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Transcript Regulation of Human Telomerase Reverse Transcriptase by c-myc and mad1

Acta Biochimica et Biophysica Sinica 2005年第1期37卷 32-38页

作者： Lin ZOU~# Peng-Hui ZHANG Chun-Li LUO Zhi-Guang TU~* Faculty of Laboratory Medicine,Chongqing University of Medical Sciences.Chongqing 400016,China Faculty of Laboratory Medicine Chongqing University of Medical SciencesChongqing 400016 China

Telomerase activity is highly positive correlated to most malignant *** telomerasereverse transcriptase(htert)is the rate-limiting factor of telomerase *** studies have shownthat the expression of htert is mainly determined by its transcript *** the transcript regula-tion factors of htert,c-myc and mad 1 are well ***,we constructed c-myc and madl eukaryoticexpression vectors,then co-transfected them with the wild-type(Tw)or mutant htert promoter(Td)luciferase reporter plasmid,which were double-mutated in the E-box sequences from CACGTG to CACCTGof *** change of luciferase activity in different cells was *** results showed that Tw wasobviously activated in T24 and EJ bladder cancer cells,but not in normal fibrocytes,c-myc and madl hadpositive and negative effects respectively on the Tw transcript in a dose-dependent manner,while the roles ofc-myc and madl in regulating the Td transcript were reversed,c-myc combined with madl can down-regulate Tw but not *** observations indicate that c-myc and madl can regulate the htert transcriptin a different manner in htert positive cells,but not in normal *** may provide an insight into sometelornerase-related carcinogenesis mechanisms.

关键词： c-myc: mad1 htert promoter transcript regulation

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Antitumor Effect of a Novel Adeno-associated Virus Vector Targeting to Telomerase Activity in Tumor Cells

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Acta Biochimica et Biophysica Sinica 2004年第7期36卷 492-500页

作者： Yi-Gang WANG1,2#, Jin-Hui WANG1#, Yan-Hong ZHANG1, Qing GU2*, and Xin-Yuan LIU1* 1Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China School of Life Science, Nanchang University, Nanchang 330047, China Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Graduate School of the Chinese Academy of SciencesShanghai 200031 China School of Life Science Nanchang UniversityNanchang 330047 China

Telomerase activity is a wide tumor marker. Human telomerase reverse transcriptase (htert), the catalytic subunit of the telomerase, is transcriptionally upregulated exclusively in about 90% of cancer cells. In this study, we constructed a novel adeno-associated virus (AAV) vector containing the human interferon-β (hIFN-β) gene under the control of htert promoter (AAV-htert-hIFN-β) and investigated its antitumor effect against various human cancer cells in vitro. AAV-htert-hIFN-β displayed cancer-specific hIFN-β expression and cytotoxicity. The cytotoxic ratio was positively correlated with the time length of infection. AAV-htert-hIFN-β-mediated apoptotic morphology was observed by transmission electron microscopy. Flow cytometry assay also revealed that the cytotoxicity of AAV-htert-hIFN-β was mainly an apoptotic process. These data indicate that AAV in combination with htert-mediated therapeutic gene expression may open new possibilities for long-lasting and targeting gene therapy of varieties of cancers.

关键词： adeno-associated virus (AAV) telomerase htert promoter human interferon-β cancer

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htert-targeted *** purine nucleoside phosphorylase gene/ 6-methylpurine deoxyribose therapy for pancreatic cancer

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Chinese Medical Journal 2007年第15期120卷 1348-1352页

作者： ZHOU Jia-hua TANG Bo LIU Xun-liang HE Dao-wei YANG De-tong Department of Biliary-Pancreatic Surgery First Affiliated Hospital of Nanjing Medical University Nanjing 210029 China National Key Opening Laboratory of Biology and Medicine and Pharmacology Technology Nanjing University Nanjing 210008 China Clinical Medicine School of Southeast University Nanjing 210009 China Department of Biliary-Pancreatic Surgery Zhongda Hospital of Southeast University Nanjing 210009 China

Background Pancreatic cancer is one of the most common tumors and has a 5-year survival for all stages of less than 5%. Most patients with pancreatic cancer are diagnosed at an advanced stage and therefore are not candidates for surgical resection. In recent years, investigation into alternative treatment strategies for this aggressive disease has led to advances in the field of gene therapy for pancreatic cancer. E. coil purine nucleoside phosphorylase/6-methylpurine deoxyribose （ePNP/MePdR） is a suicide gene/prodrug system where PNP enzyme cleaves nontoxic MePdR into cytotoxic membrane-permeable compounds 6-methylpurine （MeP） with high bystander activity, htert is expressed in cell lines and tissues for telomerase activity. In this study we examined the efficacy of ePNP under the control of htert promoter sequences and assessed the selective killing effects of the ePNP/prodrug MePdR system on pancreatic tumors. Methods Recombinant pET-PNP was established. The protein of E. coil PNPase was expressed and an antibody to E. coil PNPase was prepared. Transcriptional activities of htert promoter sequences were analyzed using a luciferase reporter gene. A recombinant phtert-ePNP vector was constructed. The ePNP/MePdR system affects SW1990 human pancreatic cancer cell lines in vitro. Results The htert promoter had high transcriptional activity and conferred specificity on cancer cell lines. The antibody to E. coil PNPase was demonstrated to be specific for the ePNP protein. The MePdR treatment induced a high in vitro cytotoxicity on the sole htert-ePNP-producing cell lines and affected SW1990 cells in a dose-dependent manner. Conclusions The htert promoter control of the ePNP/MePdR system can provide a beneficial anti-tumor treatment in pancreatic cancer cell lines including a good bystander killing effect.

关键词： htert promoter Escherichia coli purinenucleoside phosphorylase pancreatic cancer gene therapy

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Increased Activity of the Human Telomerase Catalytic Subunit promoter by the VEGF Enhancer in Human Cancer Cells

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International Journal of Technology Management 2014年第9期 140-142页

作者： Huwei1 Mengxingyu Tianyuhua Zangyujing Hurui College of Life Sciences Jilin Agriculture University Jilin Province China College of Agriculture Eastern Liaoning University Liaoning Province China

We attempted to improve the activity of htert promoter by fusing the vascular endothelial growth factor （VEGF） enhancer. To determine the potential as cancer specific promoters, we measured the reporter gene transfection assay driven by the htert promoter and the VEGF enhancer in human cancer cells. We found that the htert promoter containing VEGF enhancer conferred strong expression of the reporter gene only in different cancer cell lines but not in normal human cells. Retrovirus vector expressing HSV-TK controlled by the htert promoter and the VEGF enhancer was constructed. A549 cells infected with LN-enh-hT-TK was significantly suppressed and induced to apoptosis more than those infected with LN-hT-TK. The apoptosis ratio ofA549 cell infected with two kinds of retrovirus cell with GCV in lower concentration is 20.94% and 50.7%. It suggested that there is significant differentiation between the assay groups. Our results demonstrated the possible application of htert promoter and the VEGF enhancer in targeted cancer gene therapy.

关键词： htert promoter VEGF enhancer retrovirus targeted cancer gene therapy

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Suppression of Colorectal Cancer Growth by a Novel Adeno-associated Virus Vector-mediated IFN-β through Targeting the Telomerase Activity in vivo

Suppression of Colorectal Cancer Growth by a Novel Adeno-ass...

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华东六省一市生物化学与分子生物学会2008年学术交流会

作者： Yigang Wang~1 Lingfeng He~(1,2) Fang Huang~1 1 Kangjiang Zhang~1 Gongchu Li~1 Guoqing He~1 Xinyuan Liu~(1,2) (1 Xinyuan Institute of Medicine and Biotechnology,College of Life Science,Zhejiang Sci-Tech University 2 Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai 200031,China.)

Although the antiviral actions of interferons(IFNs)are fast observed,up to date,Type I IFNs(α/β)protein have been widely used as a clinical anticancer agent due to their antiproliferative effects via induction of apoptosis,activation of antitumor immunity and inhibition of angiogenesis ***,there are some limitations in antitumoral clinical trials of type I IFNs such as short halt-life and systemic toxicity at high ***-associated virus (AAV)has rapidly become a promising gene delivery vehicle for its excellent advantage of nonimmunogenic,low pathogenicity and long-term gene ***,lack of tissue specificity caused low efficiency of AAV transfer to target *** application of human telomerase reverse transcriptase(htert)promoter is a good targeting strategy for AAV in cancer gene therapy as htert is transcriptionally upregulated in most cancer ***,htert promoter becomes a prior candidate to improve the targeting of *** present work,a novel tumor targeting AAV harbouring IFN-βgene under the control of htert promoter(AAV-htert-IFN-β) was ***-βexpression was observed in tumor cells infected with AAV-htert-IFN-βAAV-htert-IFN-βdisplayed cancer-specific cytotoxicity and induced tumor cell apoptosis via activation of caspase pathway and release of cytochrome ***,in animal experiments, administration of AAV-htert-IFN-βsignificantly suppressed the growth of colorectal cancer xenograft and resulted in tumor cells *** data suggested that AAVs in combination with htert-mediated IFN-βexpression could exert potential antitumor activity and provide a novel targeting approach to cancer therapy.

关键词： Type I IFNs(α/β) Adeno-associated virus htert promoter antitumor efficacy

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