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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 沈湯龍(Tang-Long Shen) | |
| dc.contributor.author | Yu-Chi Lin | en |
| dc.contributor.author | 林育琦 | zh_TW |
| dc.date.accessioned | 2021-06-16T10:15:02Z | - |
| dc.date.available | 2016-09-02 | |
| dc.date.copyright | 2013-09-02 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-08-19 | |
| dc.identifier.citation | Bell, H. S., and Ryan, K. M. (2005). Intracellular signalling and cancer: complex pathways lead to multiple targets. Eur. J. Cancer 41, 206-215.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60296 | - |
| dc.description.abstract | Growth factor receptor bound protein-7 (Grb7) 為一不具有酵素活性的銜接蛋白(adaptor)，屬Grb family的一員，其具有數個功能性區域可與許多訊息分子產生交互作用而活化多重之訊息傳遞路徑以調控細胞功能。由目前研究中指出Grb7基因在某些乳癌細胞中會與Her2/erbB2 ( human epidermal growth factor 2 )有共同大量表現(co-amplification)的現象，並可能參與癌症的轉移(metastasis)、侵襲(invasive)及腫瘤生成(tumorigenesis)的過程。為了進一步探討Grb7所參與之訊息調控，先前實驗室由酵母菌雙雜合分析(yeast two-hybrid assay)中篩選會與Grb7進行交互作用之下游蛋白，發現Grb7與Pin1蛋白( peptidyl-prolyl cis/trans isomerase )間具有大量結合之現象。Pin1為一可針對磷酸化受質蛋白之特定pSer/Thr motif進行cis/trans異構化以調控蛋白的穩定、活化及構形。因此本研究嘗試進一步探討Grb7和Pin1的交互作用在細胞訊息傳遞上所可能扮演之功能性角色，藉由共免疫沉降和定點突變分析證實Pin1和Grb7具有直接之交互作用，且確認Grb7上Pin1可能之主要結合位置為pSer194-Pro motif。另外，藉由lentiviral-based gene silencing技術，發現在Pin1基因表現抑制的情況下，Grb7的蛋白表現量有提高之趨勢，進一步透過即時定量RT-PCR及cycloheximide pulse-chase分析中顯示Pin1可能在磷酸化蛋白之後修飾機制中透過與Grb7之pSer194-Pro motif結合而負向調控Grb7蛋白的穩定性。為進一步闡明Pin1在參與Grb7所媒介之訊息傳遞路徑，我們也期望找出參與兩者間交互作用之相關訊息分子以及Pin1蛋白在Grb7介導之細胞功能上所扮演之調控角色。藉此，希望對Grb7和Pin1蛋白間之研究可協助我們對癌症生成的過程及訊息路徑有更進一步的了解並提供相關疾病未來治療策略的研究和應用。 | zh_TW |
| dc.description.abstract | Growth factor receptor bound protein-7 (Grb7) is a multi-domain adaptor protein that mediates the coupling of tyrosine kinases with their downstream signaling pathways to regulate various cellular functions. The Grb7 gene is often co-amplified with EGF or HER2/erbB2 receptors to potentiate metastasis, invasion and tumorigenesis of breast cancers. Thus, Grb7 is an adverse prognostic marker in breast cancers. Previously, in a yeast two-hybrid screening, we found a novel interaction between Pin1 and Grb7. Pin1 is a peptidyl-prolyl cis/trans isomerase capable of isomerizing the specific pSer/Thr-Pro bonds and such conformational change leading to the alterations in protein functionality, stability, and/or intracellular localization. In this study, we attempt to investigate the molecular mechanism and functional effects of the interaction between Grb7 and Pin1. By co-immunoprecipitation and mutational analysis, we found that Pin1 enables directly interacting with Grb7 through the phospho-Ser 194-Pro motif on Grb7 and the WW domain of Pin1. Moreover, knockdown of Pin1 expression through lentiviral-mediated gene silencing could retain elevated Grb7 expression. Furthermore, utilizing cycloheximide pulse-chase assay and quantitative RT-PCR analysis, we conclude that Pin1 could negatively regulate Grb7 protein stability at the post-translational level. In addition, the Grb7-Pin1 interaction could modulate cell proliferation but not cell migration or cell viability. As the result of this research, we expect that the molecular mechanisms of the interaction between Grb7 and Pin1 may be beneficial for potential applications on anti-cancer therapies since both molecules have been indicated on tumorigenecity. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T10:15:02Z (GMT). No. of bitstreams: 1 ntu-102-R00633020-1.pdf: 5096028 bytes, checksum: f41bf83649c6220f239fb243604b0150 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 中文摘要…………………………………………………………………v
Abstract…………………………………………………………………vi Introduction……………………………………………………………1 Grb7………………………………………………………………………1 Grb7 structure and function……………………………………… 2 Phosphorylation, dimerization and localization………………7 Grb7-mediated signaling and cellular function……………… 9 Grb7 in cancer……………………………………………………… 12 Pin1…………………………………………………………………… 13 Pin1 structure and function………………………………………14 Pin1 in cell cycle and cancer……………………………………16 Pin1 in pathological disease…………………………………… 18 Phosphorylation-specific prolyl isomerization mechanism………………………………………………………………19 Materials and Methods………………………………………………22 Reagents……………………………………………………………… 22 Construction of expression vectors…………………………… 23 Cell culture………………………………………………………… 25 Lentiviral production and infection……………………………25 Cell transfection and generation of stable cell pools……26 Immunoprecipitation and western blotting analysis…………27 Recombinant protein expression and purification……………28 Glutathione-S-transferase pull-down assay……………………29 Cycloheximide pulse-chase experiment………………………… 30 RNA extraction and reverse-transcription PCR……………… 31 Boyden chamber assay……………………………………………… 32 Bromodeoxyuridine incorporation assay…………………………33 Cell viability assay……………………………………………… 34 Results…………………………………………………………………35 Pin1 can directly interact with Grb7………………………… 35 Phosphorylation of Grb7 on the Ser194-Pro motif may be critical for the interaction between Grb7 and Pin1……… 36 Expression of Pin1 inversely correlated with Grb7 expression…………………………………………………………… 37 Pin1 reduces the stability of Grb7…………………………… 39 Pin1 may involve in the post-translational regulation of Grb7…………………………………………………………………… 40 Grb7-mediated downstream signaling…………………………… 41 Effects of Grb7 serine phosphorylation deficient mutants in tumor cell migration, proliferation, and cell viability…43 Discussion…………………………………………………………… 45 Figures and Figure legends……………………………………… 49 References…………………………………………………………… 65 | |
| dc.language.iso | en | |
| dc.title | Pin1蛋白在參與Grb7媒介之訊息傳遞上所扮演的調控角色 | zh_TW |
| dc.title | Regulatory role of Pin1 in Grb7-mediated cell signaling | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李士傑(Shyh-Jye Lee),詹迺立(Nei-Li Chan),丁詩同(Shih-Torng Ding),李財坤(Tsai-Kun Li),呂佩融(Pei-Jung Lu) | |
| dc.subject.keyword | growth factor receptor-bound protein-7 (Grb7),peptidyl-prolyl cis/trans isomerase (Pin1),定點突變分析,乳癌, | zh_TW |
| dc.subject.keyword | growth factor receptor-bound protein-7 (Grb7),peptidyl-prolyl cis/trans isomerase (Pin1),mutational analysis,breast cancer, | en |
| dc.relation.page | 81 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-08-19 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 植物病理與微生物學研究所 | zh_TW |
| 顯示於系所單位： | 植物病理與微生物學系 | |
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