang JY Z, et al. Inhibition of hepatocarcinoma by systemic delivery of Apoptin gene via the hepatic asialoglycoprotein receptor [J]. Cancer Gene Ther, 2007,14:66-73.
[242]Schoop R A, Baatenburg de Jong R J, Noteborn M H. Apoptin induces apoptosis in an oral cancer mouse model [J]. Cancer Biol Ther, 2008,7:1368-1373.
[243]Tabata T, Sasaki K, Iwabuchi M,. The structural organization and DNA sequence of a wheat histone H4 gene. Nucleic Acids Research. [J] 1983,11: 5865-5875.
[244]Fittipaldi A, Giacca M. Transcellular protein transduction using the Tat protein of HIV-1. Adv Drug Deliv Rev. [J] 2005,57:597-608.
[245]Collins L, Fabre, J W. Synthetic peptide vector system for optimal gene delivery to corneal endothelium. J. Gene Med. [J] 2004,6: 185-194.
[246]Dharap, S S, Wang, Y, Chandna, P, et al.Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide. Proc. Natl. Acad. Sci. U.S.A. [J] 2005,102:12962–12967.
[247]Kaouass, M, Beaulieu, R, Balicki, D. Histonefection: novel and potent non-viral gene delivery. J. Control. Release. [J] 2006,113: 245-254.
[2] Bertram J S. The molecular biology of cancer [J].Mol Aspects Med, 2000, 21:167-223.
[3]Mullen C A. Metabolic suicide genes in gene therapy, Pharmacol Ther, 1994, 63:199–207.
[4]Shi F, Rakhmilevich A L, Heise C P, et al. Intratumoral injection of interleukin-12 plasmid DNA, either naked or in complex with cationic lipid, results in similar tumor regression in a murine model [J]. Mol Cancer Ther, 2002, 1 :949-957.
[5]Barajas M, Mazzolini G, Genove G, et al. Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12 [J]. Hepatology, 2001,33:52-61.
[6]Walther W, Stein U, Fichtner I, et al. Intratumoral low-volume jet-injection for efficient nonviral gene transfer [J]. Mol Biotechnol, 2002, 21:105-115.
[7]Hanke P, Serwe M, Dombrowski F, et al. DNA vaccination with AFP-encoding plasmid DNA prevents growth of subcutaneous AFP-expressing tumors and does not interfere with liver regeneration in mice [J]. Cancer Gene Ther, 2002,9:346-355.
[8]Conry M R, White S A, Fultz P N, et al. Polynucleotide immunization of nonhuman primates against carcinoembryonic antigen [J]. Clin Cancer Res, 1998,4 :2903-2912.
[9]Wei C M, Gibson M, Spear P G, et al.Construction and isolation of a transmissible retrovirus containing the src gene of Harvey murine sarcoma virus and the thymidine kinase gene of herpes simplex virus type 1 [J]. J Virol, 1981,39:935-944.
[10]Shimotohno K, Temin H M. Formation of infectious progeny virus after insertion of herpes simplex thymidine kinase gene into DNA of an avian retrovirus [J]. Cell, 1981,26 :67-77.
[11]Barzon L, Bonaguro R, Castagliuolo I, et al. Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase [J]. Eur J Endocrinol, 2003, 148:73-80.
[12]Saudemont A, Buffenoir G, Denys A, et al. Gene transfer of CD154 and IL12 cDNA induces an anti-leukemic immunity in a murine model of acute leukemia [J]. Leukemia, 2002,16:1637-1644.
[13]Fillat C, Carrio M, Cascante A, et al. Suicide gene therapy mediated by the herpes simplex virus thymidine kinase gene/ganciclovir system: fifteen years of application [J]. Curr GeneTher,2003,3 :13-26.
[14]Lewis P F, Emerman M. Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus [J]. J Virol, 1994, 68:510-516.
[15]Miller D G, Adam M A, Miller A D. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection [J]. Mol Cell Biol, 1994,10: 4239–4242.
[16]Ind raccolo S, Habeler W, Tisato V, et al. Gene transfer in ovarian cancer cells: acomparison between retroviral and lentiviral vectors [J].Cancer Res, 2002,62:6099- 6107.
[17]Pang S, Kang M K, Kung S, et al. Anticancer effect of a lentiviral vector capable of expressing HIV-1 Vpr [J]. Clin Cancer Res, 2001,7:3567-3573.
[18]Solly S K, Trajcevski S, Frisen C, et al. Replicative retroviral vectors for cancer gene therapy [J].Cancer Gene Ther, 2003,10 :30– 39.
[19]Li Q, Kay M A, Finegold M, et al. Assessment of recombinant adenoviral vectors for hepatic gene therapy [J]. Hum Gene Ther, 1993, 4:403-409.
[20]Swisher S G, Roth J A, Komaki R, et al.Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy [J].Clin Cancer Res, 2003,9:93-101.
[21]Roy I, Holle L, Song W, et al. Efficient translocation and apoptosis induction by adenovirus encoded VP22-p53 fusion protein in human tumor cells in vitro [J]. Anticancer Res, 2002, 22 :3185-3189.
[22]Anderson S C, Johnson D E, Engler H, et al. p53 gene therapy in a rat model of hepatocellular carcinoma: intra-arterial delivery of recombinant adenovirus [J]. Clin Cancer Res, 1998,4 :1649-1659.
[23]Bramson J L, Hitt M, Gauldie J, et al. Pre-existing immunity to adenovirus does not prevent tumor regression following intratumoral administration of a vector expressing IL-12 but inhibits virus dissemination [J].Gene Ther, 1997,4 :1069-1076.
[24]Raper S E, Yudkoff M, Chirmule N, et al. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency [J]. Hum Gene Ther, 2002),13:163-175.
[25]Vlachaki M T, Hernandez-Garcia A, Ittmann M, et al.The Impact of preimmunization on adenoviral vector expression and toxicity in a subcutaneous mouse cancer model [J]. Mol Ther, 2002),6:342–348.
[26]Heise C, Hermiston T, Johnson L, et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy [J]. Nat Med, 2000, 6:1134-1139.
[27]Rodriguez R, Schuur E R, Lim H Y, et al. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells [J].Cancer Res, 1997, 57:2559-2563.
[28]Bischoff J R, Kirn D H, Williams A, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells [J]. Science, 1996,274:373-376.
[29]Parker J N, Gillespie G Y, Love C E, et al. Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors [J].Proc Natl Acad Sci USA, 2000,97:2208-2213.
[30]Moriuchi S, Wolfe D, Tamura M, et al. Double suicide gene therapy using a replication defective herpes simplex virus vector reveals reciprocal interference in a malignant glioma model [J]. Gene Ther, 2002, 9:584–591.
[31]Kanazawa T, Mizukami H, Okada T, et al. Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice [J].Gene Ther, 2003,10:51-58.
[32]Ponnazhagan S, Curiel D T, Shaw D R, et al. Adeno-associated virus for cancer gene therapy [J].Cancer Res, 2001, 61:6313-6321.
[33]Su H, Lu R, Chang J C, et al. Tissue-specific expression of herpes simplex virus thymidine kinase gene delivered by adeno-associated virus inhibits the growth of human hepatocellular carcinoma in athymic mice [J]. Proc Natl Acad Sci USA, 1997, 94:13891-13896.
[34]Vermeij J, Zeinoun Z, Neyns B, et al. Transduction of ovarian cancer cells: a recombinant adeno-associated viral vector compared to an adenoviral vector [J]. Br J Cancer, 2001, 85:1592-1599.
[35]Smith G L, Moss B. Infectious poxvirus vectors have capacity for at least 25 000 base pairs of foreign DNA [J]. Gene, 1983, 25:21-28.
[36]Gomella L G, Mastrangelo M J, McCue P A, et al. Phase I study of intravesical vaccinia virus as a vector for gene therapy of bladder cancer [J]. J Urol, 2001,166 :1291–1295.
[37]Kaufman H L, Flanagan K, Lee C S, et al. Insertion of interleukin-2 (IL-2) and interleukin-12 (IL-12) genes into vaccinia virus results in effective antitumor responses without toxicity [J]. Vaccine , 2002,20:1862-1869.
[38]Felgner P L, Gadek T R, Holm M, et al. Lipofection:a highly efficient, lipid-mediated DNA -transfection procedure [J]. Proc Natl Acad Sci USA, 1987, 84: 7413-7417
[39]Andrew M. Gene therapy: the first decade. Tibtech March, 2000, 18: 119-128
[40]Boussif O, Lezoualc’h F, Zanta M A, et al. Versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine [J]. Proc Natl Acad Sci USA , 1995,92 :7297-7301.
[41]Klemm A R, Young D, Lloyd J B. Effects of polyethyleneimine on endocytosis and lysosome stability [J]. Biochem Pharmacol, 1998, 56 41– 46.
[42]Fischer D, Bieber T, Li Y et al. A novel non-viral vector for DNA delivery based on low molecular weight, branched polyethylenimine: effect of molecular weight on transfection efficiency and cytotoxicity [J]. Pharm Res, 1999,16:1273–1279.
[43]Wightman L, Kircheis R, Rossler V, et al. Different behavior of branched and linear polyethylenimine for gene delivery in vitro and in vivo [J]. J Gene Med, 2001,3 362–372.
[44]Chollet P, Favrot M C, Hurbin A, et al. Side-effects of a systemic injection of linear polyethylenimine–DNA complexes [J]. J Gene Med, 2002, 4:84– 91.
[45]Kircheis R, Schuller S, Brunner S, et al. Polycation-based DNA complexes for tumor-targeted gene delivery in vivo [J]. J Gene Med, 1999,1:111-120.
[46]Pouton C W, Lucas P, Thomas B J, et al. Polycation-DNA complexes for gene delivery: a comparison of the biopharmaceutical properties of cationic polypeptides and cationic lipids [J]. J Control Release, 1998, 53:289-299.
[47]Ward C M, Pechar M, Oupicky D, et al. Modification of pLL/DNA complexes with a multivalent hydrophilic polymer permits folate-mediated targeting in vitro and prolonged plasma circulation in vivo [J]. J Gene Med, 2002, 4:536–547.
[48]Lee H, Jeong J H, Park T G. PEG grafted polylysine with fusogenic peptide for gene delivery: high transfection efficiency with low cytotoxicity [J]. J Control Release, 2002,79:283-291.
[49]Wu G Y, Wu C H. Receptor-mediated in vitro gene transformation by a soluble DNA carrier system [J]. J Biol Chem, 1987,262:4429-4432.
[50]Suh W, Chung J K, Park S H, et al. Anti-JL1 antibody-conjugated poly(L-lysine) for targeted gene delivery to leukemia T cells [J]. J Control Release, 2001,72:171-178.
[51]Faraasen S, Voros J, Csucs G, et al. Ligand-specific targeting of microspheres to phagocytes by surface modification with poly(L-lysine)-grafted poly(ethylene glycol) conjugate [J].Pharm Res, 2003,20:237-246.
[52]Pichon C, Goncalve s C, Midoux P. Histidine-rich peptides and polymers for nucleic acids delivery [J]. Adv Drug Deliv Rev, 2001,53:75– 94.
[53]Choi B Y, Chung J W, Park J H, et al.Gene delivery to the rat liver using cationic lipid emulsion/DNA complex: comparison between intra-arterial, intraportal and intravenous administration [J].Korean J Radiol, 2002, 3 :194-198.
[54]Legendre J Y, Trzeciak B, Deuschle U, et al. N-acyl -(α,γ-diaminobutyric acid) n hydrazide as an efficient gene transfer vectorin mammalian cells in culture [J]. Pharm Res, 1997, 14: 619-624
[55]Roy K, Mao HQ, Huang S K, et al. Oral gene delivery with chitosan- DNA nanoparticles generates immunologic protection in a murine model of peanut allergy [J]. Nature Med, 1999, 5: 387-391
[56]Koping-Hoggard M, Mel’nikovaS Y S, Varum K M, et al. Relationship between the physical shape and the efficiency of oligomeric chitosan as a gene delivery system in vitro and in vivo [J]. J Gene Med, 2003,5130– 141.
[57]M. Lee, J.W. Nah, Y. Kwon, J.J. Koh, K.S. Ko, S.W. Kim,Water-soluble and low molecular weight chitosan-based plasmid DNA delivery [J].Pharm. Res, 2001, 18 :427- 431.
[58]Vincent L, Varet J, Pille J Y, et al. Efficacy of dendrimer-mediated angiostatin and TIMP-2 gene delivery on inhibition of tumor growth and angiogenesis:in vitro and in vivo studies [J]. Int J Cancer , 2003,105: 419–429.
[59]Read M L, Bremner K H, Oupick D et al. Vectors based on reducible polycationsfacilitate intracellular release of nucleic acids [J]. J Gene Med, 2003,5 :232-245.
[60]Simon R H, Engelhardt J F, Yang Y, et al. Adenovirus -mediated gene transfer of the CFTR gene to the lung of non - human primates: atosicity study [J]. Hum Gene Tuer, 1993, 4: 771-780
[61]Donahue R E, Kessler S W, Bodine D, et al. Helper virus induced T cell lymphoma in non - human primates after retroviral gene transfer [J]. J Exp Biol, 1992, 176: 1125-1135
[62]Li S, Tseng W C, Stolz D B, et al. Dynamic changes in the characteristics of cationic lipidic vectors after exposure to mouse serum: implications for intravenous lipofection [J]. Gene Therapy, 1999, 6: 585-594
[63]Maitra A . Calcium phosphate nanoparticles: second-generation nonviral vectors in genetherapy [J]. Expert Rev Mol Diagn,2005, 5:893 -905 .
[64]Megeed Z, Haider M, Li D, et al. In vitro and in vivo evaluation of recombinant silkelastinlike hydrogels for cancer gene therapy [J]. J Control Release,2004,94:433 -445 .
[64]Balicki D, Beutler E. Gene therapy of human disease [J]. Medicine, 2002,81:69-86.
[65]Kovesdi I, Brough D E, Bruder J T, et al. Adenoviral vectors for gene transfer [J]. Curr Opin Biotechnol,1997 8:583-589.
[66]Felgner P L, Barenholz Y, Behr J P, et al. Nomenclature for synthetic gene delivery systems [J]. Hum Gene Ther, 1997,8:511-512.
[67]Mahato R I, Smith L C, Rolland A. Pharmaceutical perspectives of nonviral gene therapy [J]. Adv Genet,1999, 41:95-156.
[68]Balicki D, Reisfeld R A, Pertl U, et al. Histone H2Amediated transient cytokine gene delivery induces efficient antitumor responses in murine neuroblastoma [J]. Proc Natl Acad Sci USA, 2000,97 :11500-11504.
[69]Schwartz B, Ivanov M A, Pitard B, et al. Synthetic DNA-compacting peptides derived from human sequence enhance cationic lipid-mediated gene transfer in vitro and in vivo [J]. Gene Ther, 1999, 6: 282-292.
[70]Morris M C, Vidal P, Chaloin L, et al. A new peptide vector for efficient delivery of oligonucleotides into mammalian cells [J]. Nucleic Acids Res, 1997, 25:2730-2736.
[71]Balicki D, Beutler E. Histone H2A significantly enhances in vitro DNA transfection [J]. Mol Med 1997,3 :782-787.
[72]Balicki D, Putnam C D, Scaria P V, et al. Structure and function correlation in histone H2A peptide-mediated gene transfer [J]. Proc Natl Acad Sci USA, 2002,99:7467-7471.
[73]Kornberg R D, Lorch Y L. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome [J]. Cell, 1999,98:285-294.
[74]Palau J, Climent F, Aviles F J, et al. Interactions of histones and histone peptides with DNA. Thermal denaturation and solubility studies [J]. Biochim Biophys Acta 1977, 476:108-121.
[75]Baake M, Doenecke D, Albig W, Characterisation of nuclear localisation signals of the four human core histones [J]. J Cell Biochem, 2001,81:333-346.
[76]Cheung P, Allis CD, Sassone-Corsi P. Signaling to chromatin through histone modifications. Cell [J]2000,103, 263–271 ().
[77]Khan AU, Krishnamurthy S. Histone modifications as key regulators of transcription. Front.Biosci. [J] 2005,10, 866–872 .
[78]Iniguez-Lluhi JA . For a healthy histone code, a little SUMO in the tail keeps the acetyl away. ACS Chem. Biol. [J] 20061: 204–206.
[79]Thompson PR & Fast W. Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock ACS Chem. Biol. [J].2006, 1: 433–441.
[80]Ryser H J, Hancock R. Histones and basic polyamino acids stimulate the uptake of albumin by tumor cells in culture [J]. Science, 1965,150:501-503.
[81]Ryser H J. Uptake of protein by mammalian cells: an underdeveloped area. The penetration of foreign proteins into mammalian cells can be measured and their functions explored[J]. Science, 1968,159:390-396.
[82]Zaitsev S, Buchwalow I, Haberland A, et al. Histone H1-mediated transfection: role of calcium in the cellular uptake and intracellular fate of H1-DNA complexes [J]. Acta Histochem, 2002,104:85-92.
[83]Budker V, Hagstrom J E, Lapina O, et al. Protein/amphipathic polyamine complexes enable highly efficient transfection with minimal toxicity [J]. Biotechniques, 1997,139 :142-147.
[84]Fritz J D, Herweijer H, Zhang G F, et al. Gene transfer into mammalian cells using histone-condensed plasmid DNA [J]. Hum Gene Ther, 1996, 7: 1395-1404.
[85]Haberland A, Dalluge R, Zaitsev S, et al. Ligand-histone H1 conjugates: increased solubility of DNA complexes, but no enhanced transfection activity [J]. Somat Cell Mol Genet, 1999,25:237-245.
[86]Haberland A, Knaus T, Zaitsev S V, et al. Histone H1-mediated transfection: serum inhibition can be overcome by Ca2+ ions [J]. Pharm Res, 2000,17: 229-235.
[87]Hagstrom J E, Sebestyen M G, Budker V, et al.Complexes of non-cationic liposomes and histone H1 mediate efficient transfection of DNA without encapsulation [J]. Biochim Biophys Acta 1996, 1284:47-55.
[88]Kott M, Haberland A, Zaitsev S, et al. A new efficient method for transfection of neonatal cardiomyocytes using histone H1 in combination with DOSPER liposomal transfection reagent [J], Somat Cell Mol Genet, 1998,24: 257-261.
[89]Lucius H, Haberland A, Zaitsev S, et al. Structure of transfection-active histone H1/DNA complexes [J]. Mol Biol Rep,2001,28:157-165.
[90]Zaitsev S V, Haberland A, Otto A, et al. H1 and HMG17 extracted from calf thymus nuclei areefficient DNA carriers in gene transfer [J]. Gene Ther, 1997,4:586-592.
[91]Demirhan I, HasselmayerO, Chandra A, et al. Histone-mediated transfer and expression of the HIV-1 tat gene in Jurkat cells [J], J Hum Virol,1998, 1: 430-440.
[92]Bottger M, Zaitsev S V, Otto A, et al. Acid nuclear extracts as mediators of gene transfer and expression [J]. Biochim Biophys Acta, 1998, 1395: 78-87.
[93]Haberland A, Knaus T, Zaitsev S V, et al. Calcium ions as efficient cofactor of polycationmediated gene transfer [J]. Biochim Biophys Acta, 1999,1445:21-30.
[94]Puebla I, Esseghir S, Mortlock A, et al. A recombinant H1 histone-based system for efficient delivery of nucleic acids [J]. J Biotechnol, 2003,105:215-226.
[95]Moran F, Montero F, Azorin F, et al. Condensation of DNA by the Cterminal domain of histone H-1. A circular-dichroism study [J]. Biophys Chem, 1985, 22:125-129.
[96]Hasselmayer O, Demirhan I, Chandra A, et al. Inhibition of histone-mediated gene transfer in eucaryotic cells by anti-histone IgG [J]. Anticancer Res, 2001, 21:2377-2386.
[97]Weng L, Liu D, Li Y, An archaeal histone-like protein as an efficient DNA carrier in gene transfer [J]. Biochim BiophysActa,2004,1702:209-216.
[98]Esser D, Amanuma H, Yoshiki A, et al. A hyperthermostable bacterial histone-like protein as an efficient mediator for transfection of eukaryotic cells[J]. Nat Biotechnol, 2000,18:1211-1213.
[99]Goodwin G H, Sanders C, Johns E W. A new group of chromatinassociated proteins with a high content of acidic and basic amino acids [J]. Eur J Biochem, 1973,38:14-19.
[100]Kaneda Y, Iwai K, Uchida T. Introduction and expression of the human insulin gene in adult rat liver [J]. J Biol Chem, 1989, 264:12126-12129.
[101]Kato K, Nakanishi M, Kaneda Y, et al. Expression of hepatitis B virus surface antigen in adult rat liver. Co-introduction of DNA and nuclear protein by a simplified liposome method [J], J Biol Chem, 1991,266:3361-3364.
[102]Tomita N, Higaki J, Morishita R, et al. Direct in vivo gene introduction into rat kidney [J]. Biochem Biophys Res Commun, 1992,186:129-134.
[103]Sawa Y, Suzuki K, Bai H Z , et al. Efficiency of in vivo gene transfection into transplanted rat heart by coronary infusion of HVJ liposome [J]. Circulation,1995,92:II479-II482.
[104]Bottger M, Vogel F, Platzer M, et al. Condensation of vector DNA by the chromosomal protein HMG1 results in efficient transfection [J]. Biochim Biophys Acta,1988,950:221-228.
[105]Namiki Y, Takahashi T, Ohno T. Gene transduction for disseminated intraperitoneal tumor using cationic liposomes containing non-histone chromatin proteins: cationic liposomal gene therapy of carcinomatosa [J]. Gene Ther, 1998, 5:240-246.
[106]Mistry A R, Falciola L, Monaco L, et al. Recombinant HMG1 protein produced in Pichia pastoris: a nonviral gene delivery agent [J]. Biotechniques, 1997,22 :718-729.
[107]Haberland A, Bottger M. Nuclear proteins as gene-transfer vectors [J]. Biotechnol Appl Biochem, 2005,42:97-106.
[108]Anwer K, Bailey A, Sullivan S M. Targeted gene delivery: a twopronged approach [J]. Crit Rev Ther Drug Carr Syst, 2000,17:377-424.
[109]Lee T K, Han J S, Fan S T, et al. Gene delivery using a receptor-mediated gene transfer system targeted to hepatocellular carcinoma cells [J]. Int J Cancer,2001,93:393-400.
[110]Liu X, Tian P, Yu Y, et al. Enhanced antitumor effect of EGF R-targeted p21WAF-1 and GM-CSF gene transfer in the established murine hepatoma by peritumoral injection [J]. Cancer Gene Ther, ,2002,9:100-108.
[111]Dai F H, Chen Y, Ren C C, et al. Construction of an EGF receptor-mediated histone H1(0)-based gene delivery system [J]. J Cancer Res Clin Oncol, 2003, 129:456-462.
[112]Chen J, Stickles R J, Daichendt K A. Galactosylated histone-mediated gene-transfer and expression [J]. Hum Gene Ther, 1994,5:429–435.
[113]Junbo H, Li Q, Zaide W, et al. Receptor-mediated interleukin-2 gene transfer into human hepatoma cells [J]. Int J Mol Med, 1999, 3: 601-608.
[114]Scheule R K, George RG, BagleyJ, et al. Basis of pulmonary toxicity associated with cationic lipidmediated gene transfer to the mammalian lung [J]. Hum Gene Ther,1997,8:689-707.
[115]Tousignant J D, Gates A L, Ingram L A, et al. Comprehensive analysis of the acute toxicities induced by systemic administration of cationic lipid:plasmid DNA complexes in mice [J]. Hum Gene Ther, 2000,11: 2493-2513.
[116]Filion M C, Phillips N C. Toxicity and immunomodulatory activity of liposomal vectors formulated with cationic lipids toward immune effector cells [J]. Biochim Biophys Acta, 1997,1329: 345-356.
[117]Filion M C, Phillips N C. Anti-inflammatory activity of cationic lipids [J]. Br Jpharmacol, 1997,122:551-557.
[118]Lappalainen K, Jaaskelainen I, Syrjanen K, et al.Comparison of cell proliferation and toxicity assays using two cationic liposomes [J]. Pharm Res, 1994,11: 1127-1131.
[119]Monestier M. Autoantibodies to nucleosomes and histone-DNA complexes [J]. Methods, 1997,11 :36-43.
[120]Hardin J A, Thomas J O. Antibodies to histones in systemic lupus erythematosus: localization of prominent autoantigens on histones H1 and H2B [J]. Proc Natl Acad Sci USA, 1983, 80 :7410-7414.
[121]Iborra S, Soto M, Carrion J, et al. Vaccination with a plasmid DNA cocktail encoding the nucleosomal histones of Leishmania confers protection against murine cutaneous leishmaniosis [J].Vaccine, 2004, 22 :3865-3876.
[122]Collins L, Asuni A A, Anderton B H, et al. Efficient gene delivery to primary neuron cultures using a synthetic peptide vector system [J]. J Neurosci Methods, 2003, 125 :113-120.
[123]Zhang X, Collins L, Sawyer G J, et al.In vivo gene delivery via portal vein and bile duct to individual lobes of the rat liver using a polylysine-based nonviral DNA vector in combination with chloroquine [J]. Hum Gene Ther, 2001, 12 :2179-2190.
[124]Torchilin V P, Lukyanov A N. Peptide and protein drug delivery to and into tumors: challenges and solutions [J]. Drug Discov Today, 2003,8:259-266.
[125]Plank C, Mechtler K, Szoka F C, et al. Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery [J], Hum Gene Ther, 1996, 7:1437-1446.
[126]Yang J P, Huang L. Overcoming the inhibitory effect of serum on lipofection by increasing the charge ratio of cationic liposome to DNA [J]. Gene Ther, 1997, 4: 950-960.
[127]Mizuguchi H, Nakagawa T, Nakanishi M, et al. Efficient gene transfer into mammalian cells using fusogenic liposome [J]. Biochem Biophys Res Commun, 1996,218: 402-407.
[128]Zhou X H, Klibanov A L, Huang L. Lipophilic polylysines mediate efficient DNA transfection in mammalian cells [J]. Biochim Biophys Acta, 1991,1065:8–14.
[129]Ogris M, Brunner S, Schuller S, et al. PEGylated DNA/transferrin-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery [J]. Gene Ther, 1999, 6: 595-605.
[130]Kaneda Y, Iwai K, Uchida T. Increased expression of DNA cointroduced with nuclear-protein in adult-rat liver [J]. Science, 1989,243 :375-378.
[131]Hagstrom J E, Ludtke J J, Bassik M C, et al. Nuclear import of DNA in digitonin-permeabilized cells [J]. J Cell Sci, 1997,110:2323-2331.
[132]Conary J T, Erdos G, McGuire M, et al. Cationic liposome plasmid DNA complexes: in vitro cell entry and transgene expression augmented by synthetic signal peptides [J]. Eur J Pharm. Biopharm, 1996,42: 277-285.
[133]Zanta M A, Belguise V P, Behr J P. Gene delivery: a single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus [J]. Proc Natl Acad Sci USA, 1999,96:91-96.
[134]Collas P, Alestrom P. Rapid targeting of plasmid DNA to zebrafish embryo nuclei by the nuclear localization signal of SV40 T antigen [J]. Mol Mar Biol Biotechnol, 1997, 6: 48-58.
[135]Mosammaparast N, Jackson K R, Guo Y, et al. Nuclear import of histone H2A and H2B is mediated by a network of karyopherins [J]. J Cell Biol, 2001, 153:251-262.
[136]Mosammaparast N, Guo Y, Shabanowitz J, et al. Pathways mediating the nuclear import of histones H3 and H4 in yeast [J]. J Biol Chem, 2002,277:862-868.
[137]Moreland R B, Langevin G L, Singer R H, et al. Amino-acid-sequences that determine the nuclear-localization of yeast histone-2B [J]. Mol Cell Biol, 1987, 7: 4048-4057.
[138]Wilke M, Fortunati E, vandenBroek M, et al. Efficacy of a peptide-based gene delivery system depends on mitotic activity [J]. Gene Ther, 1996,3: 1133-1142.
[139]Itaka K, Harada A, Yamasaki Y, et al. In situ single cell observation by fluorescence resonance energy transfer reveals fast intra-cytoplasmic delivery and easy release of plasmid DNA complexed with linear polyethylenimine [J]. J Gene Med, 2004, 6 :76-84.
[140]Okuda T, Niidome T, Aoyagi H. Cytosolic soluble proteins induce DNA release from DNA-gene carrier complexes [J]. J Control Release,2004, 98 325-332.
[141]Luger K, Mader A W, Richmond R K, et al. Crystal structure of the nucleosome core particle at 2.8 A resolution [J].Nature, 1997, 389: 251-260.
[142]Zelphati O, Szoka F C. Mechanism of oligonucleotide release from cationic liposomes [J]. Proc Natl Acad Sci USA, 1996,93:11493-11498.
[143]Zelphati O, Szoka F C. Intracellular distribution and mechanism of delivery of oligonucleotides mediated by cationic lipids [J]. Pharm Res, 1996, 13:1367-1372.
[144]Zelphati O, Szoka F C. Liposomes as a carrier for intracellular delivery of antisense oligonucleotides: a real or magic bullet? [J] J Control Release, 1996,41: 99-119.
[145]Sieczkarski S B, Whittaker G R. Dissecting virus entry via endocytosis [J]. J Gen Virol. 2002, 83 :1535-1545.
[146]Bratosin D, Mazurier J, Tissier J P, et al. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review [J], Biochimie, 1998, 80: 173-195.
[147]Cardelli J. Phagocytosis and macropinocytosis in Dictyostelium: phosphoinositide-based processes, biochemically distinct [J]. Traffic, 2001,2: 311-320.
[148]Nichols B J, LippincottS J. Endocytosis without clathrin coats [J]. Trends Cell Biol, 2001,11:406-412.
[149]Schwartz J J, Zhang S G. Peptide-mediated cellular delivery [J]. Curr Opin Mol Ther, 2000, 2 :162-167.
[150]Hariton G E, Rosenbluh J, Graessmann A, et al. Direct translocation of histone molecules across cell membranes [J]. J Cell Sci, 2003, 116: 4577-4586.
[151]Murphy R F, Jorgensen E D, Cantor C R. Kinetics of histone endocytosis in Chinese hamster ovary cells. A flow cytofluorometric analysis [J], J Biol Chem, 1982, 257:1695-1701.
[152]Vives E, Charneau P, Vanrietschoten J, et al. Effects of the Tat basic domain on human-immunodeficiency-virus type-1 transactivation, using chemically synthesized tat protein and tat peptides [J]. J Virol, 1994,68: 3343-3353.
[153]Vives E, Brodin P, Lebleu B. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus [J]. J Biol Chem, 1997,272:16010-16017.
[154]Rosenbluh J, Singh S K, Gafni Y, et al. Nonendocytic penetration of core histones into petunia protoplasts and cultured cells: a novel mechanism for the introduction of macromolecules into plant cells [J]. Biochim Biophys Acta, 2004, 1664:230-240.
[155]Rosenbluh J, Hariton G E, Dagan A, et al.Translocation of histone proteins across lipid bilayers and Mycoplasma membranes [J]. J Mol Biol, 2005, 345:387-400.
[156]Gao X, Huang L. Cationic liposome-mediated gene transfer [J]. Gene Ther, 1995,2: 710-722.
[157]Niidome T, Wakamatsu M, Wada A, et al. Required structure of cationic peptide for oligonucleotide-binding and–delivering into cells [J]. J Pept Sci, 2000, 6 :271-279.
[158]Kopatz I, Remy S J, Behr J P. A model for non-viral gene delivery: through syndecan adhesion molecules and powered by actin [J]. J Gene Med, 2004,6: 769-776.
[159]Lorch Y, LaPointe J W, Kornberg R D. Nucleosomes inhibit the initiation of transcription butallow chain elongation with the displacement of histones [J]. Cell, 1987, 49: 203-210.
[160]Schlissel M S,Brown D D. The transcriptional regulation of Xenopus 5s RNA genes in chromatin: the roles of active stable transcription complexes and histone H1 [J]. Cell, 1984, 37: 903-913.
[161]Wolffe A P. Dominant and specific repression of Xenopus oocyte 5SRNA genes and satellite I DNA by histone H1 [J]. EMBO J, 1989,8 :527-537.
[162]Brown D T, Sittman DB. Identification through overexpression and tagging of the variant type of the mouse H1e and H1c genes [J]. J Biol Chem, 1993,268:713-718.
[163]Brown D T, Alexander B T, Sittman D B. Differential effect of H1 variant overexpression on cell cycle progression and gene expression [J]. Nucleic Acids Res, 1996,24: 486-493.
[164]Brown D T, Gunjan A, Alexander B T, et al. Differential effect of H1 variant overproduction on gene expression is due to differences in the central globular domain [J]. 1997, Nucleic Acids Res, 25 :5003-5009.
[165]Sun J M, Wiaderkiewicz R, Ruiz C A. Histone H5 in the control of DNA synthesis and cell proliferation [J]. Science, 1989,245:68-71.
[166]Johnson L M, FisherA G, Grunstein M. Identification of a nonbasic domain in the histone H4 N-terminus required for repression of the yeast silent mating loci [J].EMBO J, 1992,11:2201-2209.
[167]Megee P C, Morgan B A, Smith M M. Histone H4 and the maintenance of genome integrity [J].Genes Dev, 1995, 9: 1716-1727.
[168]Latner A L, Longstaff E. Transformation of mammalian cells by crude histones [J]. Br J Cancer , 1971,25:280-283.
[169]Latner A L, Turner G A, Cornell C. Increased nuclear size in BHK21 cells after treatment with non-toxic levels of calf thymus histones [J]. Exp Cell Biol, 1979,47:145-154.
[170]Bases R, Mendez F, Mendez L, et al. Stimulation of HeLa cellsurface attachment by histones [J]. Exp Cell Res, 1973, 76 :441-444.
[171]Okabe K J, Honma Y, Hayashi M, et al. Effects of histone fractions on induction of differentiation of cultured mouse myeloid leukemia cells [J]. Cancer Res, 1981, 41:1997-2002.
[172]Butler L M, Agus D B, Sche r H I, et al. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo [J].Cancer Res, 2000,60:5165-5170.
[173]Richon V M, Emiliani S, Verdin E, et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases [J]. Proc Natl Acad Sci USA, 1998,95:3003–3007.
[174]Pearse I, Glick RD, Abramson S J, et al. Hybrid polar histone deacetylase inhibitor induces apoptosis and CD95/CD95 ligand expression in human neuroblastoma [J]. Cancer Res, 1999,59:4392-4399.
[175]Qiu L, Kelso M J, Hansen C, et al. Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate [J]. Br J Cancer,1999, 80 :1252-1258.
[176]Noteborn M H, de Boer G F, van Roozelaar D J, et al. Characterization of cloned chicken anemia virus DNA that contains all elements for the infectious replication cycle [J]. J Virol, 1991, 65:3131-3139.
[177]Natesan S, Kataria J M, Dhama K, et al. Anti-neoplastic effect of chicken anemia virus VP3 protein (apoptin) in Rous sarcoma virus-induced tumours in chicken [J]. J Gen Virol, 2006, 87:2933-2940.
[178]Noteborn M H, Verschueren C A, Zantema A, et al.Identification of the promoter region of chicken anemia virus (CAV) containing a novel enhancer-like element [J].Gene, 1994, 150: 313-318.
[179]Miller M M, Jarosinski K W, Schat K A. Positive and negative regulation of chicken anemia virus transcription [J]. J Virol, 2005, 79:2859-2868.
[180]Noteborn M H, Todd D, Verschueren C A, et al. A single chicken anemia virus protein induces apoptosis [J]. J Virol, 1994,68:346-351.
[181]Phenix K V, Meehan B M, Todd D, et al. Transcriptional analysis and genome expression of chicken anaemia virus [J]. J Gen Virol, 1994, 75:905-909.
[182]Maddika S, Mendoza F J, Hauff K, et al.Cancerselective therapy of the future: apoptin and its mechanism of action [J]. Cancer Biol Ther, 2006,5:10-19.
[183]Noteborn M H. Chicken anemia virus induced apoptosis: underlying molecular mechanisms [J].Vet Microbiol, 2004,98:89-94.
[184]Heilman D W, Teodoro J G, Green M R. Apoptin nucleocytoplasmic shuttling is required for cell type-specific localization, apoptosis, and recruitment of the anaphase-promoting complex/cyclosome to PML bodies [J].J Virol, 2006,80:7535-7545.
[185]Poon I K H, Oro C, Dias M M, et al. Apoptin nuclear accumulation is modulated by a CRM1-recognized nuclear export signal that is active in normal but not in tumor cells [J]. Cancer Res, 2005,65:7059-7064.
[186]Kamada K, Kuroishi A, Kamahora T, et al. Spliced mRNAs detected during the life cycle of chicken anemia virus [J]. J Gen Virol, 2006,87 :2227-2233.
[187]Danen-Van Oorschot A A, Zhang Y H, Leliveld S R, et al. Importance of nuclear localization of apoptin for tumor-specific induction of apoptosis [J]. J Biol Chem, 2003, 278:27729-27736.
[188]Kuusisto H V, Wagstaff K M, Alvisi G, et al. The C-terminus of apoptin represents a unique tumor cell-enhanced nuclear targeting module [J]. Int J Cancer, 2008,2965-2969.
[189]Backendorf C, Visser A E, de Boer A G, et al. Apoptin: therapeutic potential of an early sensor of carcinogenic transformation [J]. Annu Rev Pharmacol Toxicol, 2008,48: 143-169.
[190]Leliveld S R, Zhang Y H, Rohn J L, et al. Apoptin induces tumor-specific apoptosis as a globular multimer [J]. J Biol Chem, 2003,278: 9042-9051.
[191]Leliveld S R, Dame R T, Mommaas M A, et al. Apoptin protein multimers form distinct higher-order nucleoprotein complexes with DNA [J]. Nucleic Acids Res, 2003,31:4805-4813.
[192]Tavassoli M, Guelen L, Luxon B A, et al. Apoptin: specific killer of tumor cells [J]? Apoptosis, 2005,10:717-724.
[193]Danen-Van Oorschot A A, Fischer D F, Grimbergen J M, et al. Apoptin induces apoptosis in human transformed and malignant cells but not in normal cells [J]. Proc Natl Acad Sci USA, 1997,94:5843-5847.
[194]Zhang Y H, Abrahams P J, van der Eb A J, et al.The viral protein Apoptin induces apoptosis in UV-C-irradiated cells from individuals with various hereditary cancer-prone syndromes [J]. Cancer Res, 1999, 59: 3010-3015.
[195]Guelen L, Paterson H, Gaken J, et al. TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells [J]. Oncogene, 2004,23 :1153-1165.
[196]Pietersen A, Erkeland S J, Rutjes S A, et al.Continuous apoptin expression in transgenic mice does not interfere with lymphocyte development and proliferation [J]. J Med Mol Biol,2005,2: 321-330.
[197]Pietersen A M, van der Eb M M, Rademaker H J, et al. Specific tumor-cell killing withadenovirus vectors containing the apoptin gene [J]. Gene Ther, 1999,6 :882-892.
[198]Maddika S, Ande S R, Wiechec E, et al. Los, Aktmediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis [J]. J Cell Sci, 2008,121:979-988.
[199]Olijslagers S J, Zhang Y H, Backendorf C, et al. Additive cytotoxic effect of apoptin and chemotherapeutic agents paclitaxel and etoposide on human tumour cells [J]. Basic Clin Pharmacol Toxicol, 2007,100:127-131.
[200]Zhuang S M, Shvarts A, van Ormondt H, et al. Apoptin, a protein derived from chicken anemia virus, induces p53-independent apoptosis in human osteosarcoma cells [J]. Cancer Res, 1995,55: 486-489.
[201]Los M, Wesselborg S, Schulze-Osthoff K. The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice [J].Immunity, 1999,10:629-639.
[202]Schwerk C, Schulze-Osthoff K. Regulation of apoptosis by alternative pre-mRNA splicing [J].Mol Cell, 2005,19:1-13.
[203]Fischer U, J?nicke R U, Schulze-Osthoff K. Many cuts to ruin: a comprehensive update of caspase substrates [J]. Cell Death Differ, 2003,10 :76-100.
[204]Danen-van Oorschot A A, van Der Eb A J, Noteborn M H. The chicken anemia virus-derived protein apoptin requires activation of caspases for induction of apoptosis in human tumor cells [J]. J Virol, 2000, 74:7072-7078.
[205]Maddika S, Booy E P, Johar D, et al.Cancer-specific toxicity of apoptin is independent of death receptors but involves the loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators by a Nur77-dependent pathway [J]. J Cell Sci, 2005,118:4485-4493.
[206]Burek M, Maddika S, Burek C J, et al. Apoptin induced cell death is modulated by Bcl-2 family members and is Apaf-1dependent [J].Oncogene, 2005, 25: 2213-2222.
[207]Danen-Van Oorschot A A, van der Eb A J, Noteborn M H. BCL-2 stimulates Apoptin-induced apoptosis [J]. Adv Exp Med Biol, 1999,457:245-249.
[208]Danen-Van Oorschot A A, Zhang Y, Erkeland SJ, et al.The effect of Bcl-2 on Apoptin in‘normal’vs transformed human cells [J].Leukemia, 1999,13 (Suppl 1): S75–S77.
[209]Liu X, Elojeimy S, El-Zawahry A M, et al. Modulation of ceramide metabolism enhancesviral protein apoptin's cytotoxicity in prostate cancer [J]. Molec Ther, 2006, 14 :637-646.
[210]Lin B, Kolluri S K, Lin F, et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3 [J].Cell, 2004,116:527-540.
[211]Huo D H, Yi L N, Yang J. Interaction with Ppil3 leads to the cytoplasmic localization of Apoptin in tumor cells [J]. Biochem Biophys Res Commun, 2008,372:14-18.
[212]Cheng C M, Huang S P, Chang Y F, et al.The viral death protein Apoptin interacts with Hippi, the protein interactor of Huntingtin-interacting protein1 [J]. Biochem Biophys Res Commun, 2003, 305 :359-364.
[213]Sun G J, Tong X, Dong Y, et al. Identification of a protein interacting with apoptin from human leucocyte cDNA library by using yeast two-hybrid screening [J]. ShengWu HuaXue Yu ShengWu WuLi XueBao (Shanghai), 2002,34:369-372.
[214]Teodoro J G., Heilman D W, Parker A E, et al.The viral protein Apoptin associates with the anaphase-promoting complex to induce G2/M arrest and apoptosis in the absence of p53 [J]. Genes Dev, 2004,18:1952-1957.
[215]Danen-van Oorschot A A, Voskamp P, Seelen M C, et al. Human death effector domain-associated factor interacts with the viral apoptosis agonist Apoptin and exerts tumor-preferential cell killing[J]. Cell Death Differ, 2004, 11 564-573.
[216]Janssen K, HofmannT G, Jans D A, et al. Apoptin is modified by SUMO conjugation and targeted to promyelocytic leukemia protein nuclear bodies [J]. Oncogene, 2007, 26 :1557-1566.
[217]Krieghoff-Henning E, Hofmann T G. Role of nuclear bodies in apoptosis signalling [J]. Biochim Biophys Acta, 2008, 1783:2185-2194.
[218]Maddika S, Wiechec E, Ande S R, et al. Interaction with PI3-kinase contributes to the cytotoxic activity of apoptin[J]. Oncogene, 2008,27 :3060-3065.
[219]Maddika S, Bay G H, Kroczak T J, et al. Akt is transferred to the nucleus of cells treated with apoptin, and it participates in apoptin-induced cell death [J]. Cell Prolif, 2007, 40 :835-848.
[220]Aki T, Yamaguchi K, Fujimiya T, et al. Phosphoinositide 3-kinase accelerates autophagic cell death during glucose deprivation in the rat cardiomyocyte-derived cell line H9c2 [J]. Oncogene, 2003,22:8529-8535.
[221]Lu B, Wang L, Stehlik C, et al. Phosphatidylinositol 3-kinase/Akt positively regulates Fas (CD95)-mediated apoptosis in epidermal Cl41 cells [J]. J Immunol, 2006,176: 6785-6793.
[222]D. Nimbalkar, M.K. Henry, F.W. Quelle, Cytokine activation of phosphoinositide 3-kinase sensitizes hematopoietic cells to cisplatin-induced death, Cancer Res. 2003,63:1034–1039.
[223]Shack S, Wang X T, Kokkonen G C, et al.Caveolin-induced activation of the phosphatidylinositol 3-kinase/Akt pathway increases arsenite cytotoxicity [J]. Mol Cell Biol, 2003, 23 :2407-2414.
[224]Maddika S, Panigrahi S, Wiechec E, et al. Unscheduled Akt-triggered activation of CDK2 as a key effector mechanism of apoptin's anticancer toxicity [J]. Mol Cell Biol, 2009, 29:1235-1248.
[225]Lei H, Furlong P J, Ra J H, et al. AKT activation and response to interferon-beta in human cancer cells [J]. Cancer Biol Ther, 2005,4:709-715.
[226]Tang D, Okada H, Ruland J, et al. Akt is activated in response to an apoptotic signal [J]. J Biol Chem, 2001, 276: 30461-30466.
[227]van Gorp A G , Pomeranz K M, Birkenkamp K U, et al. Chronic protein kinaseB , (PKB/c-akt) activation leads to apoptosis induced by oxidative stress-mediated Foxo3a transcriptional up-regulation [J]. Cancer Res, 2006,66:10760-10769.
[228]Nogueira V, Park Y, Chen C C, et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis [J]. Cancer Cell, 2008,14: 458-470.
[229]Los M, Maddika S, Erb B, et al. Switching Akt: from survival signaling to deadly response [J]. BioEssays, 2009, 31:492-495.
[230]Poon I K, Oro C, Dias M M, et al. A tumor cell-specific nuclear targeting signal within chicken anemia virus VP3/Apoptin [J]. J Virol, 2005,79:1339-1341.
[231]Rohn J L, Noteborn M H. The viral death effector Apoptin reveals tumor-specific processes [J]. Apoptosis, 2004, 9 :315-322.
[232]Rohn J L, Zhang Y H, Aalbers R I J M, et al. A tumorspecific kinase activity regulates the viral death protein apoptin [J]. J Biol Chem, 2002, 277: 50820-50827.
[233]Lee Y H, Cheng C M, Chang Y F, et al. Apoptin T108 phosphorylation is not required for its tumor-specific nuclear localization but partially affects its apoptotic activity [J]. Biochem Biophys Res Commun, 2007, 354: 391-395.
[234]Leliveld S R, Dame R.T, Rohn J L, et al. Apoptin's functional N- and C-termini independently bind DNA [J]. FEBS Lett, 2004,557:155-158.
[235]Nakayama S, Torikoshi Y, Takahashi T, et al. Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells [J]. Breast Cancer Res, 2009,11:R12.
[236]Gil-Gomez G, Berns A, Brady H J. A link between cell cycle and cell death: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis [J]. EMBO J, 1998,17: 7209-7218.
[237]Liu Q, Fu H, Xing R, et al. Survivin knockdown combined with apoptin overexpression inhibits cell growth significantly [J].Cancer Biol Ther, 2008, 7;1053-1060.
[238]Panigrahi S, Klonisch T, Los M.The art of killing: double stroke with apoptin and survivinas anovelapproachin cancer therapy [J].Cancer Biol Ther, 2008,7:1061-1062.
[239]Lian H, Jin N, Li X, et al. Induction of an effective anti-tumor immune response and tumor regression by combined administration of IL-18 and Apoptin [J]. Cancer Immunol Immunother, 2007,56:181-192.
[240]Li X, Jin N, Mi Z, et al. Antitumor effects of a recombinant fowlpox virus expressing Apoptin in vivo and in vitro [J]. Int J Cancer, 2006,119:2948-2957.
[241]Peng D J, Sun J, Wang JY Z, et al. Inhibition of hepatocarcinoma by systemic delivery of Apoptin gene via the hepatic asialoglycoprotein receptor [J]. Cancer Gene Ther, 2007,14:66-73.
[242]Schoop R A, Baatenburg de Jong R J, Noteborn M H. Apoptin induces apoptosis in an oral cancer mouse model [J]. Cancer Biol Ther, 2008,7:1368-1373.
[243]Tabata T, Sasaki K, Iwabuchi M,. The structural organization and DNA sequence of a wheat histone H4 gene. Nucleic Acids Research. [J] 1983,11: 5865-5875.
[244]Fittipaldi A, Giacca M. Transcellular protein transduction using the Tat protein of HIV-1. Adv Drug Deliv Rev. [J] 2005,57:597-608.
[245]Collins L, Fabre, J W. Synthetic peptide vector system for optimal gene delivery to corneal endothelium. J. Gene Med. [J] 2004,6: 185-194.
[246]Dharap, S S, Wang, Y, Chandna, P, et al.Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide. Proc. Natl. Acad. Sci. U.S.A. [J] 2005,102:12962–12967.
[247]Kaouass, M, Beaulieu, R, Balicki, D. Histonefection: novel and potent non-viral gene delivery. J. Control. Release. [J] 2006,113: 245-254.
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