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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29939完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許金玉 | |
| dc.contributor.author | Chia-Hung Huang | en |
| dc.contributor.author | 黃嘉宏 | zh_TW |
| dc.date.accessioned | 2021-06-13T01:26:10Z | - |
| dc.date.available | 2007-08-08 | |
| dc.date.copyright | 2007-08-08 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-07-17 | |
| dc.identifier.citation | 1. Amit, I., L. Yakir, M. Katz, Y. Zwang, M. D. Marmor, A. Citri, K. Shtiegman, I. Alroy, S. Tuvia, Y. Reiss, E. Roubini, M. Cohen, R. Wides, E. Bacharach, U. Schubert, and Y. Yarden. 2004. Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding. Genes Dev 18:1737-52.
2. Babst, M., G. Odorizzi, E. J. Estepa, and S. D. Emr. 2000. Mammalian tumor susceptibility gene 101 (TSG101) and the yeast homologue, Vps23p, both function in late endosomal trafficking. Traffic 1:248-58. 3. Black, D. M., and E. Solomon. 1993. The search for the familial breast/ovarian cancer gene. Trends Genet 9:22-6. 4. Bray, S. J. 2006. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678-89. 5. Burgdorf, S., P. Leister, and K. H. Scheidtmann. 2004. TSG101 interacts with apoptosis-antagonizing transcription factor and enhances androgen receptor-mediated transcription by promoting its monoubiquitination. J Biol Chem 279:17524-34. 6. Chang, J. G., T. H. Su, H. J. Wei, J. C. Wang, Y. J. Chen, C. P. Chang, and C. J. Jeng. 1999. Analysis of TSG101 tumour susceptibility gene transcripts in cervical and endometrial cancers. Br J Cancer 79:445-50. 7. Chen, Y. J., P. H. Chen, S. Y. Lin, and J. G. Chang. 1999. Analysis of aberrant transcription of TSG101 in hepatocellular carcinomas. Eur J Cancer 35:302-8. 8. Cheng, T. H., and S. N. Cohen. 2007. Human MDM2 isoforms translated differentially on constitutive versus p53-regulated transcripts have distinct functions in the p53/MDM2 and TSG101/MDM2 feedback control loops. Mol Cell Biol 27:111-9. 9. Cornelisse, C. J., R. S. Cornelis, and P. Devilee. 1996. Genes responsible for familial breast cancer. Pathol Res Pract 192:684-93. 10. Feng, G. H., C. J. Lih, and S. N. Cohen. 2000. TSG101 protein steady-state level is regulated posttranslationally by an evolutionarily conserved COOH-terminal sequence. Cancer Res 60:1736-41. 11. Fitzgerald, K., A. Harrington, and P. Leder. 2000. Ras pathway signals are required for notch-mediated oncogenesis. Oncogene 19:4191-8. 12. Huang, M.-y. 2003. Exploring the effect of ETF and ETS-1 binding site mutation on the activity of TSG101 promoter. 國立中山大學生物科學所碩士論文. 13. King, R. J. 1993. William L. McGuire Memorial Symposium. Estrogen and progestin effects in human breast carcinogenesis. Breast Cancer Res Treat 27:3-15. 14. Langston, A. A., K. E. Malone, J. D. Thompson, J. R. Daling, and E. A. Ostrander. 1996. BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med 334:137-42. 15. Li, L., and S. N. Cohen. 1996. Tsg101: a novel tumor susceptibility gene isolated by controlled homozygous functional knockout of allelic loci in mammalian cells. Cell 85:319-29. 16. Lin, P. M., T. C. Liu, J. G. Chang, T. P. Chen, and S. F. Lin. 1998. Aberrant TSG101 transcripts in acute myeloid leukaemia. Br J Haematol 102:753-8. 17. Lo, Y. F., T. C. Chen, S. C. Chen, and C. C. Chao. 2000. Aberrant expression of TSG101 in Taiwan Chinese breast cancer. Breast Cancer Res Treat 60:259-66. 18. Longnecker, M. P. 1995. Alcohol consumption and risk of cancer in humans: an overview. Alcohol 12:87-96. 19. Maucuer, A., J. H. Camonis, and A. Sobel. 1995. Stathmin interaction with a putative kinase and coiled-coil-forming protein domains. Proc Natl Acad Sci U S A 92:3100-4. 20. McIver, B., S. K. Grebe, L. Wang, I. D. Hay, A. Yokomizo, W. Liu, J. R. Goellner, C. S. Grant, D. I. Smith, and N. L. Eberhardt. 2000. FHIT and TSG101 in thyroid tumours: aberrant transcripts reflect rare abnormal RNA processing events of uncertain pathogenetic or clinical significance. Clin Endocrinol (Oxf) 52:749-57. 21. Morabia, A., M. Bernstein, S. Heritier, and N. Khatchatrian. 1996. Relation of breast cancer with passive and active exposure to tobacco smoke. Am J Epidemiol 143:918-28. 22. O'Boyle, J. D., M. L. Proctor, K. M. Fong, W. M. Lin, D. S. Miller, and C. Y. Muller. 1999. Role of TSG101 in uterine cervix cancer. Gynecol Oncol 75:401-5. 23. Oh, H., C. Mammucari, A. Nenci, S. Cabodi, S. N. Cohen, and G. P. Dotto. 2002. Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1). Proc Natl Acad Sci U S A 99:5430-5. 24. Oh, K. B., M. J. Stanton, W. W. West, G. L. Todd, and K. U. Wagner. 2007. Tsg101 is upregulated in a subset of invasive human breast cancers and its targeted overexpression in transgenic mice reveals weak oncogenic properties for mammary cancer initiation. Oncogene:1-10. 25. Oh, Y., M. L. Proctor, Y. H. Fan, L. K. Su, W. K. Hong, K. M. Fong, Y. S. Sekido, A. F. Gazdar, J. D. Minna, and L. Mao. 1998. TSG101 is not mutated in lung cancer but a shortened transcript is frequently expressed in small cell lung cancer. Oncogene 17:1141-8. 26. Pathak, D. R., and A. S. Whittemore. 1992. Combined effects of body size, parity, and menstrual events on breast cancer incidence in seven countries. Am J Epidemiol 135:153-68. 27. Pornillos, O., S. L. Alam, R. L. Rich, D. G. Myszka, D. R. Davis, and W. I. Sundquist. 2002. Structure and functional interactions of the Tsg101 UEV domain. Embo J 21:2397-406. 28. Rountree, M. R., K. E. Bachman, and S. B. Baylin. 2000. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25:269-77. 29. Ruland, J., C. Sirard, A. Elia, D. MacPherson, A. Wakeham, L. Li, J. L. de la Pompa, S. N. Cohen, and T. W. Mak. 2001. p53 accumulation, defective cell proliferation, and early embryonic lethality in mice lacking tsg101. Proc Natl Acad Sci U S A 98:1859-64. 30. Singletary, S. E., C. Allred, P. Ashley, L. W. Bassett, D. Berry, K. I. Bland, P. I. Borgen, G. Clark, S. B. Edge, D. F. Hayes, L. L. Hughes, R. V. Hutter, M. Morrow, D. L. Page, A. Recht, R. L. Theriault, A. Thor, D. L. Weaver, H. S. Wieand, and F. L. Greene. 2002. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20:3628-36. 31. Sun, Z., J. Pan, G. Bubley, and S. P. Balk. 1997. Frequent abnormalities of TSG101 transcripts in human prostate cancer. Oncogene 15:3121-5. 32. Sun, Z., J. Pan, W. X. Hope, S. N. Cohen, and S. P. Balk. 1999. Tumor susceptibility gene 101 protein represses androgen receptor transactivation and interacts with p300. Cancer 86:689-96. 33. Watanabe, M., Y. Yanagi, Y. Masuhiro, T. Yano, H. Yoshikawa, J. Yanagisawa, and S. Kato. 1998. A putative tumor suppressor, TSG101, acts as a transcriptional suppressor through its coiled-coil domain. Biochem Biophys Res Commun 245:900-5. 34. Willeke, F., R. Ridder, P. Bork, R. Klaes, G. Mechtersheimer, M. Schwarzbach, D. Zimmer, M. Kloor, T. Lehnert, C. Herfarth, and M. von Knebel Doeberitz. 1998. Identical variant TSG101 transcripts in soft tissue sarcomas and various non-neoplastic tissues. Mol Carcinog 23:195-200. 35. Xiao, W., S. L. Lin, S. Broomfield, B. L. Chow, and Y. F. Wei. 1998. The products of the yeast MMS2 and two human homologs (hMMS2 and CROC-1) define a structurally and functionally conserved Ubc-like protein family. Nucleic Acids Res 26:3908-14. 36. Xie, W., L. Li, and S. N. Cohen. 1998. Cell cycle-dependent subcellular localization of the TSG101 protein and mitotic and nuclear abnormalities associated with TSG101 deficiency. Proc Natl Acad Sci U S A 95:1595-600. 37. Xu, C. F., J. Greenman, and E. Solomon. 1998. Truncated TSG101 transcripts are present in peripheral blood from both familial breast cancer patients and controls. Eur J Cancer 34:1077-80. 38. Zhu, G., R. Gilchrist, N. Borley, H. W. Chng, M. Morgan, J. F. Marshall, R. S. Camplejohn, G. H. Muir, and I. R. Hart. 2004. Reduction of TSG101 protein has a negative impact on tumor cell growth. Int J Cancer 109:541-7. 39. 馬家琳. 1998. 台灣地區肺癌檢體中TSG101基因之研究. 台灣大學醫學院生物化學暨分子生物研究所碩士論文. 40. 葉宗陳. 2003. 細胞內TSG101蛋白之定位分析. 中山大學生物科學學系碩士論文. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29939 | - |
| dc.description.abstract | TSG101最早由發現Stanly N. Cohen所發現，在該篇研究中顯示TSG101表現不論過多或過少皆會造成細胞癌化，而在後續的研究更深入的瞭解TSG101在分子層次的功能與影響。總總的研究皆顯示TSG101影響範圍廣泛，但在癌症的臨床檢體中，卻鮮少發現TSG101突變，有趣的是，乳癌、子宮頸癌、肝癌、肺癌等臨床檢體中均可發現多種TSG101的剪接變異體。本實驗室先前發現在乳癌檢體中，TSG101剪接變異體TSG101-Δ154-1054的出現與術後復發（systemic recurrence）相關；TSG101-Δ154-1054和TSG101-Δ133-447同時出現與術後復發則有更高的相關。
因此本篇研究建立穩定表現TSG101-Δ154-1054之細胞株，觀察這些細胞株的phenotype，發現一旦表現TSG101-Δ154-1054可增加soft-agar colony formation的能力，卻不改變生長速度與血清需求程度。而在分子層次上，則發現wildtype-TSG101些微增加。以western blot方式探討與細胞生長相關之蛋白可發現MDM2-p90與p21也些微增加，但此改變卻不影響p53與Rb；OP18亦不受影響；CDC2明顯減少，連帶p-CDC2也隨之減少。在soft-agar colony formation相關途徑中發現HER3些微減少，HER2則無變化，EGFR family的下游基因ERK1/2則不受影響，但survivin mRNA卻減少。若強迫細胞暫時表現TSG101-Δ133-447，更可發現survivin mRNA減少甚至消失。 總括本篇論文，我們建立了穩定表現TSG101-Δ154-1054的細胞株，發現此類細胞株之soft-agar colony formation能力上升，但生長速度與血清需求程度則不改變。而影響soft-agar colony formation之訊息傳導路徑，則有待更進一步的研究。 | zh_TW |
| dc.description.abstract | In 1996, Stanly N. Cohen found whether up- or down-regulation of TSG101 would cause tumorigenesis and several follow-up researches further elucidated the molecular mechanism of TSG101. Notwithstanding TSG101 are known as influential proteins, the mutation of TSG101 is barely found in clinical data. What is interesting is several TSG101 splicing variants are reported instead. Clinical data show TSG101 splicing variants are found in breast cancer, cervical cancer, hepatocarcinomas, and lung cancer. We previously found that in breast cancer the TSG101-Δ154-1054 correlates significantly with systemic recurrence (p=0.05). Moreover, the co-existence of TSG101-Δ154-1054 and TSG101-Δ133-447 shows even higher correlation with systemic recurrence (p=0.0028).
In this thesis, we built-up 3 stable clones which over-expressed TSG101-Δ154-1054, and then assessed the tumorigenic activity of these 3 clones. We found that in these clones, the ability of soft-agar colony formation was primarily enhanced while the growth-rate and serum requirement were slightly or even not changed. Based on the western blot, wildtype-TSG101s were stabilize by TSG101-Δ154-1054. And we investigated the relative protein in cell cycle regulation. MDM2-p90, and p21 were slightly increased, but p53, Rb and OP18 were not influenced. CDC2 were even decreased. In the sight of the increase in soft-agar colony formation, the specific splicing variant could also reduce HER3 but HER2. However, the downstream proteins ERK1/2 were not influenced. Additionally, transient expression of TSG101-Δ133-447 could even abolish survivin mRNA. To sum up, TSG101-Δ154-1054 stimulated the soft-agar colony formation but didn’t accelerate the proliferation. The molecular mechanism of the soft-agar colony formation still needs more investigation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T01:26:10Z (GMT). No. of bitstreams: 1 ntu-96-R94442013-1.pdf: 1501865 bytes, checksum: 8a2c571db435b36fec698ee61b98ecdd (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | 口試委員會審定書.................................................................i
謝誌................................................................................ ii 摘要............................................................................... iii Abstract........................................................................... iv 目錄................................................................................ v 圖次............................................................................... vii 附錄索引......................................................................... viii 緒論................................................................................1 一、乳癌介紹............................................................................. 2 二、TSG101 介紹........................................................................ 5 三、TSG101 促進癌化之方式........................................................... 8 四、TSG101 與乳癌之關係.............................................................. 8 五、研究動機與實驗目的................................................................ 9 研究材料及方法................................................................. 11 一、 研究材料.......................................................................... 12 第一節 實驗材料來源........................................................... 12 第二節 乳癌細胞株 (Breast cancer cell line) ................................ 14 第三節 乳癌檢體引子 (primers) ............................................... 14 二、 研究方法.......................................................................... 15 第一節 TSG101-△154-1054 表達載體的構築.............................. 15 第二節 TSG101-△133-447 表達載體的構築................................ 20 第三節 建立穩定表達TSG101-△154-1054 的細胞株..................... 21 第四節 細胞癌化程度分析 (Tumorigenicity assays) ........................ 25 結果.............................................................................. 27 一、 TSG101 剪接變異體表現載體之構築........................................... 28 第一節 TSG101-Δ154-1054 表現載體之構築............................... 28 第二節 TSG101-Δ133-447 表現載體之構築................................ 28 二、 表達TSG101-Δ154-1054 會促進乳癌細胞株的soft-agar colony formation的能力............................................................................. 29 第一節 篩選穩定表現TSG101-Δ154-1054 細胞株.......................... 29 第二節 穩定表現TSG101-Δ154-1054 細胞株之癌化程度分析............ 29 第三節 分析表達TSG101-Δ154-1054 之乳癌細胞中一些分子的status.. 30 討論.............................................................................. 31 圖... .............................................................................. 35 附錄.............................................................................. 47 參考文獻......................................................................... 55 | |
| dc.language.iso | zh-TW | |
| dc.subject | 軟洋菜膠細胞群落形成 | zh_TW |
| dc.subject | 乳癌 | zh_TW |
| dc.subject | 術後復發 | zh_TW |
| dc.subject | 癌症易感基因101 | zh_TW |
| dc.subject | 剪接變異體 | zh_TW |
| dc.subject | systemic recurrence | en |
| dc.subject | soft-agar colony formation | en |
| dc.subject | splicing variant | en |
| dc.subject | TSG101 | en |
| dc.subject | breast cancer | en |
| dc.title | 分析TSG101 剪接變異體對細胞癌化的影響 | zh_TW |
| dc.title | The Impact of TSG101 Splicing Variant on Tumorigenic
Activity of Breast Cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蔡錦華,李明學 | |
| dc.subject.keyword | 乳癌,術後復發,癌症易感基因101,剪接變異體,軟洋菜膠細胞群落形成, | zh_TW |
| dc.subject.keyword | breast cancer,systemic recurrence,TSG101,splicing variant,soft-agar colony formation, | en |
| dc.relation.page | 59 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-07-18 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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