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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李文森(Wen-Sen Lee) | |
dc.contributor.author | Ho-Ching Yang | en |
dc.contributor.author | 楊和慶 | zh_TW |
dc.date.accessioned | 2021-05-20T21:14:09Z | - |
dc.date.available | 2013-03-03 | |
dc.date.available | 2021-05-20T21:14:09Z | - |
dc.date.copyright | 2011-03-03 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-02-10 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/10251 | - |
dc.description.abstract | 內皮細胞參與多樣化的生理過程,包括血管生成、止血及發炎。在本實驗室先前研究指出,黃體素在生理濃度下(500 nM)會抑制人類臍靜脈內皮細胞的增生,此種抑制作用是透過增加p53的表現來達成。在給予黃體素處理後的十分鐘內就可觀察到細胞內磷酸化的ERK蛋白質量的增加,但是黃體素處理後所誘導的p53增加則在給藥後二十三小時才會出現。使用NCBI資料庫分析,發現p53基因啟動子上面有NF-κB、HLH及EBPβ等轉錄因子結合位置,在許多細胞內轉錄因子當中,NF-κB被認為與血管細胞血管增生功能有密切關係,本篇的研究主題是觀察NF-κB在黃體素誘導p53向上調節所扮演的角色。經由分析細胞中蛋白質表現量發現,黃體素並不會刺激細胞內NF-κB的總量增加,但是在黃體素誘導p53蛋白表現量增加之前的時間點可觀察到IκBα有被磷酸化的現象,之後NF-κB經由細胞質進入細胞核,增加NF-κB與p53基因的結合,影響p53的表現。使用NF-κB抑制劑Bay11-7082可以減少黃體素增加p53的表現。本實驗室的先前研究結果顯示黃體素是透過活化ERK路徑,增加p53蛋白的表現。本研究給予ERK-1/2抑制劑 U0126或PD98059會減少IκBα的磷酸化作用,顯示黃體素增加IκBα的磷酸化作用是透過活化ERK。利用基因序列刪除法,我們的實驗結果顯示NF-κB結合位置對於黃體素誘導p53啟動子活性具有決定性的角色,而HLH及EBPβ結合位置對於p53基因啟動子也提供部份調節的作用。我們的研究亦發現黃體素受器PR-A,在經過黃體素刺激後會進入細胞核內,而PR-B沒有出現這種現象;從免疫共沈澱的實驗結果中,發現到NF-κB與PR-A的結合有增加的現象,而這二者因子結合增加的現象,暗示PR-A可能會調節NF-κB的作用來調控p53的表現,進而抑制血管內皮細胞的增生。 | zh_TW |
dc.description.abstract | Endothelial cells are involved in a diversity of physiologic processes including angiogenesis, hemostasis, and inflammation. Previously, our laboratory has demonstrated that progesterone at a physiological concentration (500 nM) inhibited proliferation of human umbilical venous endothelial cells (HUVEC) through a p53-dependent pathway and the ERK-mediated pathway is involved in the progesterone-induced increase of p53. The progesterone-induced increase of the level of phosphorylated ERK was observed at 10 min after treatment, while the increased p53 level was not observed until 23 h after treatment. Based on the NCBI database, the human p53 gene promoter contains three transcription factor binding sites including NF-κB, HLH, and EBPβ. It has been indicated that NF-κB might be involved in the regulation of angiogenesis. Accordingly, the aim of this study is to investigate how NF-κB regulates p53 in HUVEC. Our data showed that the total protein levels of NF-κB in progesterone-treated HUVEC were not changed significantly. However, progesterone increased IκBα phosphorylation as well as NF-κB nuclear translocation and binding onto the p53 promoter. Treatment of HUVEC with NF-κB inhibitor, Bay11-7082, reduced the progesterone-induced increase of p53, suggesting that progesterone induced increase of p53 through increase of IκBα phosphorylation, which in turn increased NF-κB nuclear translocation and binding onto the p53 promoter. Treatment of HUVEC with an ERK inhibitor, U0126 or PD98059, reduced the progesterone-induced increase of IκBα phosphorylation, suggesting that progesterone increased IκBα phosphorylation through the ERK pathway. Using gene deletion, our data suggest that the NF-κB binding site on the p53 gene promoter is essential for progesterone-induced p53 up-regulation, wherease the HLH and EBPβ binding sites might also play important roles in regulating the p53 promoter activity. Progesterone receptor-A (PR-A), but not PR-B, translocated into the nucleus after treatment with progesterone. Immunoprecipitation showed that progesterone increased the binding between NF-κB and PR-A. These results suggested that PR-A might participate in NF-κB-regulated p53 expression and further inhibited the proliferation of vascular endothelial cells. | en |
dc.description.provenance | Made available in DSpace on 2021-05-20T21:14:09Z (GMT). No. of bitstreams: 1 ntu-100-R96441013-1.pdf: 6467421 bytes, checksum: 9cb2dc663df69fb553e4cc21113f8cb5 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | 目錄
口試委員會審定書 i 縮寫表 ii 誌謝 iv 中文摘要 v ABSTRACT vi 目錄 viii 圖目錄 x 表目錄 xi 一 緒論 -1- 1.1 血管生成的概念 -1- 1.2 黃體素受器的作用 -4- 1.3 黃體素的非基因體效應 -6- 1.4 NF-κB複合物的作用 -8- 1.5 NF-κB與p53的交互作用 -11- 二 實驗材料與方法 -13- 2.1 溶液與藥品的配製 -13- 2.2 常用儀器 -23- 2.3 實驗方法 -25- 三 實驗結果 -37- 3.1 黃體素誘導NF-κB由血管內皮細胞的細胞質進入細胞核。 -37- 3.2 黃體素透過NF-κB的活化來增加血管內皮細胞P53的表現。 -37- 3.3 黃體素增加IκBα的磷酸化並且減少IκBα與NF-κB的結合。 -38- 3.4 黃體素增加IκBα的磷酸化作用是透過活化ERK的途徑。 -38- 3.5 黃體素可以增加NF-κB與p53 gene的結合。 -39- 3.6 p53 gene啟動子上面具有轉錄因子NF-κB、HLH、EBPβ的結合位置。 -39- 3.7 移除p53 gene啟動子上面的NF-κB結合位置幾乎完全阻斷黃體素對於p53 gene的啟動子活性。 -41- 3.8 黃體素增加PR-A由內皮細胞的細胞質進入細胞核。 -41- 3.9 黃體素可以增加NF-κB與PR-A的結合。 -42- 四 討論 -43- 參考資料 -68- 圖目錄 圖一 黃體素誘導NF-κB由血管內皮細胞的細胞質進入細胞核。 -50- 圖二 黃體素透過NF-κB的活化來增加血管內皮細胞P53的表現。 -51- 圖三 黃體素可以增加內皮細胞IκBα的磷酸化作用。 -52- 圖四 黃體素可以降低內皮細胞NF-κB與IκBα的結合。 -53- 圖五 黃體素增加IκBα的磷酸化作用是透過活化ERK的途徑。 -54- 圖六 黃體素可以增加NF-κB與p53 gene的結合。 -55- 圖七 p53 gene啟動子上面具有轉錄因子NF-κB、HLH、EBPβ的結合位置。 -56- 圖八 p53 gene deletion construct建構。 -57- 圖九 確認NF-κB以及相關轉錄因子結合位置在p53啟動子上的重要性。 -58- 圖十 黃體素可以增加PR-A由內皮細胞的細胞質進入細胞核。 -59- 圖十一 黃體素可以增加NF-κB與PR-A的結合。 -60- 圖十二 黃體素可以增加細胞質與細胞核NF-κB與PR-A的結合。 -61- 附圖一 黃體素透過NF-κB調節p53的表現。 -63- 表目錄 表一 染色質免疫沈澱實驗所使用的引子。 -64- 表二 p53 gene deletion construct所使用的引子。 -65- 表三 p53 gene deletion construct插入子序列。 -66- | |
dc.language.iso | zh-TW | |
dc.title | 在人類臍靜脈內皮細胞中NF-κB在黃體素誘導p53向上調節的角色 | zh_TW |
dc.title | Role of NF-κB in regulating the progesterone-induced p53 up-regulation in HUVEC | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-1 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 胡孟君(Meng-Chun Hu) | |
dc.contributor.oralexamcommittee | 何元順(Yuan-Shun Ho) | |
dc.subject.keyword | 黃體素,黃體素受器,NF-κB,IκBα,p53, | zh_TW |
dc.subject.keyword | Progesterone,Progesterone receptor,NF-κB,IκBα,p53, | en |
dc.relation.page | 77 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2011-02-10 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
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