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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李財坤(Tsai-Kun Li) | |
| dc.contributor.author | Ting-Hsiang Huang | en |
| dc.contributor.author | 黃鼎翔 | zh_TW |
| dc.date.accessioned | 2021-06-13T16:27:19Z | - |
| dc.date.available | 2006-07-20 | |
| dc.date.copyright | 2005-07-20 | |
| dc.date.issued | 2005 | |
| dc.date.submitted | 2005-07-14 | |
| dc.identifier.citation | Adams, J. (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell, 5, 417-421.
Andegeko, Y., Moyal, L., Mittelman, L., Tsarfaty, I., Shiloh, Y. and Rotman, G. (2001) Nuclear retention of ATM at sites of DNA double strand breaks. J Biol Chem, 276, 38224-38230. Andoh, T., Ishii, K., Suzuki, Y., Ikegami, Y., Kusunoki, Y., Takemoto, Y. and Okada, K. (1987) Characterization of a mammalian mutant with a camptothecin-resistant DNA topoisomerase I. Proc Natl Acad Sci U S A, 84, 5565-5569. Bakkenist, C.J. and Kastan, M.B. (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature, 421, 499-506. Balajee, A.S. and Geard, C.R. (2004) Replication protein A and gamma-H2AX foci assembly is triggered by cellular response to DNA double-strand breaks. Exp Cell Res, 300, 320-334. Barrows, L.R., Holden, J.A., Anderson, M. and D'Arpa, P. (1998) The CHO XRCC1 mutant, EM9, deficient in DNA ligase III activity, exhibits hypersensitivity to camptothecin independent of DNA replication. Mutat Res, 408, 103-110. Bharti, A.K., Olson, M.O., Kufe, D.W. and Rubin, E.H. (1996) Identification of a nucleolin binding site in human topoisomerase I. J Biol Chem, 271, 1993-1997. Bjornsti, M.A., Benedetti, P., Viglianti, G.A. and Wang, J.C. (1989) Expression of human DNA topoisomerase I in yeast cells lacking yeast DNA topoisomerase I: restoration of sensitivity of the cells to the antitumor drug camptothecin. Cancer Res, 49, 6318-6323. Bjornsti, M.A. and Wang, J.C. (1987) Expression of yeast DNA topoisomerase I can complement a conditional-lethal DNA topoisomerase I mutation in Escherichia coli. Proc Natl Acad Sci U S A, 84, 8971-8975. Brill, S.J. and Sternglanz, R. (1988) Transcription-dependent DNA supercoiling in yeast DNA topoisomerase mutants. Cell, 54, 403-411. Canman, C.E., Lim, D.S., Cimprich, K.A., Taya, Y., Tamai, K., Sakaguchi, K., Appella, E., Kastan, M.B. and Siliciano, J.D. (1998) Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science, 281, 1677-1679. Caserta, M., Camilloni, G., Venditti, S., Venditti, P. and Di Mauro, E. (1994) Conformational information in DNA: its role in the interaction with DNA topoisomerase I and nucleosomes. J Cell Biochem, 55, 93-97. Champoux, J.J. (1976) Evidence for an intermediate with a single-strand break in the reaction catalyzed by the DNA untwisting enzyme. Proc Natl Acad Sci U S A, 73, 3488-3491. Champoux, J.J. (1977) Strand breakage by the DNA untwisting enzyme results in covalent attachment of the enzyme to DNA. Proc Natl Acad Sci U S A, 74, 3800-3804. Chatterjee, S., Cheng, M.F., Trivedi, D., Petzold, S.J. and Berger, N.A. (1989) Camptothecin hypersensitivity in poly(adenosine diphosphate-ribose) polymerase-deficient cell lines. Cancer Commun, 1, 389-394. Cliby, W.A., Lewis, K.A., Lilly, K.K. and Kaufmann, S.H. (2002) S phase and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function. J Biol Chem, 277, 1599-1606. Cromie, G.A., Connelly, J.C. and Leach, D.R. (2001) Recombination at double-strand breaks and DNA ends: conserved mechanisms from phage to humans. Mol Cell, 8, 1163-1174. D'Arpa, P., Beardmore, C. and Liu, L.F. (1990) Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res, 50, 6919-6924. Daroui, P., Desai, S.D., Li, T.K., Liu, A.A. and Liu, L.F. (2004) Hydrogen peroxide induces topoisomerase I-mediated DNA damage and cell death. J Biol Chem, 279, 14587-14594. de Lange, T. (2002) Protection of mammalian telomeres. Oncogene, 21, 532-540. Desai, S.D., Li, T.K., Rodriguez-Bauman, A., Rubin, E.H. and Liu, L.F. (2001) Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. Cancer Res, 61, 5926-5932. Desai, S.D., Liu, L.F., Vazquez-Abad, D. and D'Arpa, P. (1997) Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J Biol Chem, 272, 24159-24164. Desai, S.D., Zhang, H., Rodriguez-Bauman, A., Yang, J.M., Wu, X., Gounder, M.K., Rubin, E.H. and Liu, L.F. (2003) Transcription-dependent degradation of topoisomerase I-DNA covalent complexes. Mol Cell Biol, 23, 2341-2350. Durocher, D. and Jackson, S.P. (2001) DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol, 13, 225-231. El-Khamisy, S.F., Saifi, G.M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J.R. and Caldecott, K.W. (2005) Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature, 434, 108-113. Falck, J., Coates, J. and Jackson, S.P. (2005) Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature, 434, 605-611. Ferreira, M.G., Miller, K.M. and Cooper, J.P. (2004) Indecent exposure: when telomeres become uncapped. Mol Cell, 13, 7-18. Furuta, T., Takemura, H., Liao, Z.Y., Aune, G.J., Redon, C., Sedelnikova, O.A., Pilch, D.R., Rogakou, E.P., Celeste, A., Chen, H.T., Nussenzweig, A., Aladjem, M.I., Bonner, W.M. and Pommier, Y. (2003) Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. J Biol Chem, 278, 20303-20312. Ha, L., Ceryak, S. and Patierno, S.R. (2003) Chromium (VI) activates ataxia telangiectasia mutated (ATM) protein. Requirement of ATM for both apoptosis and recovery from terminal growth arrest. J Biol Chem, 278, 17885-17894. Haluska, P., Jr., Saleem, A., Edwards, T.K. and Rubin, E.H. (1998) Interaction between the N-terminus of human topoisomerase I and SV40 large T antigen. Nucleic Acids Res, 26, 1841-1847. Hertzberg, R.P., Caranfa, M.J. and Hecht, S.M. (1989) On the mechanism of topoisomerase I inhibition by camptothecin: evidence for binding to an enzyme-DNA complex. Biochemistry, 28, 4629-4638. Hsiang, Y.H., Hertzberg, R., Hecht, S. and Liu, L.F. (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem, 260, 14873-14878. Hsiang, Y.H., Lihou, M.G. and Liu, L.F. (1989) Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res, 49, 5077-5082. Hsiang, Y.H. and Liu, L.F. (1988) Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res, 48, 1722-1726. Hsiang, Y.H. and Liu, L.F. (1989) Evidence for the reversibility of cellular DNA lesion induced by mammalian topoisomerase II poisons. J Biol Chem, 264, 9713-9715. Huang, T.T., Wuerzberger-Davis, S.M., Seufzer, B.J., Shumway, S.D., Kurama, T., Boothman, D.A. and Miyamoto, S. (2000) NF-kappaB activation by camptothecin. A linkage between nuclear DNA damage and cytoplasmic signaling events. J Biol Chem, 275, 9501-9509. Jesenberger, V. and Jentsch, S. (2002) Deadly encounter: ubiquitin meets apoptosis. Nat Rev Mol Cell Biol, 3, 112-121. Karlseder, J., Broccoli, D., Dai, Y., Hardy, S. and de Lange, T. (1999) p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science, 283, 1321-1325. Kastan, M.B. and Lim, D.S. (2000) The many substrates and functions of ATM. Nat Rev Mol Cell Biol, 1, 179-186. Kastan, M.B., Lim, D.S., Kim, S.T., Xu, B. and Canman, C. (2000) Multiple signaling pathways involving ATM. Cold Spring Harb Symp Quant Biol, 65, 521-526. Kaufmann, S.H. (1998) Cell death induced by topoisomerase-targeted drugs: more questions than answers. Biochim Biophys Acta, 1400, 195-211. Kozlov, S., Gueven, N., Keating, K., Ramsay, J. and Lavin, M.F. (2003) ATP activates ataxia-telangiectasia mutated (ATM) in vitro. Importance of autophosphorylation. J Biol Chem, 278, 9309-9317. Lenz, H.J. (2003) Clinical update: proteasome inhibitors in solid tumors. Cancer Treat Rev, 29 Suppl 1, 41-48. Li, L.H., Fraser, T.J., Olin, E.J. and Bhuyan, B.K. (1972) Action of camptothecin on mammalian cells in culture. Cancer Res, 32, 2643-2650. Li, T.K., Houghton, P.J., Desai, S.D., Daroui, P., Liu, A.A., Hars, E.S., Ruchelman, A.L., LaVoie, E.J. and Liu, L.F. (2003) Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug. Cancer Res, 63, 8400-8407. Li, T.K. and Liu, L.F. (2001) Tumor cell death induced by topoisomerase-targeting drugs. Annu Rev Pharmacol Toxicol, 41, 53-77. Lisby, M., Barlow, J.H., Burgess, R.C. and Rothstein, R. (2004) Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell, 118, 699-713. Lisby, M. and Rothstein, R. (2004) DNA repair: keeping it together. Curr Biol, 14, R994-996. Liu, L.F., Desai, S.D., Li, T.K., Mao, Y., Sun, M. and Sim, S.P. (2000) Mechanism of action of camptothecin. Ann N Y Acad Sci, 922, 1-10. Mao, Y., Desai, S.D., Ting, C.Y., Hwang, J. and Liu, L.F. (2001) 26 S proteasome-mediated degradation of topoisomerase II cleavable complexes. J Biol Chem, 276, 40652-40658. Mattern, M.R., Kerrigan, D.J. and Pommier, Y. (1987) Nucleoid sedimentation analysis of DNA strand breaks induced in cells exposed to DNA intercalating agents. Pharmacol Ther, 34, 303-319. Morgan, S.E. and Kastan, M.B. (1997) p53 and ATM: cell cycle, cell death, and cancer. Adv Cancer Res, 71, 1-25. Morris, E.J. and Geller, H.M. (1996) Induction of neuronal apoptosis by camptothecin, an inhibitor of DNA topoisomerase-I: evidence for cell cycle-independent toxicity. J Cell Biol, 134, 757-770. Pandita, T.K., Lieberman, H.B., Lim, D.S., Dhar, S., Zheng, W., Taya, Y. and Kastan, M.B. (2000) Ionizing radiation activates the ATM kinase throughout the cell cycle. Oncogene, 19, 1386-1391. Panta, G.R., Kaur, S., Cavin, L.G., Cortes, M.L., Mercurio, F., Lothstein, L., Sweatman, T.W., Israel, M. and Arsura, M. (2004) ATM and the catalytic subunit of DNA-dependent protein kinase activate NF-kappaB through a common MEK/extracellular signal-regulated kinase/p90(rsk) signaling pathway in response to distinct forms of DNA damage. Mol Cell Biol, 24, 1823-1835. Park, S.Y., Lam, W. and Cheng, Y.C. (2002) X-ray repair cross-complementing gene I protein plays an important role in camptothecin resistance. Cancer Res, 62, 459-465. Pizzolato, J.F. and Saltz, L.B. (2003) The camptothecins. Lancet, 361, 2235-2242. Plo, I., Liao, Z.Y., Barcelo, J.M., Kohlhagen, G., Caldecott, K.W., Weinfeld, M. and Pommier, Y. (2003) Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. DNA Repair (Amst), 2, 1087-1100. Pommier, Y., Redon, C., Rao, V.A., Seiler, J.A., Sordet, O., Takemura, H., Antony, S., Meng, L., Liao, Z., Kohlhagen, G., Zhang, H. and Kohn, K.W. (2003) Repair of and checkpoint response to topoisomerase I-mediated DNA damage. Mutat Res, 532, 173-203. Porter, S.E. and Champoux, J.J. (1989) The basis for camptothecin enhancement of DNA breakage by eukaryotic topoisomerase I. Nucleic Acids Res, 17, 8521-8532. Pouliot, J.J., Robertson, C.A. and Nash, H.A. (2001) Pathways for repair of topoisomerase I covalent complexes in Saccharomyces cerevisiae. Genes Cells, 6, 677-687. Pouliot, J.J., Yao, K.C., Robertson, C.A. and Nash, H.A. (1999) Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes. Science, 286, 552-555. Rolfe, M., Chiu, M.I. and Pagano, M. (1997) The ubiquitin-mediated proteolytic pathway as a therapeutic area. J Mol Med, 75, 5-17. Samejima, K., Svingen, P.A., Basi, G.S., Kottke, T., Mesner, P.W., Jr., Stewart, L., Durrieu, F., Poirier, G.G., Alnemri, E.S., Champoux, J.J., Kaufmann, S.H. and Earnshaw, W.C. (1999) Caspase-mediated cleavage of DNA topoisomerase I at unconventional sites during apoptosis. J Biol Chem, 274, 4335-4340. Sancar, A., Lindsey-Boltz, L.A., Unsal-Kacmaz, K. and Linn, S. (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem, 73, 39-85. Sastry, S. and Ross, B.M. (1998) Mechanisms for the processing of a frozen topoisomerase-DNA conjugate by human cell-free extracts. J Biol Chem, 273, 9942-9950. Shaiu, W.L. and Hsieh, T.S. (1998) Targeting to transcriptionally active loci by the hydrophilic N-terminal domain of Drosophila DNA topoisomerase I. Mol Cell Biol, 18, 4358-4367. Shao, R.G., Cao, C.X., Zhang, H., Kohn, K.W., Wold, M.S. and Pommier, Y. (1999) Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes. Embo J, 18, 1397-1406. Shay, J.W. and Wright, W.E. (2004) Telomeres are double-strand DNA breaks hidden from DNA damage responses. Mol Cell, 14, 420-421. Shiloh, Y. (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer, Vol. 3, pp. 155-168. Siu, W.Y., Lau, A., Arooz, T., Chow, J.P., Ho, H.T. and Poon, R.Y. (2004) Topoisomerase poisons differentially activate DNA damage checkpoints through ataxia-telangiectasia mutated-dependent and -independent mechanisms. Mol Cancer Ther, 3, 621-632. Smith, P.J., Makinson, T.A. and Watson, J.V. (1989) Enhanced sensitivity to camptothecin in ataxia-telangiectasia cells and its relationship with the expression of DNA topoisomerase I. Int J Radiat Biol, 55, 217-231. Smogorzewska, A. and de Lange, T. (2004) Regulation of telomerase by telomeric proteins. Annu Rev Biochem, 73, 177-208. Sordet, O., Liao, Z., Liu, H., Antony, S., Stevens, E.V., Kohlhagen, G., Fu, H. and Pommier, Y. (2004) Topoisomerase I-DNA complexes contribute to arsenic trioxide-induced apoptosis. J Biol Chem, 279, 33968-33975. Squires, S., Ryan, A.J., Strutt, H.L. and Johnson, R.T. (1993) Hypersensitivity of Cockayne's syndrome cells to camptothecin is associated with the generation of abnormally high levels of double strand breaks in nascent DNA. Cancer Res, 53, 2012-2019. Stewart, L., Ireton, G.C. and Champoux, J.J. (1996) The domain organization of human topoisomerase I. J Biol Chem, 271, 7602-7608. Takai, H., Smogorzewska, A. and de Lange, T. (2003) DNA damage foci at dysfunctional telomeres. Curr Biol, 13, 1549-1556. Theard, D., Coisy, M., Ducommun, B., Concannon, P. and Darbon, J.M. (2001) Etoposide and adriamycin but not genistein can activate the checkpoint kinase Chk2 independently of ATM/ATR. Biochem Biophys Res Commun, 289, 1199-1204. Thomsen, B., Mollerup, S., Bonven, B.J., Frank, R., Blocker, H., Nielsen, O.F. and Westergaard, O. (1987) Sequence specificity of DNA topoisomerase I in the presence and absence of camptothecin. Embo J, 6, 1817-1823. Ting, N.S. and Lee, W.H. (2004) The DNA double-strand break response pathway: becoming more BRCAish than ever. DNA Repair (Amst), 3, 935-944. Trask, D.K. and Muller, M.T. (1988) Stabilization of type I topoisomerase-DNA covalent complexes by actinomycin D. Proc Natl Acad Sci U S A, 85, 1417-1421. Trigueros, S. and Roca, J. (2002) Failure to relax negative supercoiling of DNA is a primary cause of mitotic hyper-recombination in topoisomerase-deficient yeast cells. J Biol Chem, 277, 37207-37211. Tsao, Y.P., Russo, A., Nyamuswa, G., Silber, R. and Liu, L.F. (1993) Interaction between replication forks and topoisomerase I-DNA cleavable complexes: studies in a cell-free SV40 DNA replication system. Cancer Res, 53, 5908-5914. Wall, M.E., Taylor, H., Ambrosio, L. and Davis, K. (1969) Plant antitumor agents. A convenient separation of tannins from other plant constituents. J Pharm Sci, 58, 839-841. Walowsky, C., Fitzhugh, D.J., Castano, I.B., Ju, J.Y., Levin, N.A. and Christman, M.F. (1999) The topoisomerase-related function gene TRF4 affects cellular sensitivity to the antitumor agent camptothecin. J Biol Chem, 274, 7302-7308. Wan, S., Capasso, H. and Walworth, N.C. (1999) The topoisomerase I poison camptothecin generates a Chk1-dependent DNA damage checkpoint signal in fission yeast. Yeast, 15, 821-828. Wang, J.C. (1971) Interaction between DNA and an Escherichia coli protein omega. J Mol Biol, 55, 523-533. Wang, J.C. (1985a) DNA topoisomerases. Annu Rev Biochem, 54, 665-697. Wang, J.C. (1985b) DNA topoisomerases: nature's solution to the topological ramifications of the double-helix structure of DNA. Harvey Lect, 81, 93-110. Wang, J.C. (1996) DNA topoisomerases. Annu Rev Biochem, 65, 635-692. Wassermann, K., Markovits, J., Jaxel, C., Capranico, G., Kohn, K.W. and Pommier, Y. (1990) Effects of morpholinyl doxorubicins, doxorubicin, and actinomycin D on mammalian DNA topoisomerases I and II. Mol Pharmacol, 38, 38-45. Watson, J.D. and Crick, F.H. (1953) Genetical implications of the structure of deoxyribonucleic acid. Nature, 171, 964-967. Watters, D.J. (2003) Oxidative stress in ataxia telangiectasia. Redox Rep, 8, 23-29. Wu, J. and Liu, L.F. (1997) Processing of topoisomerase I cleavable complexes into DNA damage by transcription. Nucleic Acids Res, 25, 4181-4186. Xu, Y. (2003) Regulation of p53 responses by post-translational modifications. Cell Death Differ, 10, 400-403. Xu, Y. and Villalona-Calero, M.A. (2002) Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol, 13, 1841-1851. Yamashita, Y., Kawada, S., Fujii, N. and Nakano, H. (1991) Induction of mammalian DNA topoisomerase I and II mediated DNA cleavage by saintopin, a new antitumor agent from fungus. Biochemistry, 30, 5838-5845. Yang, J., Yu, Y., Hamrick, H.E. and Duerksen-Hughes, P.J. (2003) ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses. Carcinogenesis, 24, 1571-1580. Yang, S.W., Burgin, A.B., Jr., Huizenga, B.N., Robertson, C.A., Yao, K.C. and Nash, H.A. (1996) A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. Proc Natl Acad Sci U S A, 93, 11534-11539. Zhou, B.B. and Bartek, J. (2004) Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer, 4, 216-225. Zhou, B.B. and Elledge, S.J. (2000) The DNA damage response: putting checkpoints in perspective. Nature, 408, 433-439. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/38166 | - |
| dc.description.abstract | 第一型去氧核糖核酸拓蹼異構酶(DNA topoisomerase I)目標藥物，喜樹鹼(camptothecin)，為一種針對複製期細胞特性的抗癌藥物。目前對細胞經抗癌藥物camptothecin 處理所引起之細胞反應仍未明瞭。近來研究陸續顯示，在高濃度camptothecin 處理下，對非複製期與不具週期性的細胞造成毒殺作用，而camptothecin 亦能引起與複製無關的細胞反應，例如: 轉錄作用(transcription)引發之topoisomerase I-DNA 可切性複合體(cleavable complex)遭蛋白解體(proteasome)程序降解(degradation)。本篇論文指出，由camptothecin 對細胞所誘發的DNA 損壞訊息(DNA damage signals)，例如: ATM 蛋白的自體磷酸化(autophosphorylation)，細胞週期有關的Chk2蛋白與腫瘤抑制蛋白p53 的磷酸化現象，在處以藥物抑制細胞轉錄作用後(阻礙topoisomerase I-DNA 可切性複合體降解)，能降低蛋白磷酸化程度。此外，利用蛋白解體抑制劑亦能減少由camptothecin 引起DNA 損壞訊息活化程度，達到與細胞轉錄作用抑制劑雷同的效果。綜合上述實驗結果，我們推論: 轉錄作用引發之topoisomerase I-DNA 可切性複合體遭蛋白解體程序降解能有效暴露DNA 斷點(DNA breaks)。本篇論文顯示，RNA 聚合酶(RNA polymerase)與topoisomerase I-DNA 可切性複合物之間的撞擊，與伴隨而來的可切性複合體遭蛋白解體降解，在camptothecin所引起非複製期細胞之細胞反應與毒害效果上，扮演不可或缺的決定性角色。 | zh_TW |
| dc.description.abstract | Camptothecin, a DNA topoisomerase I-targeting drug, has been suggested to be a S-phase specific anticancer drug. However, the cellular responses to camptothecin remain largely unclear. Recent studies indicated that the high concentration of camptothecin could kill the non-S phase and non-cycling cells. In addition, camptothecin also induces the replication-independent cellular responses, such as the transcription- and proteasome-dependent degradation of topoisomerase I-DNA cleavable complexes. In this thesis, we showed that inhibition of RNA transcription, thereby blocking topoisomerase I-DNA cleavable complexes degradation, prevented various camptothecin-induced DNA damage signals, e.g. ATM autophosphorylation, phosphorylation of Chk2 and p53 activation. Proteasome inhibitors also prevented the activation of camptothecin-induced signaling pathways like transcription inhibitors did. Taken together, our results indicate that the transcription- dependent and proteasome-mediated degradation of topoisomerase I-DNA cleavable complexes removes topoisomerase I away from DNA damage and thereby exposes DNA breaks. Our results suggest a novel pathway in which the collision between RNA polymerase and cleavable complexes coupled with subsequent proteasomal degradation of topoisomerase-DNA cleavable complexes play essential roles in determining cellular responses and cytotoxicity of camptothecin in the non-S phase cells. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T16:27:19Z (GMT). No. of bitstreams: 1 ntu-94-R92445104-1.pdf: 3201951 bytes, checksum: 825400465ab5803e0c54c45911aceccb (MD5) Previous issue date: 2005 | en |
| dc.description.tableofcontents | 中 文 摘 要 …………………………………………………………………………1
ABSTRACT …………………………………………………………………………..2 INTRODUCTION …………………………………………………………………….3 1. Ataxia telangiectasia mutated and DNA damage signaling pathways 1-1. Activation of ATM kinase 1-2. ATM-mediated DNA damage signaling pathways 1-3. The importance of ATM kinase 2. Topoisomerase 2-1. Structure of TOP1 2-2. Functions of TOP1 2-3. Formation of TOP1 cleavable complex 3. Camptothecin 3-1 History 3-2 Mechanism(s) of action 3-3 Other TOP1-targeting compounds 4. The processing of TOP1-mediated DNA damage 4-1. Collisions between TOP1 cleavable complexes and replication forks (the replication collision model) 4-2. Collisions between TOP1cleavable complexes and RNA polymerase (the transcription collision model) 4-3. Proteolytic processing pathways for DNA TOP1 SPECIFIC AIMS …………………………………………………………………….18 MATERIAL & METHODS …………………………………………………………19 - Cell lines and cell culture condition - Chemicals - Antibodies - Preparing for cell lysates - Western blot analysis - In vitro ATM kinase assay - Immunofluorescence Assay RESULTS ……………………………………………………………………………23 - Autophosphorylation of ATM and ATM foci formation induced by CPT - ATM kinase activity is activated in vitro in CPT-treated cellular extract - Activation of p53 and multiple signal transducers by CPT - Inhibition of transcription effectively blocks CPT-mediated autophosphorylation of ATM on Ser1981 and phosphorylation of p53 on Ser15 - The inhibitory effect of DRB on CPT-induced cellular responses is specifically dependent on its ability to inhibit transcription elongation - Aphidicolin and DRB attenuate distinct signaling pathways activated by CPT - Proteolytic degradation of TOP1 is in part responsible for various CPT-activated DNA damage pathways - TRIP of, but not RIP of, DNA TOP1 cleavable complexes is required for formation of ATM foci - The TRIP pathway-associated cellular responses occurred only in CPT-treated, but not in IR-treated cells DISCUSSIONS ……………………………………………………………………...34 - The roles of PIKK family in TOP1-capped DNA damage - Distinct pathways arise from TRIP and RIP of TOP1-mediated DNA damage: determinants of cellular responses with potential clinical relevance -The linkage between the cellular proteolytic pathways and processing pathways of TOP1-capped DNA damage - The specificity of TRIP pathways for protein-linked DNA damage and its implications - Conclusion remarks FIGURES ……………………………………………………………………………43 - Figure 1 - Figure 2 - Figure 3 - Figure 4 - Figure 5 - Figure 6 - Figure 7 - Figure 8 - Figure 9 APPENDIXES ...………………………………………………………………….…53 - Appendix 1 - Appendix 2 REFERENCES ……………………………………………………………………....57 | |
| dc.language.iso | en | |
| dc.subject | 可切性複合體 | zh_TW |
| dc.subject | 拓蹼異構酶 | zh_TW |
| dc.subject | 轉錄作用 | zh_TW |
| dc.subject | 喜樹鹼 | zh_TW |
| dc.subject | topoisomerase I | en |
| dc.subject | proteasome | en |
| dc.subject | transcription | en |
| dc.subject | cleavable complex | en |
| dc.subject | ATM | en |
| dc.title | 轉錄作用調控DNA 損壞訊息路徑活化之探討 | zh_TW |
| dc.title | Transcription-mediated activation of DNA damage
signaling pathway | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 93-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林敬哲(Jing-Jer Lin),鄧述諄(Shu-Chun Teng) | |
| dc.subject.keyword | 拓蹼異構酶,轉錄作用,喜樹鹼,可切性複合體, | zh_TW |
| dc.subject.keyword | topoisomerase I,ATM,cleavable complex,transcription,proteasome, | en |
| dc.relation.page | 64 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2005-07-15 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-94-1.pdf 未授權公開取用 | 3.13 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。