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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳小梨 | |
| dc.contributor.author | Tsung-Wei Ma | en |
| dc.contributor.author | 馬琮瑋 | zh_TW |
| dc.date.accessioned | 2021-06-15T04:44:27Z | - |
| dc.date.available | 2012-09-09 | |
| dc.date.copyright | 2010-09-09 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-08-09 | |
| dc.identifier.citation | Alroy I, Yarden Y.(1997)”The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions.” FEBS Lett. 410(1):83-6.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45669 | - |
| dc.description.abstract | 第四人類表皮生長因子接受器(ErbB4)是人類表皮生長因子接受器家族的第四位成員。由於表皮生長因子接受器(EGFR)的醣化位置及其功能已被確認及研究，而ErbB4擁有和EGFR相似的蛋白質胞外結構，因此也被預測為醣化蛋白。根據信息RNA切割處理的不同，ErbB4擁有四種等形(isoforms)，每一種等形在結構及功能方面均有所不同。在先前的研究中，EGFR、ErbB2以及ErbB3被發現大量表現於前列腺癌中，ErbB4則否。此外，EGFR及ErbB2的配體腫瘤生長因子α(TGFα)表現於大多數的前列腺癌細胞中，然而ErbB4的配體新分化因子(NDF)卻只會表現在仍可死亡(not immortalized)、尚未轉型(not transformed)的前列腺表皮細胞。這些研究暗示ErbB4扮演前列腺癌抑制分子的角色。此外，也有其他研究顯示ErbB4的表現可抑制前列腺癌細胞聚落形成的能力。根據以上的資料來推論，ErbB4很可能在前列腺癌中扮演抑制者的角色。
雄性激素受體(Androgen receptor, AR)是已被廣為研究的分子。目前已知它會高量表現於前列腺癌中，並於其中擔任重要的轉錄因子，調控一系列下游基因的表現，維持前列腺癌細胞的生長，並致使其更加惡化。已有研究指出，IGF-1及IL-6可誘發下游訊息傳遞路徑PI3K/Akt/Mdm2活化，並經由此一路徑提升雄性激素受體的polyubiquitylation及蛋白質毀壞。 我們的研究證實ErbB4為醣化蛋白。本篇研究的主角是ErbB4(JMbCYT1)以及ErbB4(JMbCYT1) N358Q，一個較缺乏醣化的ErbB4(JMbCYT1)突變蛋白。在此，我們也提出一個ErbB4影響AR的全新機制－在不需依賴配體刺激的情況下，過度表現ErbB4(JMbCYT1)可引發下游訊息傳遞分子PI3K/Akt/Mdm2活化， 導致AR轉錄下游基因能力下降，提高AR蛋白的polyubiquitylation及毀壞，並致使前列腺癌細胞生長率顯著下降。然而，相較於ErbB4(JMbCYT1)，過度表現較缺乏醣化的ErbB4(JMbCYT1)N358Q突變蛋白只能引發些微的下游訊息傳遞分子PI3K/Akt/Mdm2活化，也只能導致AR轉錄下游基因能力小幅下降，AR蛋白毀壞小幅提升，以及前列腺癌細胞生長率小幅下降。這些結果顯示，醣化對於ErbB4的正常功能是必需的。 | zh_TW |
| dc.description.abstract | ErbB4 is the fourth member of ErbB receptor tyrosine kinase family. With similar organization of extracellular domains to EGFR, of which the N-glycosylation sites are determined and studied, ErbB4 is predicted to be an N-glycosylated protein. According to different mRNA splicing, there are four isoforms of ErbB4, each has structural and functional differences from others. In previous research, ErbB1 (EGFR), ErbB2 and ErbB3 have been reported to being highly expressed in prostate cancer while ErbB4 has not. Otherwise, TGFα, the ligand of ErbB1 and ErbB2, is expressed in majority of prostate cancer cells, while the ligand of ErbB4, Neu Differentiation Factor/Heregulin (NDF), is expressed only in immortalized, non-transformed prostate epithelial cells. The above researches imply that ErbB4 may play a role as prostate tumor repressor. Furthermore, some researches also indicate that ErbB4 expression inhibits colony formation of prostate cancer cells. With the above information, ErbB4 can be hypothesized to be a prostate tumor suppressor.
Androgen receptor (AR), a well-studied molecule, is known to be highly expressed in prostate cancer and functions as an important transcription factor to regulate the expression of a great number of genes, then guides the prostate cancer cells into a malignant stage or maintains prostate cancer cell growth. Some researches point out that IGF-1 and IL-6 can induce downstream signaling pathway PI3K/Akt/Mdm2 then increase polyubiquitylation and proteasome-mediated protein degradation of AR. In our study, ErbB4 is proven to be an N-glycosylated protein. ErbB4(JMbCYT1) and ErbB4(JMbCYT1) N358Q mutant, which is a de-N-glycosylated ErbB4, were under investigation. Here we provide a whole new mechanism through which ErbB4 affects AR protein. Overexpression of ErbB4(JMbCYT1) downregulates AR transactivation through a ligand-independent way, upregulates polyubiquitylation and proteasome-mediated protein degradation of AR through activation of PI3K/Akt/Mdm2 pathway, and also abolishes proliferation of prostate cancer cells. However, overexpression of de-N-glycosylated ErbB4(JMbCYT1) N358Q can only induce slight activation of PI3K/Akt/Mdm2 pathway, downregulate AR protein, AR transactivation and proliferation of prostate cancer cells slightly when compared with ErbB4(JMbCYT1), indicates that N-glycosylation is required for ErbB4 function. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T04:44:27Z (GMT). No. of bitstreams: 1 ntu-99-R97445114-1.pdf: 1315671 bytes, checksum: c69ccc2ed178a6dd3ba30c6b1e97029b (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 口試委員會審定書………………………………...............................i
誌謝……………………………………………………………………….ii 中文摘要…………………………………………………………… iii 英文摘要………………………………………………………………v CHAPTER 1 INTRODUCTION………………………………………1 1.1 ErbB4 (Her4, Human epidermal growth factor receptor4)...…………1 1.2 ErbB4 plays a controversial role in cancer …………………………2 1.3 N-Glycosylation of epidermal growth factor recpetor (EGFR/ErbB1) and ErbB4…………………………………………………………4 1.4 AR plays an important role in prostate cancer ………...........................6 1.5 The crosstalk between EGFR/HER2 and AR/prostate cance..….…….8 1.6 The effect of ErbB4 on prostate cancer…………………………...……9 1.7 Aims of the thesis……..…………...….…………………...….………11 CHAPTER 2 MATERIALS AND METHODS..………………..……...12 2.1 Cell culture and drug treatment……………………………………….12 2.2 Determination of N-glycosylation site of ErbB4 and construction of pcDNA3.1-ErbB4(JMbCYT1)N358Q mutant…….………………….13 2.3 Calcium phosphate transient transfection …...……………...………...14 2.4 Luciferase activity assay……...……………………………….… ..…15 2.5 Lentivirus production, titration and infection…………………………15 2.6 Immunoprecipitation ………………………...……………………… 16 2.7 Western blotting assay………...………………..………………..……17 2.8 RNA extraction…………………..……………………………………18 2.9 RT-PCR Analysis……………………………………...………………19 2.10 ErbB4 phosphorylation assay………………………...……………...21 2.11 Cell proliferation assay……………………………...……………….22 CHAPTER 3 RESULTS…………………………………...…………….23 3.1 ErbB4 is an N-glycosylated transmembrane protein………...………..23 3.2 ErbB4 reduces AR protein expression and its transcription activity….25 3.3 ErbB4 promotes AR degradation through proteasome-mediated protein degradation…………............................................................................27 3.4 Glycosylated ErbB4-activated PI3K-Akt-Mdm2 signaling pathway induces AR protein degradation…...………….………………………29 3.5 ErbB4 decreases proliferation rates of AR-expressing prostate cancer cell line, LNCaP…………..…..............................................................30 3.6 ErbB4 decreases proliferation rates of both non-AR-expressing and AR-stably-expressing PC-3 prostate cancer cell line PC-3...…………31 CHAPTER 4 DISCCUSION……………………………………………34 REFERENCES …………………………………………………...……..40 FIGURES………………………………………………………...………47 APPENDIX………………………………………………………………58 | |
| dc.language.iso | en | |
| dc.subject | Akt | zh_TW |
| dc.subject | 第四人類表皮生長因子接受器 | zh_TW |
| dc.subject | Mdm2 | zh_TW |
| dc.subject | polyubiquitylation | zh_TW |
| dc.subject | 醣化 | zh_TW |
| dc.subject | PI3K | zh_TW |
| dc.subject | 雄性激素受體 | zh_TW |
| dc.subject | N-glycosylation | en |
| dc.subject | polyubiquitylation | en |
| dc.subject | Mdm2 | en |
| dc.subject | Akt | en |
| dc.subject | ErbB4 | en |
| dc.subject | AR | en |
| dc.subject | PI3K | en |
| dc.title | 醣化ErbB4影響雄性激素受體蛋白之機制探討 | zh_TW |
| dc.title | The glycosylated ErbB4 receptor-mediated signaling regulates androgen receptor | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 葉秀慧,鄧述諄 | |
| dc.subject.keyword | 第四人類表皮生長因子接受器,雄性激素受體,醣化,PI3K,Akt,Mdm2,polyubiquitylation, | zh_TW |
| dc.subject.keyword | ErbB4,AR,N-glycosylation,PI3K,Akt,Mdm2,polyubiquitylation, | en |
| dc.relation.page | 58 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-08-09 | |
| 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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