The Experts below are selected from a list of 2460 Experts worldwide ranked by ideXlab platform
Xiaotang Wang - One of the best experts on this subject based on the ideXlab platform.
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posttranscriptional regulation of the Telomerase htert by gambogic acid in human gastric carcinoma 823 cells
Cancer Letters, 2008Co-Authors: Qing Zhao, Hongyan Gu, Jun Yu, Qi Qi, Yong Yang, Shi Zeng, Na Lu, Xiaotang WangAbstract:We previously reported that gambogic acid (GA), a natural product, was an effective Telomerase Inhibitor by repressing hTERT promoter. In this study, posttranscriptional regulation of the Telomerase hTERT by GA was investigated in BGC-823 human gastric carcinoma cells. The Telomerase activity was detected by PCR-TRAP assay. RT-PCR assay and Western blot were performed to examine the repression of Telomerase hTERT and c-Myc after GA or c-Myc-specific siRNA treatment. The results indicated that GA repressed Telomerase activity and hTERT transcriptional activity via down-regulation of c-Myc expression in BGC-823 human gastric carcinoma cells. We further observed that hTERT transcriptional activity was not completely blocked by c-Myc-specific siRNA, suggesting that additional factors are involved in the repression of Telomerase activity. The results of Western blot and immunoprecipitation assay revealed that GA inhibits the phosphorylation of Akt. The further results also confirmed that celecoxib, an Inhibitor of Akt phosphorylation, could significantly repressed Telomerase activity alone and enhance the repression of Telomerase activity combined with GA. These data suggested that GA inhibits the posttranslational modification of hTERT by inhibiting the phosphorylation of Akt. Collectively, we suggest that GA represses Telomerase activity not only by repressing hTERT transcriptional activity via c-Myc but also by posttranslational modification of hTERT via Akt.
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inhibition of human Telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma smmc 7721 cells
Life Sciences, 2006Co-Authors: Hongyan Gu, Jun Yu, Li Zhao, Qi Qi, Fei Liang, Xiaotang WangAbstract:The activation of human Telomerase, a process regulated by the human Telomerase reverse transcriptase (hTERT), is a crucial step during cellular immortalization and malignant transformation. We have reported that gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburyi tree, is an effective Telomerase Inhibitor and thus displays potent anticancer activity both in vitro and in vivo. Here we present the direct interaction of GA with oncogene c-MYC, a ubiquitous transcription factor involved in the control of cell proliferation and differentiation, as the molecular mechanism of GA's Inhibitory effect on Telomerase activity. Consistent with the recently reported association between c-MYC overexpression and induction of Telomerase activity, we find here that GA treatment of a human hepatoma cell line SMMC-7721 significantly reduced the expression of c-MYC in a time- and concentration-dependent manner accompanied with the down-regulation of the hTERT transcription and the ultimate reduction in Telomerase activity. Our results indicate that the hTERT is a target of c-MYC activity and identify a feasible mechanism of GA's potent anticancer activity.
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inhibition of human Telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma smmc 7721 cells
Life Sciences, 2006Co-Authors: Qinglong Guo, Li Zhao, Fei Liang, Sensen Lin, Qidong You, Zi Tan, Xiaotang WangAbstract:The activation of human Telomerase, a process regulated by the human Telomerase reverse transcriptase (hTERT), is a crucial step during cellular immortalization and malignant transformation. We have reported that gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburyi tree, is an effective Telomerase Inhibitor and thus displays potent anticancer activity both in vitro and in vivo. Here we present the direct interaction of GA with oncogene c-MYC, a ubiquitous transcription factor involved in the control of cell proliferation and differentiation, as the molecular mechanism of GA's Inhibitory effect on Telomerase activity. Consistent with the recently reported association between c-MYC overexpression and induction of Telomerase activity, we find here that GA treatment of a human hepatoma cell line SMMC-7721 significantly reduced the expression of c-MYC in a time- and concentration-dependent manner accompanied with the down-regulation of the hTERT transcription and the ultimate reduction in Telomerase activity. Our results indicate that the hTERT is a target of c-MYC activity and identify a feasible mechanism of GA's potent anticancer activity.
Hongyan Gu - One of the best experts on this subject based on the ideXlab platform.
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posttranscriptional regulation of the Telomerase htert by gambogic acid in human gastric carcinoma 823 cells
Cancer Letters, 2008Co-Authors: Qing Zhao, Hongyan Gu, Jun Yu, Qi Qi, Yong Yang, Shi Zeng, Na Lu, Xiaotang WangAbstract:We previously reported that gambogic acid (GA), a natural product, was an effective Telomerase Inhibitor by repressing hTERT promoter. In this study, posttranscriptional regulation of the Telomerase hTERT by GA was investigated in BGC-823 human gastric carcinoma cells. The Telomerase activity was detected by PCR-TRAP assay. RT-PCR assay and Western blot were performed to examine the repression of Telomerase hTERT and c-Myc after GA or c-Myc-specific siRNA treatment. The results indicated that GA repressed Telomerase activity and hTERT transcriptional activity via down-regulation of c-Myc expression in BGC-823 human gastric carcinoma cells. We further observed that hTERT transcriptional activity was not completely blocked by c-Myc-specific siRNA, suggesting that additional factors are involved in the repression of Telomerase activity. The results of Western blot and immunoprecipitation assay revealed that GA inhibits the phosphorylation of Akt. The further results also confirmed that celecoxib, an Inhibitor of Akt phosphorylation, could significantly repressed Telomerase activity alone and enhance the repression of Telomerase activity combined with GA. These data suggested that GA inhibits the posttranslational modification of hTERT by inhibiting the phosphorylation of Akt. Collectively, we suggest that GA represses Telomerase activity not only by repressing hTERT transcriptional activity via c-Myc but also by posttranslational modification of hTERT via Akt.
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inhibition of human Telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma smmc 7721 cells
Life Sciences, 2006Co-Authors: Hongyan Gu, Jun Yu, Li Zhao, Qi Qi, Fei Liang, Xiaotang WangAbstract:The activation of human Telomerase, a process regulated by the human Telomerase reverse transcriptase (hTERT), is a crucial step during cellular immortalization and malignant transformation. We have reported that gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburyi tree, is an effective Telomerase Inhibitor and thus displays potent anticancer activity both in vitro and in vivo. Here we present the direct interaction of GA with oncogene c-MYC, a ubiquitous transcription factor involved in the control of cell proliferation and differentiation, as the molecular mechanism of GA's Inhibitory effect on Telomerase activity. Consistent with the recently reported association between c-MYC overexpression and induction of Telomerase activity, we find here that GA treatment of a human hepatoma cell line SMMC-7721 significantly reduced the expression of c-MYC in a time- and concentration-dependent manner accompanied with the down-regulation of the hTERT transcription and the ultimate reduction in Telomerase activity. Our results indicate that the hTERT is a target of c-MYC activity and identify a feasible mechanism of GA's potent anticancer activity.
Fei Liang - One of the best experts on this subject based on the ideXlab platform.
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inhibition of human Telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma smmc 7721 cells
Life Sciences, 2006Co-Authors: Hongyan Gu, Jun Yu, Li Zhao, Qi Qi, Fei Liang, Xiaotang WangAbstract:The activation of human Telomerase, a process regulated by the human Telomerase reverse transcriptase (hTERT), is a crucial step during cellular immortalization and malignant transformation. We have reported that gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburyi tree, is an effective Telomerase Inhibitor and thus displays potent anticancer activity both in vitro and in vivo. Here we present the direct interaction of GA with oncogene c-MYC, a ubiquitous transcription factor involved in the control of cell proliferation and differentiation, as the molecular mechanism of GA's Inhibitory effect on Telomerase activity. Consistent with the recently reported association between c-MYC overexpression and induction of Telomerase activity, we find here that GA treatment of a human hepatoma cell line SMMC-7721 significantly reduced the expression of c-MYC in a time- and concentration-dependent manner accompanied with the down-regulation of the hTERT transcription and the ultimate reduction in Telomerase activity. Our results indicate that the hTERT is a target of c-MYC activity and identify a feasible mechanism of GA's potent anticancer activity.
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inhibition of human Telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma smmc 7721 cells
Life Sciences, 2006Co-Authors: Qinglong Guo, Li Zhao, Fei Liang, Sensen Lin, Qidong You, Zi Tan, Xiaotang WangAbstract:The activation of human Telomerase, a process regulated by the human Telomerase reverse transcriptase (hTERT), is a crucial step during cellular immortalization and malignant transformation. We have reported that gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburyi tree, is an effective Telomerase Inhibitor and thus displays potent anticancer activity both in vitro and in vivo. Here we present the direct interaction of GA with oncogene c-MYC, a ubiquitous transcription factor involved in the control of cell proliferation and differentiation, as the molecular mechanism of GA's Inhibitory effect on Telomerase activity. Consistent with the recently reported association between c-MYC overexpression and induction of Telomerase activity, we find here that GA treatment of a human hepatoma cell line SMMC-7721 significantly reduced the expression of c-MYC in a time- and concentration-dependent manner accompanied with the down-regulation of the hTERT transcription and the ultimate reduction in Telomerase activity. Our results indicate that the hTERT is a target of c-MYC activity and identify a feasible mechanism of GA's potent anticancer activity.
Li Zhao - One of the best experts on this subject based on the ideXlab platform.
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inhibition of human Telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma smmc 7721 cells
Life Sciences, 2006Co-Authors: Hongyan Gu, Jun Yu, Li Zhao, Qi Qi, Fei Liang, Xiaotang WangAbstract:The activation of human Telomerase, a process regulated by the human Telomerase reverse transcriptase (hTERT), is a crucial step during cellular immortalization and malignant transformation. We have reported that gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburyi tree, is an effective Telomerase Inhibitor and thus displays potent anticancer activity both in vitro and in vivo. Here we present the direct interaction of GA with oncogene c-MYC, a ubiquitous transcription factor involved in the control of cell proliferation and differentiation, as the molecular mechanism of GA's Inhibitory effect on Telomerase activity. Consistent with the recently reported association between c-MYC overexpression and induction of Telomerase activity, we find here that GA treatment of a human hepatoma cell line SMMC-7721 significantly reduced the expression of c-MYC in a time- and concentration-dependent manner accompanied with the down-regulation of the hTERT transcription and the ultimate reduction in Telomerase activity. Our results indicate that the hTERT is a target of c-MYC activity and identify a feasible mechanism of GA's potent anticancer activity.
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inhibition of human Telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma smmc 7721 cells
Life Sciences, 2006Co-Authors: Qinglong Guo, Li Zhao, Fei Liang, Sensen Lin, Qidong You, Zi Tan, Xiaotang WangAbstract:The activation of human Telomerase, a process regulated by the human Telomerase reverse transcriptase (hTERT), is a crucial step during cellular immortalization and malignant transformation. We have reported that gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburyi tree, is an effective Telomerase Inhibitor and thus displays potent anticancer activity both in vitro and in vivo. Here we present the direct interaction of GA with oncogene c-MYC, a ubiquitous transcription factor involved in the control of cell proliferation and differentiation, as the molecular mechanism of GA's Inhibitory effect on Telomerase activity. Consistent with the recently reported association between c-MYC overexpression and induction of Telomerase activity, we find here that GA treatment of a human hepatoma cell line SMMC-7721 significantly reduced the expression of c-MYC in a time- and concentration-dependent manner accompanied with the down-regulation of the hTERT transcription and the ultimate reduction in Telomerase activity. Our results indicate that the hTERT is a target of c-MYC activity and identify a feasible mechanism of GA's potent anticancer activity.
Kazuo Shinya - One of the best experts on this subject based on the ideXlab platform.
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s stereoisomer of telomestatin as a potent g quadruplex binder and Telomerase Inhibitor
Organic and Biomolecular Chemistry, 2011Co-Authors: Takayuki Doi, Kazuo Shinya, Kazuaki Shibata, Masahito Yoshida, Motoki Takagi, Masayuki Tera, Kazuo Nagasawa, Takashi TakahashiAbstract:Total synthesis of the (S)-stereoisomer of telomestatin (1) was accomplished. (S)-Telomestatin exhibited potency four times that of the natural product, (R)-telomestatin, which was the most potent Telomerase Inhibitor previously reported. In the circular dichroism spectral analysis of the complexes possessing randomly structured single-stranded d[TTAGGG]4 oligonucleotide, (S)-telomestatin, like (R)-telomestatin, induced an antiparallel G-quadruplex structure. The melting temperature (Tm) value of the (S)-isomer complex was greater than that of the (R)-telomestatin complex. Therefore, it is concluded that the stereochemistry of the thiazoline of telomestatin is important to the binding ability of a G-quadruplex binder, and (S)-telomestatin as a G-quadruplex binder is more potent than the natural product.
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g quadruplex stabilization by telomestatin induces trf2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3 telomeric overhang in cancer cells
Oncogene, 2006Co-Authors: Hidetoshi Tahara, Kazuo Shinya, Hiroyuki Seimiya, H Yamada, Takashi TsuruoAbstract:Inhibition of Telomerase activity by Telomerase Inhibitors induces a gradual loss of telomeres, and this in turn causes cancer cells to enter to a crisis stage. Here, we report the Telomerase Inhibitor telomestatin, which is known to stabilize G-quadruplex structures at 3' single-stranded telomeric overhangs (G-tails), rapidly dissociates TRF2 from telomeres in cancer cells within a week, when given at a concentration that does not cause normal cells to die. The G-tails were dramatically reduced upon short-term treatment with the drug in cancer cell lines, but not in normal fibroblasts and epithelial cells. In addition, telomestatin also induced anaphase bridge formation in cancer cell lines. These effects of telomestatin were similar to those of dominant negative TRF2, which also causes a prompt loss of the telomeric G-tails and induces an anaphase bridge. These results indicate that telomestatin exerts its anticancer effect not only through inhibiting telomere elongation, but also by rapidly disrupting the capping function at the very ends of telomeres. Unlike conventional Telomerase Inhibitors that require long-term treatments, the G-quadruplex stabilizer telomestatin induced prompt cell death, and it was selectively effective in cancer cells. This study also identifies the TRF2 protein as a therapeutic target for treating many types of cancer which have the TRF2 protein at caps of the telomere DNA of each chromosome.
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the Telomerase Inhibitor telomestatin induces telomere shortening and cell death in arabidopsis
Biochimica et Biophysica Acta, 2006Co-Authors: Lili Zhang, Kazuo Shinya, Katsunori Tamura, Hideo TakahashiAbstract:The cellular response to telomere dysfunction in plants was investigated with the use of telomestatin, an Inhibitor of human Telomerase activity. Telomestatin bound to plant telomeric repeat sequence, and inhibited Telomerase activity in suspension-cultured cells of Arabidopsis thaliana and Oryza sativa (rice) in a dose-dependent manner. The Inhibitor did not affect transcript level of the TERT gene, which encodes the catalytic subunit of Telomerase, in the plant cells. Inhibition of Telomerase activity by telomestatin resulted in rapid shortening of telomeres and the induction of cell death by an apoptosis-like mechanism in Arabidopsis cells. These results suggest that Telomerase contributes to the survival of proliferating plant cells by maintaining telomere length, and that telomere erosion triggers cell death.
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Telomerase Inhibitor telomestatin a specific mechanism to interact with telomere structure
Nihon rinsho. Japanese journal of clinical medicine, 2004Co-Authors: Kazuo ShinyaAbstract:A novel Telomerase Inhibitor, telomestatin, isolated from Streptomyces anulatus is the most potent Telomerase Inhibitor so far. Telomestatin specifically inhibited Telomerase without affecting reverse transcriptases and polymerases. In addition, telomestatin induced telomere shortening, but its ratio was extremely faster than that observed in physiological telomere shortening. These results suggested the existence of other mechanisms to inhibit Telomerase. Telomeres consist of guanine rich sequences which compose a characteristic three-dimensional structure designated as G-quadruplex. Stabilization of G-quadruplex structure inhibited the catalysis of not only Telomerase but also other DNA interacting molecules. Telomestatin potently stabilized G-quadruplex structure in a specific manner. G-quadruplex structure is also involved in a lot of oncogene promoters. Thus, telomestatin provide the novel therapeutic molecular target for cancer chemotherapy.
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activity of a novel g quadruplex interactive Telomerase Inhibitor telomestatin sot 095 against human leukemia cells involvement of atm dependent dna damage response pathways
Oncogene, 2003Co-Authors: Tetsuzo Tauchi, Kazuo Shinya, Goro Sashida, Masahiko Sumi, Akihiro Nakajima, Takashi Shimamoto, Junko H Ohyashiki, Kazuma OhyashikiAbstract:The Telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive Telomerase Inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited Telomerase activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of Telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 microM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21(CIP1) and p27(KIP1). These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that Telomerase Inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.
