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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 李財坤(Tsai-Kun Li) | |
dc.contributor.author | Chia-Chin Tsai | en |
dc.contributor.author | 蔡佳芷 | zh_TW |
dc.date.accessioned | 2021-06-13T15:46:55Z | - |
dc.date.available | 2013-08-13 | |
dc.date.copyright | 2008-08-13 | |
dc.date.issued | 2008 | |
dc.date.submitted | 2008-06-30 | |
dc.identifier.citation | Abdulla, M. & Chmielnicka, J. (1989) New aspects on the distribution and metabolism of essential trace elements after dietary exposure to toxic metal. Biol Trace Elem Res 23, 25-53.
Acan, N.L. & Tezcan, E.F. (1995) Inhibition kinetics of sheep brain glutathione reductase by cadmium ion. Biochem Mol Med 54, 33-37. Asmuss, M., Mullenders, L.H., Eker, A. & Hartwig, A. (2000) Differential effects of toxic metal compounds on the activities of Fpg and XPA, two zinc finger proteins involved in DNA repair. Carcinogenesis 21, 2097-2104. Aruoma, O.I., Halliwell, B., Hoey, B.M. & Butler, J. (1989) The antioxidant action of N-acetylcysteine : its reaction with hydrogen peroxide, hydroxyl radical, superoxide and hypochlorous acid. Free Rad Biol Med 6, 593-597. Bader, N. & Grune, T. (2006) Protein oxidation and proteolysis. Biol Chem 387 1351-1355. Bartoli, M. & Richard, I. (2005) Calpains in muscle wasting. Biochem 37, 2115-2133. Be´chet, D., Tassa, A., Taillandier, D., Combaret, L., & Attaix, D. (2005) Lysosomal proteolysis in skeletal muscle. Biochem 37, 2098-2114. Champoux, J.J. (2001) DNA topoisomerases : structure, function and mechanism. Annu Rev Biochem 70, 369-413. Chang, S., Hu, T. & Hsieh, T.S. (1998) Analysis of a core domain in Drosophila DNA topoisomerase II. Targeting of an antitumor agent ICRF-159. J Biol Chem 273, 19822-19828. Chun, Y.S., Choi, E., Kim, G.T., Choi, H., Kim, C.H., Lee, M.J., Kim, M.S. & Park, J.W. (2000) Cadmium blocks hypoxia-inducible factor (HIF)-1-mediated response to hypoxia by stimulating the proteasome-dependent degradation of HIF-1 alpha. Eur J Biochem 267, 4198-4204. Combs, G.F., Jr, & Gray, W.P. (1998) Chemopreventive agents : selenium. Pharmacol Ther 79, 179-192. Dally, H. & Hartwig, A. (1997) Induction and repair inhibition of oxidative DNA damage by nickel(II) and cadmium(II) in mammalian cells. Carcinigenesis 18, 1021-1026. Desai, S. D., Liu, L. F., Vazquez-Abad, D. & 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., Li, T.K., Rodriguez-Bauman, A., Rubin, E.H. & Liu, L.F. (2001) Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as aresistance mechanism to camptothecin in tumor cells. Cancer Res 61, 5926-5932. Devi, K.D., Banu, B.S., Mahboob, M., Jamil, K. & Grover, P. (2001) In vivo genotoxic effect of cadmium chloride in mice leukocytes using comet assay. Teratog Carcinog Mutagen 21, 325-333. Di Simplicio, P., Lupis, E. & Rossi, R. (1996) Biochim Biophys Acta 1289, 252-260. Fan, J.R., Peng, A.L., Chen, H.C., Lo, S.C., Huang, T.H. & Li, T.K. (2008) Cellular processing pathways contribute to the activation of etoposide-induced DNA damage responses. DNA repair (In press) Figueiredo-Pereira, M.E., Yakushin, S. & Cohen, G. (1998) Disruption of the intracellular sulfhydryl homeostasis by cadmium-induced oxidative stress leads to protein thiolation and ubiquitination in neuronal cells. J Biol Chem 273, 12703-12709. Filipic, M., Fatur, T. & Vudrag, M. (2006) Molecular mechanisms of cadmium induced mutagenicity. Hum Exp Toxicol 25, 67-77. Friberg, L., Kjellstrom, T. & Nordberg, G.F. (1986) Cadmium. Handbook on the toxicology of metals, 2nd edition. 84, 130. Goering, P.L., Waalkes, M.P. & Klaassen, C.D. (1994) Handbook of experimental pharmacology: toxicology of metals, biochemical effects. Toxicology of cadmium 115, 189-214. Grune, T., Reinheckel, T. & Davies, K.J. (1997) Degradation of oxidized proteins in mammalian cells. FASEB J 11, 526-534. Heddle, J.G., Barnard, F.M., Wentzell, L.M. & Maxwell, A. (2000) The interaction of drugs with DNA gyrase : a model for the molecular basis of quinolone action. Nucleosides Nucleotides Nucleic Acids 19, 1249-1264. Hedstrom, L. (2002) Serine Protease Mechanism and Specificity. Chem Rev 102, 4501-4523. Horiguchi, H., Teranishi, H., Niiya, K., Aoshima, K., Katoh, T., Sakuragawa, N. & Kasuya, M. (1994) Hypoproduction of erythropoietin contributes to anemia in chronic cadmium intoxication : clinical study on Itai-iai disease in Japen. Arch Toxicol 68, 632-636. Horiguchi, H., Sato, M., Konno, N. & Fukushima, M. (1996) Long-term cadmium exposure induces anemia in rats through hypoinduction of erythropoietin in the kidneys. Arch Toxicol 71, 11-19. Horiguchi, H. (2007) Anemia induced by cadmium intoxication. Nippon Eiseigaku Zasshi 62, 888-904. Ishizaki, A. & Funkushima, M. (1968) Studies on 'Itai-itai' disease (Review). Nippon Eiseigaku Zasshi 23, 271-285. Jin, T., Lu, J. & Nordberg, M. (1998) Toxicokinetics and biochemistry of cadmium with special emphasis on the role of metallothionein. Neurotoxicology 19, 529-535. Kasprzak, K.S. (2002) Oxidative DNA and protein damage in metal-induced toxicity and carcinogenesis. Free Rad Biol Med 32, 958-67. Klaassen, C.D. & Liu, J. (1997) Role of metallothionein in cadmium-induced hepatotoxicity and nephrotoxicity. Drug Metab Rev 29, 79-102. Klaassen, C.D. & Liu, J. (1997) Role of metallothionein in cadmium-induced hepatotoxicity and nephrotoxicity. Drug Metab Rev 29, 79-102. Kingma, P.S., Burden, D.A. & Osheroff, N. (1999) Binding of Etoposide to Topoisomerase II in the Absence of DNA: Decreased Affinity as a Mechanism of Drug Resistance. Biochem 3, 3457-3461. Kondoh, M., Araragi, S., Sato, K., Higashimoto, M., Takiguchi, M. & Sata, M. (2002) Cadmium induces apoptosis partly via caspase-9 activation in HL-60 cells. Toxicology 170, 111-117. Irwin, R.J., VanMouwerik, M., Stevend, L., Seese, M.D. & Basham, W. (1997) National Park Service, Water Resources Division, Fort Collins, CO. Environmental Contaminants Encyclopedia Lee, S.A., Dritschilo, A. & Jung, M. (2001) Role of ATM in oxidative stress-mediated C-Jun phosphorylation in response to ionizing radiation and CdCl2. J. Biol Chem 276, 11783-11790. Leppard, J.B. & Champoux, J.J. (2005) Human DNA topoisomerase I : relaxation, roles and damage control. Chromosoma 114, 75-85. Lilis, R. & Landrigan, P.J. (1994) Renal and urinary tract disorders. Ouucpational health Lim T.K., Chen, A.Y., Yu, C., Mao, Y., Wang, H. & Liu, L.F. (1999) Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress. Genes Dev 13, 1553-1560. Li, T.K. & Liu, L.F. (2001) Tumor cell death induced by topoisomerase-targeting drugs. Annu Rev Pharmacol Toxicol 41, 53-77. Liu, L.F. (1989) DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 58, 351-375. IARC. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. (1993) Monographs on the evaluation of carcinogenic risk to humans 58, 119-238. Love, K.R., Catic, A., Schlieker, C. & Ploegh, H.L. (2007) Mechanisms, biology and inhibitors of deubiquitinating enzymes. Nat Chem Biol 3, 697-705. Meplan, C., Mann, K. & Hainaut, P. (1999) Cadmium induces conformational modifications of wild-type p53 and suppresses p53 response to DNA damage in cultured cells. J Biol Chem 274, 31663-31670 Meresse, P., Dechaux, E., Monneret, C. & Bertounesque, E. (2004) Etoposide : discovery and medicinal chemistry. Curr Med Chem 11, 244, 6049-6055. Nagata, C., Nagao, Y., Shibuya, C., Kashiki, Y. & Shimizu, H. (2005) Urinary cadmium and serum levels of estrogens and androgens in postmenopausal Japanese woman. Cancer Epidemiol Biomarkers Prev 14, 705-708. Nagaraja, V., Sikder, D. & Jain, P. (2002) DNA topoisomerase I from mycobacteria -a potential drug target. Curr Pharm Des 8, 1995-2007. Oh, S.H. & Lim, S.C. (2006) A rapid and transient ROS generation by cadmium triggers apoptosis via caspase-dependent pathway in HepG2 cells and this is inhibited through N-acetylcysteine-mediated catalase upregulation. Toxicol Applied Pharmacol 212, 212 – 223. Piscator, M. (1986) The nephropathy of chronic cadmium poisoning. Cadmium. Handbook of Experimental Pharmacology Vol.80, pp.194, Springer, New York Rock, K.L., Gramm, C., Rothstein, L., Clark, K., Stein, R., Dick, L., Hwang, D. & Goldberg, A.L. (1994) Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78, 761–771. Robison, S.H., Cantoni, O. & Costa, M. (1984) Analysis of metal-induced DNA lesions and DNA-repair replication in mammalian cells. Mutat Res 131, 173-181. Safe, S. (2003) Cadmium’s disguise dupes the estrogen receptor. Nat Medicine 9, 1000-1001. Savolainen, H. (1995) Cadmium-associated renal disease. Ren Fail 17, 483-487. Shah, I.M. & Di Napoli, M. (2007) The ubiquitin-proteasome system and proteasome inhibitors in central nervous systems disease. Cardiovasc Hematol Disord Drug Drug Targets 4, 250-273. Simgh, N.P., Mc Coy, M.T., Tice, R.R. & Schneider, E.L. (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 9, 175-184. Stadtman, E.R. (1992) Protein oxidation and aging. Science 257, 1220-1224. Stohs, S.J. & Bagchi, D. (1995) Oxidative mechanisms in the toxicity of metal irons. Free Radic Med 18, 321-336. Strick, R., Strissel, P.L., Borgers, S.L. & Rowley, J.D. (2000) Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. Proc Natl Acad Sci 97, 4790-4795. Tabata, M., Tabata, R., Grabowski, D.R., Bukowski, R.M., Ganapathi, M.K. & Ganapathi, R. (2001) Roles of NF-kappaB and 26S proteasome in apoptotic cell death induced by topoisomerase I and II poisons in human nonsmall cell lung carcinoma. J Biol Chem 276, 8029-8036. Tanaka, M., Yanagi, M., Shirota, K., Une, Y., Nomura, Y., Masaoka, T. & Akahori, F. (1995) Effect of cadmium in the zinc deficient rat. Vet Hum Toxicol 37, 203-208. Thevenod, F. & Friedmann, J.M. (1999) Cadmium-mediated oxidative stress in kidney proximal tubule cells induces degradation of Na+/K+-ATPase through proteasomal and endo-/lysosomal proteolytic pathways. FASEB J 13, 1751-1761. Thomson, R.H. (1987) Naturally Occurring Quinones Vol. III, Chapman and Hall, London. Valko, M., Rhodes, C.J., Moncol, J., Izakovic, M. & Mazur, M. (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160, 1-40. Victor, B.C. & Sloane, B.F. (2002) Cysteine cathepsin non-inhibitory binding partners : modulating intracellular trafficking and function. Biol Chem 11, 1131-1140. Waalkes, M.P. (2002) Metal carcinogenesis. Handbook of heavy metals in the environment 121-46. Wang, H., Mao, Y., Chen, A.Y., Zhou, N., LaVoie, E.J. & Liu, L.F. (2001) Stimulation of topoisomerase II-mediated DNA damage via a mechanism involving protein thiolation. Biochemistry 40, 3316-3323. Wang, J.C. (1985) DNA topoisomerases : nature’s solution to the topological ramification of the double-helix structure of DNA. Harvey Lect 81, 93-110. Wang, J.C. (1996) DNA topoisomerases. Annu Rev Biochem 65, 635-692. Wang, J.C. (2002) Cellular roles of DNA topoisomerases : A molecular perspective. Nat Rev Cell Biol 3, 430-440. Waisberg, M., Joseph, P., Hale, B. & Beyersmann, D. (2003) Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology 198, 95-117. Zhou, N., Xiao, H., Li, T.K., Nur-E-Kamal, A. & Liu, L.F. (2003) DNA damage - mediated apoptosis induced by selenium compounds. J Biol Chem 278, 29532-29537. Zolotarjova, N., Ho, C., Mellgren, R.L., Askari, A. & Huang, W.H. (1994) Different sensitivities of native and oxidized forms of Na+/K+-ATPase to intracellular proteinases. Biochim Biophys Acta 1192, 125-131. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37844 | - |
dc.description.abstract | 鎘,具有毒性及致癌性,是一種有硫化巨分子能力的過渡金屬。然而目前為止對於其毒性及致癌性的詳細機轉並無一致性的報導,因此我們試圖利用組織培養系統來探討鎘所造成的毒性之可能機制。有趣的是,我們發現在暴露於鎘之後,DNA拓樸異構酶的蛋白質表現量有減少的跡象,意味著鎘或許可以活化細胞中蛋白質降解系統(proteolytic systems)。此外,我們利用許多不同的蛋白酶抑制劑,來探討在鎘所誘發的蛋白質降解及細胞毒性中各種蛋白質降解酶可能扮演的角色。初步的研究結果指出鎘所誘發的蛋白質降解可能與26S proteasome、metalloproteases、serine proteases、cysteine proteases以及活性氧分子(reactive oxygen species, ROS)等有關。另外,我們亦發現鎘會造成DNA斷裂且隨著處理濃度的增加而DNA斷裂的情形會更為嚴重;同時亦證實第二型拓樸異構酶可能參與在其中,並且反映於鎘所造成之細胞毒性。綜合上述結果,我們證實並討論鎘誘發之蛋白質降解與第二型拓樸異構酶造成DNA斷裂以及活性氧分子對於鎘所引發的細胞毒性之可能重要性。 | zh_TW |
dc.description.abstract | Cadmium (Cd2+), a macromolecule-thiolating metal, exhibits cytotoxic and carcinogenic activities. However, no unified mechanism for Cd2+-mediated toxicity and/or carcinogenicity has been reported or proposed. Here, we explored the underlying molecular mechanism(s) of Cd2+-induced toxicity in a tissue culture system. Surprisingly, we have found that the protein levels of DNA topoisomerases were greatly reduced upon cellular exposure to Cd2+, suggesting that Cd2+ might activate cellular proteolytic systems. Moreover, the proteolytic systems involved in the cadmium-induced degradation and cytotoxicity were investigated with multiple protease inhibitors. Our results suggest the potential involvements of 26S proteasome, metalloproteases, serine and cysteine proteases as well as reactive oxygen species (ROS) in Cd2+-activated proteolysis. In addition, we also found that Cd2+ induces the formation of chromosomal DNA fragmentation in a dose-dependent manner. Interestingly, the formation of these Cd2+-induced DNA breakages can be partially antagonized by a lot of TOP2 catalytic inhibitors such as ICRF-193, aclarubicin, merbarone and novobiocin. It appears that TOP2 might play a role in Cd2+-induced DNA breakage during acute cadmium stress. Furthermore, we showed that TOP2-mediated DNA breakage contributes to the cytotoxic action of Cd2+ in addition to Cd2+-induced proteases and ROS. The importance of Cd2+-induced proteolytic systems, TOP2-mediated DNA breakage and ROS formation in its cytotoxicity was discussed. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T15:46:55Z (GMT). No. of bitstreams: 1 ntu-97-R95445101-1.pdf: 2301622 bytes, checksum: de186a76df38eea1b86fb0dad7f49d09 (MD5) Previous issue date: 2008 | en |
dc.description.tableofcontents | ACKNOWLEDGEMENTS
中文摘要 ABSTRACT INTRODUCTION…………………………………………………………………….1 1. DNA topoisomerase 1-1. Subfamilies of DNA topoisomerases 1-1.1 Type I topoisomerases 1-1.2 Type II topoisomerases 1-2. Topoisomerase poisoning & cell response 1-2.1 Drug-stabilized topoisomerase-DNA cleavable complex 1-2.2 Thiol-reactive metals 2. Cadmium 2-1. Cadmium & Itai-Itai Disease 2-2. Cadmium & Fidelity 2-3. Cadmium & Apoptosis 2-4. Cadmium & ROS 2-5. Cadmium & Proteolysis 3. Proteolytic systems 3-1. Ubiquitin-proteasome system 3-2. Proteases & Other proteolytic systems 3-3. Cellular proteolytic systems & Biological functions MOTIVATION & HYPOTHESIS…………………………………………………..15 SPECIFIC AIMS……………………………………………………………………16 MATERIALS & METHODS………………………………………………………..17 1. Materials - Cell & culture medium - Chemicals - Antibodies 2. Experimental Methods - Western blot analysis - FACScan flow cytometric analysis - MTT assay - Comer assay (alkaline single cell gel electrophoresis assay) RESULTS…………………………………………………………………………...21 - Cadmium induces a time- and dose-dependent decrease in the protein level of topoisomerases - The potential involvement of 26S proteasome in the decrease of topoisomerase proteins upon cadmium treatment - What kinds of proteases might be involved in the degradation induced by cadmium treatment - Whether the decrease of topoisomerases induced by cadmium is through ROS formation - Cytotoxicity of cadmium in HCT116 cells - Both Cd2+-activated ROS and proteolytic systems contribute significantly to cytotoxic action of Cd2+ - Cellular exposure to cadmium induced DNA breakage - Cadmium induced the formation of DNA breakage in a dose-dependent manner - TOP2 might play a role in cadmium-induced DNA breakage during acute cadmium stress - Topoisomerase II-mediated DNA breakage contributes slightly to the cytotoxic action of Cd2+ DISCUSSION………………………………………………………………………29 - Activation of proteolytic systems under acute cadmium stress - Induction of TOP2-mediated DNA breakage after cadmium treatment TABLES & FIGURES………………………………………………………………32 - Table 1. Subfamilies of DNA topoisomerases - Table 2. Composition of the protease inhibitors set - Figure 1. A schematic illustration for the potential relationship between cadmium and its biological responses was proposed - Figure 2. Cadmium induces topoisomerase degradation in a dose- and time-dependent - Figure 3. The potential involvement of 26S proteasome in cadmium -induced topoisomerases degradation - Figure 4. Degradation effects of topoisomerases caused by cadmium were partially antagonized by pretreatment with several protease inhibitors - Figure 5. Quantification results of Figure 4 - Figure 6. Cadmium increases intracellular ROS levels in a dose- dependent fashion in HCT116 cells - Figure 7. NAC efficiently antagonized the ROS induced by H2O2 or cadmium - Figure 8. The involvement of ROS in regulation of cadmium-induced topoisomerases degradation - Figure 9. Cytotoxicity of cadmium in HCT116 cells - Figure 10. Cd2+-activated ROS contributes significantly to cytotoxic action of Cd2+ - Figure 11. Cd2+-activated proteolytic systems mediate significantly to cytotoxic action of Cd2+ - Figure 12. The induction of DNA breakage by cadmium treatment - Figure 13. Cadmium induced DNA breakage in a dose-dependent manner - Figure 14. Quantification results of Figure 13 - Figure 15. ICRF-193 specifically antagonizes Cd2+-induced DNA breakage - Figure 16. Aclarubicin treatment reduces both VP-16- and Cd2+-induced DNA fragmentation - Figure 17. Merbarone treatment reduces both VP-16- and Cd2+-induced DNA fragmentation - Figure 18. Novobiocin treatment reduces both VP-16- and Cd2+-induced DNA fragmentation - Figure 19. TOP2-mediated DNA damage contributes to Cd2+-induced cytotoxicity - Figure 20. The crosstalk between the direct and indirect effects of acute Cd2+ stress REFERENCES……………………………………………………………………..38 CURRICULUM VITAE……………………………………………………………..61 | |
dc.language.iso | en | |
dc.title | 急性鎘中毒活化之蛋白質降解系統與第二型拓樸異構酶調控DNA損壞之探討 | zh_TW |
dc.title | Activation of proteolytic systems and TOP2-mediated DNA damage in HCT116 cells under acute cadmium stress | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳振陽(Jen-Yang Chen),李明學(Ming-Shyue Lee) | |
dc.subject.keyword | 鎘,拓樸異構酶,降解系統,DNA損壞, | zh_TW |
dc.subject.keyword | cadmium,topoisomerase,proteolytic system,DNA damage, | en |
dc.relation.page | 61 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2008-06-30 | |
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 |
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