請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17229
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 鄧述諄(Shu-Chun Teng) | |
dc.contributor.author | Wei-Wen Chang | en |
dc.contributor.author | 張瑋文 | zh_TW |
dc.date.accessioned | 2021-06-08T00:02:02Z | - |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-15 | |
dc.identifier.citation | Baysal, B.E. (2002). Hereditary paraganglioma targets diverse paraganglia. Journal of medical genetics 39, 617-622.
Carelli, V., Rugolo, M., Sgarbi, G., Ghelli, A., Zanna, C., Baracca, A., Lenaz, G., Napoli, E., Martinuzzi, A., and Solaini, G. (2004). Bioenergetics shapes cellular death pathways in Leber's hereditary optic neuropathy: a model of mitochondrial neurodegeneration. Biochimica et biophysica acta 1658, 172-179. Chen, L.B. (1988). Mitochondrial membrane potential in living cells. Annual review of cell biology 4, 155-181. Gebert, N., Gebert, M., Oeljeklaus, S., von der Malsburg, K., Stroud, D.A., Kulawiak, B., Wirth, C., Zahedi, R.P., Dolezal, P., Wiese, S., et al. (2011). Dual function of Sdh3 in the respiratory chain and TIM22 protein translocase of the mitochondrial inner membrane. Molecular cell 44, 811-818. Gerald, D., Berra, E., Frapart, Y.M., Chan, D.A., Giaccia, A.J., Mansuy, D., Pouyssegur, J., Yaniv, M., and Mechta-Grigoriou, F. (2004). JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 118, 781-794. Gill, A.J. (2012). Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. Pathology 44, 285-292. Gill, A.J., Benn, D.E., Chou, A., Clarkson, A., Muljono, A., Meyer-Rochow, G.Y., Richardson, A.L., Sidhu, S.B., Robinson, B.G., and Clifton-Bligh, R.J. (2010). Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Human pathology 41, 805-814. Ishii, T., Yasuda, K., Akatsuka, A., Hino, O., Hartman, P.S., and Ishii, N. (2005). A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis. Cancer Res 65, 203-209. Jackson, A.L., and Loeb, L.A. (2001). The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutation research 477, 7-21. Josse, L., Li, X., Coker, R.D., Gourlay, C.W., and Evans, I.H. (2011). Transcriptomic and phenotypic analysis of the effects of T-2 toxin on Saccharomyces cerevisiae: evidence of mitochondrial involvement. FEMS Yeast Res 11, 133-150. Kaelin, W.G., Jr., and Ratcliffe, P.J. (2008). Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30, 393-402. Kerscher, O., Sepuri, N.B., and Jensen, R.E. (2000). Tim18p is a new component of the Tim54p-Tim22p translocon in the mitochondrial inner membrane. Molecular biology of the cell 11, 103-116. Killian, J.K., Kim, S.Y., Miettinen, M., Smith, C., Merino, M., Tsokos, M., Quezado, M., Smith, W.I., Jr., Jahromi, M.S., Xekouki, P., et al. (2013). Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer discovery 3, 648-657. Klein RD, L.R., Young WF (2009). Hereditary paraganglioma-pheochromocytoma syndromes. GeneReviews http://wwwncbinlmnihgov/books/NBK1548/. Koning, A.J., Lum, P.Y., Williams, J.M., and Wright, R. (1993). DiOC6 staining reveals organelle structure and dynamics in living yeast cells. Cell Motil Cytoskeleton 25, 111-128. Kresnowati, M.T.A.P., van Winden, W.A., Almering, M.J.H., ten Pierick, A., Ras, C., Knijnenburg, T.A., Daran-Lapujade, P., Pronk, J.T., Heijnen, J.J., and Daran, J.M. (2006). When transcriptome meets metabolome: fast cellular responses of yeast to sudden relief of glucose limitation. Mol Syst Biol 2. Kubo, Y., Takagi, H., and Nakamori, S. (2000). Effect of gene disruption of succinate dehydrogenase on succinate production in a sake yeast strain. J Biosci Bioeng 90, 619-624. Lemire, B.D., and Oyedotun, K.S. (2002). The Saccharomyces cerevisiae mitochondrial succinate:ubiquinone oxidoreductase. Biochimica et biophysica acta 1553, 102-116. Letouze, E., Martinelli, C., Loriot, C., Burnichon, N., Abermil, N., Ottolenghi, C., Janin, M., Menara, M., Nguyen, A.T., Benit, P., et al. (2013). SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer cell 23, 739-752. Meisinger, C., Pfanner, N., and Truscott, K.N. (2006). Isolation of yeast mitochondria. Methods Mol Biol 313, 33-39. Momose, Y., and Iwahashi, H. (2001). Bioassay of cadmium using a DNA microarray: genome-wide expression patterns of Saccharomyces cerevisiae response to cadmium. Environ Toxicol Chem 20, 2353-2360. Muller, U. (2011). Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC). Neurogenetics 12, 175-181. Ohno, S. (1970). Evolution by gene duplication. Oliveira, E.M., Martins, A.S., Carvajal, E., and Bon, E.P. (2003). The role of the GATA factors Gln3p, Nil1p, Dal80p and the Ure2p on ASP3 regulation in Saccharomyces cerevisiae. Yeast 20, 31-37. Panizza, E., Ercolino, T., Mori, L., Rapizzi, E., Castellano, M., Opocher, G., Ferrero, I., Neumann, H.P., Mannelli, M., and Goffrini, P. (2013). Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. Human molecular genetics 22, 804-815. Quinlan, C.L., Orr, A.L., Perevoshchikova, I.V., Treberg, J.R., Ackrell, B.A., and Brand, M.D. (2012). Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem. Rintala, E., Toivari, M., Pitkanen, J.P., Wiebe, M.G., Ruohonen, L., and Penttila, M. (2009). Low oxygen levels as a trigger for enhancement of respiratory metabolism in Saccharomyces cerevisiae. BMC Genomics 10. Rutter, J., Winge, D.R., and Schiffman, J.D. (2010). Succinate dehydrogenase - Assembly, regulation and role in human disease. Mitochondrion 10, 393-401. Scherens, B., Feller, A., Vierendeels, F., Messenguy, F., and Dubois, E. (2006). Identification of direct and indirect targets of the Gln3 and Gat1 activators by transcriptional profiling in response to nitrogen availability in the short and long term. FEMS Yeast Res 6, 777-791. Selak, M.A., Armour, S.M., MacKenzie, E.D., Boulahbel, H., Watson, D.G., Mansfield, K.D., Pan, Y., Simon, M.C., Thompson, C.B., and Gottlieb, E. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7, 77-85. Sickmann, A., Reinders, J., Wagner, Y., Joppich, C., Zahedi, R., Meyer, H.E., Schonfisch, B., Perschil, I., Chacinska, A., Guiard, B., et al. (2003). The proteome of Saccharomyces cerevisiae mitochondria. Proc Natl Acad Sci U S A 100, 13207-13212. Slane, B.G., Aykin-Burns, N., Smith, B.J., Kalen, A.L., Goswami, P.C., Domann, F.E., and Spitz, D.R. (2006). Mutation of succinate dehydrogenase subunit C results in increased O2.-, oxidative stress, and genomic instability. Cancer Res 66, 7615-7620. Szeto, S.S., Reinke, S.N., Oyedotun, K.S., Sykes, B.D., and Lemire, B.D. (2012). Expression of Saccharomyces cerevisiae Sdh3p and Sdh4p paralogs results in catalytically active succinate dehydrogenase isoenzymes. The Journal of biological chemistry 287, 22509-22520. Walker, D.W., Hajek, P., Muffat, J., Knoepfle, D., Cornelison, S., Attardi, G., and Benzer, S. (2006). Hypersensitivity to oxygen and shortened lifespan in a Drosophila mitochondrial complex II mutant. Proc Natl Acad Sci U S A 103, 16382-16387. Wang, C.P., Chen, T.C., Chang, Y.L., Ko, J.Y., Yang, T.L., Lo, F.Y., Hu, Y.L., Chen, P.L., Wu, C.C., and Lou, P.J. (2012). Common genetic mutations in the start codon of the SDH subunit D gene among Chinese families with familial head and neck paragangliomas. Oral oncology 48, 125-129. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17229 | - |
dc.description.abstract | 人類SDH由四個次單元SDHA、SDHB、SDHC、SDHD組成,是TCA循環和電子傳遞鏈進行的樞紐酵素,其中SDHD會和SDHC一起鑲嵌在粒線體內層膜上負責將電子傳遞給complex III。副神經節瘤 (PGL)為罕見的腫瘤疾病,30%的PGL病人具有SDH遺傳性基因突變,其中近半數為SDHD異常,臨床症狀主要為好發於頭頸部的良性瘤,但目前腫瘤形成的機制仍未知,利用酵母菌具有和人類基因高度同源的優勢,我們以酵母菌做為動物模式探討PGL的致病機制。酵母菌的SDH同樣由四個次單元組成,分別為Sdh1、Sdh2、Sdh3和Sdh4,比對hSDHD和酵母菌的蛋白序列後發現一個功能未知的蛋白,Shh4/Ylr164W,相較於Sdh4有較高的序列相似度,在實驗室先前的研究中發現,單獨拿掉shh4對酵母菌的生長影響不大,但在sdh4缺失的酵母菌中拿掉shh4時明顯降低酵母菌的生長速度,此外在進入生長停滯期時,同時拿掉sdh4和shh4比單獨拿掉sdh4有更顯著的粒線體膜電位下降,因此推測Shh4在酵母菌中扮演Sdh4備份蛋白的角色,演化上人類的SDHD較有可能從SHH4演變而來,SDH4則因較無抵抗環境壓力的能力而逐漸被淘汰。為了確認此推論,我們比較不同壓力下蛋白質的表現時,發現Shh4在特定壓力下表現量會比Sdh4高;拿掉Sdh4時Shh4表現量明顯上升;以及Sdh3的穩定度在同時拿掉Sdh4和Shh4時較單獨拿掉Sdh4不穩定,由核基因的突變率也觀察到相同趨勢,以及在人類細胞中表現臨床點突變基因時發現蛋白質不穩定的表現相似於在SDH4缺失的酵母菌中Shh4表現點突變的型態,因此進一步推測基因缺失造成細胞內活性氧化物上升,使得基因益加不穩定是導致腫瘤形成的原因。 | zh_TW |
dc.description.abstract | Gene duplication and divergence are common in evolution. The mitochondrial succinate dehydrogenase (SDH) is an essential complex of the electron transport chain and of the tricarboxylic acid cycle. Mutation in human succinate dehydrogenase subunit SDHD frequently leads to cancer formation. In addition to the originally discovered and assigned yeast SDHD subunit Sdh4, another conserved homolog Shh4 has recently been noticed in the budding yeast. Interestingly, Shh4 is upregulated under several stresses and can substitute for Sdh4 in sdh4∆ cells. Mitochondria membrane potential and stability of SDH complex are further compromised and ROS production and mutation frequency are enhanced in sdh4∆ shh4∆ double mutants than sdh4∆ cells. Missense mutations found in the human SDHD gene in cancer patients were created in Sdh4 and Shh4. Surprisingly, growth defect merely appeared in the chimera of human deficient SDHD in Shh4 and this defect is due to the instability of the protein. Altogether, the sequence comparison and functional analysis favor a hypothesis that the succinate dehydrogenase in humans is evolved from yeast Shh4. Besides, SDH mutation leads to the disassembly of SDHC-SDHD complex, mitochondria damage, ROS production, genome instability and tumor formation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T00:02:02Z (GMT). No. of bitstreams: 1 ntu-102-R00445124-1.pdf: 1227355 bytes, checksum: e7e1576bda646aceddc143bacf781484 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 論文口試委員審定書 I
致謝 II 摘要 III Abstract V Contents VI Introduction 1 Materials and Methods 4 Yeast strains and Media 4 Co-immunoprecipitation from mitochondrial lysates 5 Analysis of membrane potential 5 Analysis of ROS production 6 Measurement of mutation frequency 7 Chimera protein expression 7 Oxygen consumption test 7 Results 9 A yeast mitochondrial novel protein, Shh4/Ylr164w displays stronger sequence conservation to hSDHD than Sdh4 9 Shh4p is upregulated under several stresses 9 Shh4 plays a minor role in yeast mitochondria complex II 10 Deletion of SHH4 further emphasized the deficient phenotype in sdh4 11 Shh4 can substitute for Sdh4 in sdh4 cells 12 Deletion of Shh4p further increases ROS and cause the upregulation of mutation frequency in sdh4 cells 12 The conserved SDHD variants cause more severe respiration growth inhibition in Shh4 by influencing protein stability 13 Discussions 16 Table 20 Figures 22 References 30 Appendix 37 | |
dc.language.iso | en | |
dc.title | 酵母菌中琥珀酸去氫酶D的直系同源物:臨床和演化意義 | zh_TW |
dc.title | Succinate dehydrogenase D orthologs in yeast:Clinic and evolutionary implications | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林敬哲(Jing-Jer Lin),婁培人(Pei-jen Lou) | |
dc.subject.keyword | 琥珀酸去氫酶,D, | zh_TW |
dc.subject.keyword | SHH4, | en |
dc.relation.page | 38 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2013-08-15 | |
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-102-1.pdf 目前未授權公開取用 | 1.2 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。