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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳小梨(Show-Li Chen) | |
dc.contributor.author | Hshan-Hao Chen | en |
dc.contributor.author | 陳軒豪 | zh_TW |
dc.date.accessioned | 2021-06-08T04:15:59Z | - |
dc.date.copyright | 2010-09-09 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-08-04 | |
dc.identifier.citation | Alimirah, F., R. Panchanathan, et al. (2007). 'Expression of androgen receptor is negatively regulated by p53.' Neoplasia 9(12): 1152-1159.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22349 | - |
dc.description.abstract | 雄激素受體(androgen receptor , AR)調控許多生物功能,包括前列腺細胞的生長和凋亡。雄激素標靶細胞中,AR蛋白表現被嚴格調控。雖然受體在一般情況中被持續的降解,當細胞遭遇到不同的狀態或接收到不同的訊息傳遞時,雄激素受體的降解也隨之而波動,這一過程主要藉由泛素蛋白酶體 (ubiquitin-proteasome) 途徑。在我們先前的研究中,核受體交互作用蛋白 (nuclear receptor interaction protein, NRIP) 可與AR結合並做為輔助因子。它也可以穩定AR蛋白。在這裡我們證明了不論是否有配體存在下,DNA損傷結合蛋白2 (DNA damage-binding protein 2 , DDB2) 與AR在體外皆有相互作用。在LNCap細胞中,當大量表達DDB2會增加AR與泛素結合的程度。另外在AR表現陽性的LNCap和PC3-AR細胞轉殖入DDB2時,會在細胞核中強化AR蛋白酶體的降解,而且細胞的生長與對照組比較有顯著減緩。而此現象則在AR表現陰性的PC3細胞中重現。在另一方面,我們製作了NRIP雙突變(突變 WDXR基序),它無法結合到DDB1但仍可與AR蛋白結合。而我們使用NRIP雙突變與 DDB2競爭對AR結合。此外,目前已知DDB1可與DCAFs (DDB2-cullin 4–associated factors) 結合作為一種轉錄因子。使用RT-PCR發現,雙突變的NRIP還可以增加AR調控的基因,前列腺特異性抗原 (prostate specific antigen, PSA)。總結來說,我們新發現了AR和DDB2之間的結合作用。DDB2可能為DDB1-CUL4 E3 ligase的substrate受體使AR降解。 NRIP可以干擾的AR - DDB2結合並進一步穩定AR。 | zh_TW |
dc.description.abstract | The androgen receptor controls several biological functions including prostate cell growth and apoptosis. In androgen target cells, androgen receptor protein level is strictly regulated. Although receptor turnover is a continuous process and in dynamic fluctuations in receptor levels that are mediated primarily by the ubiquitin-proteasome pathway to responding the relative cellular conditions or different signal pathways. In our previous study, NRIP can associate with AR and act as a cofactor. It’s also can stabilize AR protein. Here, we show that the DNA damage-binding protein 2 (DDB2) interacts with AR in vitro regardless of ligand present. And overexpression of DDB2 proteins in LNCap cells enhance AR protein ubiqutin level. In AR-positive LNCap and PC3-AR cells transfected with DDB2 , the AR amount decreased that were correlated the declined the cells growth rates compared with the controls. The phenomenons can not be reproduced in AR-negative PC-3 cells, imply that DDB2 decreasing cell growth is AR dependent. On the other hand, we produced a NRIP double mutant (mutations in arginine residues of the two WDXR motifs) which lost DDB1 binding affinity but still can bind to AR protein. Additionally this mutant of NRIP can displace DDB2 for AR binding. Also, it’s has been reported that DDB1 may act as a transcription factor. In RT-PCR, the NRIP double mutant still can enhance AR-mediated gene, PSA expressing, indicating that NRIP enhancing AR gene expression is DDB1-independent. In sum, we identify the DDB2 is a novel AR interacting protein. And DDB2 acts as a substrate receptor of DDB1-CUL4 E3 ligase to target AR protein degradation. NRIP can interfere the AR-DDB2 binding to stabilize AR. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T04:15:59Z (GMT). No. of bitstreams: 1 ntu-99-R97445112-1.pdf: 1488220 bytes, checksum: 5f71c6d09dda11b422d1ea545b85e9b2 (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | 口試委員會審定書
誌謝 中文摘要 ABSTRACT CHAPTER 1 INTRODUCTION…………………………………………….………….1 1.1 Androgen receptor…………...…………………………………….....1 1.2 Mechanisms of androgen receptor degradation…………..……..……2 1.3 DDB1 and CUL4, the E3 ligase.……………..……………………....3 1.4 The DNA damage binding protein 2, DDB2……………………………………..4 1.5 The characteristic and discovery of Nuclear Receptor Interaction Protein…………………………………………………………...…...6 1.6 Aim of the Thesis…………………………………….....……………7 CHAPTER 2 MATERIAL AND METHODS…………………..………………….….9 2.1 Cell culture and Drug Treatment .………………………………….9 2.2 Transient Transfection…………...………………………….………..9 2.3 Co-immunoprecipitation and Western Blot Analysis ...………….…11 2.4 Plasmid constructions……...………………………………..………12 2.5RNA extraction and Reverse Transcription-PCR………….………...13 2.6 Cell proliferation assay……………………...………………………14 2.7 Fractionation of nuclear or cytoplasm proteins…………………..…15 2.8 GST fusion proteins and pull-down assays…………………………16 CHAPTER 3 RESULTS………………………………………………...…………….18 3.1 DDB2 can interact with AR in vitro………………..........………..18 3.2 DDB2 enhance the ubiquitin level of AR in vivo.………….......…...19 3.3 Biological significance of DDB2 effects………………...…….........20 3.4 NRIP competes with DDB2 for interacting AR……………….……21 3.5 WDXR motif on NRIP is essential for binding DDB1………...…....22 3.6 The mechanism of NRIP-enhancing AR mediated transcription activity is independent on DDB1-CUL4 pathway……….………...…..23 3.7 The mechanism of NRIP-enhancing AR mediated transcription activity is independent on DDB1-CUL4 pathway………………...…….24 CHAPTER 4 DISCCUSION……………………………………………….…………25 REFERENCES …………………………………….…………...……..31 FIGURES……………………………………………….……...………36 APPENDIX…………………………………………….……...……….47 | |
dc.language.iso | en | |
dc.title | DDB2促進雄性激素受體蛋白降解作用及NRIP穩定雄性激素受體蛋白之機制探討 | zh_TW |
dc.title | Investigation of the mechanisms of DDB2-mediated AR degradation and NRIP - stabilizing AR protein. | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 鄧述諄(Shu-Chun Teng),吳君泰(June-Tai Wu) | |
dc.subject.keyword | 雄激素受體,DNA損傷結合蛋白2,核受體交互作用蛋白,泛素黏合酵素Cul4-DDB1,攝護腺癌, | zh_TW |
dc.subject.keyword | AR,DDB2,CUL4-DDB1,NRIP,Prostate cancer, | en |
dc.relation.page | 49 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2010-08-04 | |
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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