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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 鄧述諄(Shu-Chun Teng) | |
| dc.contributor.author | Ya-Lan Chang | en |
| dc.contributor.author | 張雅嵐 | zh_TW |
| dc.date.accessioned | 2021-06-07T17:59:01Z | - |
| dc.date.copyright | 2012-09-19 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-08-09 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16042 | - |
| dc.description.abstract | Hereditary paraganglioma (PGL) is a rare tumor that is mostly benign and mainly arises in the head, neck and abdomen. The first gene shown to be directly linked to PGL syndrome was SDHD. 87–100% of SDHD mutation carriers develop tumors. However, the exact mechanism for tumorigenesis of PGL is elusive. SDHD encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme, succinate dehydrogenase (SDH), which is a complex II component of the electron transport chain. In yeast Saccharomyces cerevisiae, Sdh4 is an ortholog of hSDHD, which major performs the succinate dehydrogenase function in the Sdh complex. Here we discovered a yeast mitochondrial novel protein, Shh4/Ylr164w, which displays higher sequence conservation to hSDHD than Sdh4. The protein expression level of Shh4 is increased when cells enter aerobic respiration. In nonfermentable carbon source, deletion of SHH4 further decreases the growth of sdh4△ cells. Deletion of SHH4 further decreases the mitochondrial membrane potential of sdh4△ cells in stationary phase. Deletion of SDH4 upregulates SHH4 expression. Furthermore, SHH4 overexpression rescues the inviable phenotype of sdh4△ upon growth on a nonfermentable carbon source. Shh4 is associated with Sdh3 and deletion of SDH4 increases the interaction between Sdh3 and Shh4. We also investigated the mechanism of PGL tumorigenesis by using S. cerevisiae as a model organism. As our result showed, the level of reactive oxygen species (ROS) and mutation frequency were increased in the SDH4 and SHH4 double-deleted cells. Altogether; these results demonstrate that Shh4 is another subunit of succinate dehydrogenase in yeast. Our data suggest that the deficiency of hSDHD/Sdh4p/Shh4p may result in an increased production of ROS which contributes to an increase in mutation frequency, genome instability, and PGL tumorigenesis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T17:59:01Z (GMT). No. of bitstreams: 1 ntu-101-R99445112-1.pdf: 1542246 bytes, checksum: 00d365108fe452b6b5d2900f28d46660 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 論文口試委員審定書 I
致謝 II 摘要 III Abstract IV Contents VI Introduction 1 Materials and Methods 5 Yeast strains and Media 5 Plasmid construction 6 Yeast transformation 6 E. coli transformation 7 Yeast mating and tetrad dissection 7 Protein extraction by TCA immunoprecipitation 8 Western blot analysis 8 Spotting assay 9 Co-immunoprecipitation from mitochondrial lysates 9 Analysis of membrane potential 10 Analysis of ROS production 11 Measurement of mutation frequency 11 Results 13 Yeast Shh4 displays stronger sequence conservation to hSDHD than yeast Sdh4 13 Shh4p is upregulated under several stresses 13 Shh4 expression is increased when cells enter aerobic respiration 14 Deletion of SHH4 further decreases the growth and mitochondrial membrane potential of sdh4△ cells 15 Upregulation of SHH4 in sdh4△ cells rescue the inviable phenotype of sdh4△ 17 Deletion of SDH4 increases the interaction between Sdh3 and Shh4 18 Lacking Shh4 in sdh4△ cells can further decrease the stability of Sdh3 19 Double deletions of SDH4 and SHH4 increase ROS generation and contribute to mutator phenotype 20 hSDHD is not expressed in Saccharomyces cerevisiae 21 sdh4 (Y120C) is a loss function mutation, but plasmids bearing shh4 (Y112C) or shh4 (G104D) is poorly expressed in Saccharomyces cerevisiae 22 Discussions 23 Table 27 Figures 29 References 44 Appendix 48 | |
| dc.language.iso | en | |
| dc.subject | 突變機率 | zh_TW |
| dc.subject | 遺傳性副神經節瘤 | zh_TW |
| dc.subject | 腫瘤形成 | zh_TW |
| dc.subject | 琥珀酸脫氫酶 | zh_TW |
| dc.subject | 複合體 | zh_TW |
| dc.subject | 粒線體 | zh_TW |
| dc.subject | 活性氧化物 | zh_TW |
| dc.subject | tumorigenesis | en |
| dc.subject | mutation frequency | en |
| dc.subject | reactive oxygen species | en |
| dc.subject | mitochondria | en |
| dc.subject | SDH complex | en |
| dc.subject | Hereditary Paraganglioma | en |
| dc.title | 利用酵母菌系統探討人類SDHD(Sdh4/Shh4)參與遺傳性副神經節瘤之機制 | zh_TW |
| dc.title | Yeast as a Model to Investigate the Mechanism of hSDHD(Sdh4/Shh4)-mediated Hereditary Paraganglioma | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李立仁,李財坤,黃偉邦,婁培人 | |
| dc.subject.keyword | 遺傳性副神經節瘤,腫瘤形成,琥珀酸脫氫酶,複合體,粒線體,活性氧化物,突變機率, | zh_TW |
| dc.subject.keyword | Hereditary Paraganglioma,tumorigenesis,SDH complex,mitochondria,reactive oxygen species,mutation frequency, | en |
| dc.relation.page | 48 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2012-08-09 | |
| 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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