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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 胡孟君(Meng-Chun Hu) | |
dc.contributor.author | Tsai-Chun Lai | en |
dc.contributor.author | 賴財春 | zh_TW |
dc.date.accessioned | 2021-07-11T15:30:53Z | - |
dc.date.available | 2021-10-11 | |
dc.date.copyright | 2018-10-11 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-08-16 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78941 | - |
dc.description.abstract | 轉錄因子作為轉錄作用起始的輔助因子,擔任生物體內參與調控基因表現的重責。本篇論文分別探討liver receptor homologue-1 (LRH-1) 以及GATA2/3於細胞中的分子機制。首先,LRH-1主要表現在肝腸組織以及卵巢,於肝臟代謝中扮演重要角色藉以維持生理恆定。現今有關調控LRH-1蛋白質穩定性的分子機制知之甚少。首先,我們發現LRH-1蛋白質水解路徑係經泛素蛋白酶體調控,其後說明LRH-1 蛋白質水解受CUL4-DDB1泛素連接酶調節。DNA damage-binding protein 2 (DDB2) 已知為一CUL4-DDB1之受質辨識組成單元,我們發現DDB2會影響LRH-1蛋白質生成量,並且證實DDB2直接與LRH-1的DNA-binding domain產生交互作用,並且促進LRH-1蛋白質泛素化使其送往蛋白酶體進行蛋白質水解。在人類肝癌細胞株HepG2中,我們發現胰島素會使內生性LRH-1蛋白質隨著處理劑量以及時間增加而增多,但LRH-1 mRNA表現量則不受影響。而胰島素處理降低LRH-1泛素化程度,顯示胰島素透過抑制泛素–蛋白酶體路徑調節LRH-1。此外,DDB2過量表現也降低LRH-1的轉錄活性,以及其下游基因之表現,而DDB2 knockdown卻發現glucokinase (GCK) 表現增加進而影響到HepG2對於葡萄糖吸收以及乳酸生成的能力,說明DDB2調控LRH-1之蛋白質穩定性,進而控制LRH-1在肝臟中的葡萄糖代謝功能。
LRH-1已知能夠調控許多類固醇生成酵素之表現,而HSD3B酵素參與三種固醇類賀爾蒙之合成,其中HSD3B1在胎盤的表現對於懷孕期間黃體素的產生十分重要。為了瞭解人類胎盤中HSD3B1基因調控的機制,我們分別將2.2 kb長度的啟動子片段以及個別片段刪除之啟動子選殖至具有螢光素酶 (luciferase) 報導基因的質體上,再進一步轉染入人類胎盤細胞株JEG-3進行分析。實驗結果發現近端-238/+337序列具有最高之轉錄活性,並發現此片段中具有兩個GATA位點,位點突變會大大地降低其在JEG-3細胞中的啟動子活性。進一步,我們發現GATA2以及GATA3能夠活化HSD3B1啟動子活性。EMSA實驗證實GATA2會結合到JEG-3細胞中的HSD3B1啟動子上的GATA片段。在JEG-3細胞中將GATA2 knockdown會顯著地降低HSD3B1表現,然而,GATA3 knockdown則是增加HSD3B1表現。最後,於西方墨點法分析發現GATA2在人類胎盤組織中具有高量表現,而非GATA3。本篇研究找出對於調控HSD3B1轉錄必要之GATA motif,並說明GATA2為一調控人類胎盤HSD3B1轉錄之重要分子。 | zh_TW |
dc.description.abstract | Transcription factors function as cofactor in gene transcription and account for regulation of gene expression. This study is aimed to figure out the molecular and cellular mechanisms of Liver receptor homologue-1 (LRH-1) and GATA2/3. Firstly, LRH-1 is predominantly expressed in enterohepatic tissues and ovary, and which is critical for hepatic metabolism to sustain homeostasis. Currently, the molecular mechanism underlying LRH-1 protein stability is poorly understood. First, we found that LRH-1 proteolysis is via ubiquitin-proteasome system, and we proved that CUL4-DDB1 ubiquitin ligase is involved in LRH-1 proteolysis. Furthermore, DNA damage-binding protein 2 (DDB2), functions as a well-known substrate recognition component of CUL4-DDB1, we observed that DDB2 affects LRH-1 protein levels, and indicated that DDB2 interacts with LRH-1 DNA-binding domain and targets LRH-1 for ubiquitin-proteasomal degradation. In human hepatoma (HepG2) cells, we observed that protein levels of endogenous LRH-1 are increased in a dosage- and time-dependent manner by insulin treatment, but without a change in mRNA levels of LRH-1. Then, insulin treatment decreased LRH-1 ubiquitination levels, indicating that insulin may stabilize LRH-1 protein via suppression of UPS. Moreover, overexpression of DDB2 diminished LRH-1 transcriptional activation and expression of target genes, whereas knockdown of DDB2 increased the expression of glucokinase (GCK) and influenced glucose uptake and lactate production in HepG2 cells, inferring that DDB2 regulates LRH-1 protein stability and modulates the hepatic glucose metabolism.
LRH-1 directly regulates expression of several steroidogenic enzymes, and HSD3B enzyme is essential for synthesis of three type steroid hormones. Among them, HSD3B1 expression is essential to produce progesterone for pregnancy maintenance. To understand the mechanisms of human HSD3B1 activation in the placenta, 2.2 kb of 5′-flanking sequence and 5′-deletions were fused to the luciferase reporter gene and transfected into human JEG-3 cells. The proximal -238/+337 sequence had the highest transcriptional activity, and we identified two GATA sites. Mutations of GATA sites greatly reduced promoter activity in JEG-3 cells, demonstrating the importance of GATA sites. Next, we observed that GATA2 and GATA3 both elevated HSD3B1 promoter activity. EMSA revealed the specific binding of GATA2 and GATA3 to the GATA sequences. GATA2 knockdown significantly reduced HSD3B1 expression in JEG-3 cells; however, GATA3 knockdown increased HSD3B1 expression. Western blot analysis revealed high levels of GATA2 but not GATA3 in human placental tissues. This study identified GATA motifs as essential control elements for HSD3B1 transcription and GATA2 as a novel transcriptional regulator of HSD3B1 expression in the human placenta. | en |
dc.description.provenance | Made available in DSpace on 2021-07-11T15:30:53Z (GMT). No. of bitstreams: 1 ntu-107-D00441002-1.pdf: 2111072 bytes, checksum: 7b605fbfee92f49b914c9bcdb413436c (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 目錄
誌謝 I 目錄 II 表次 IV 圖次 V 中文摘要 VII 英文摘要 IX Chapter I. DDB2 E3 ligase regulates LRH-1 proteolysis and hepatic glucose metabolism 1 Introduction 1 Physiological functions of liver receptor homologue-1 (LRH-1) 1 LRH-1 co-regulators and post-translational modification 2 Ubiquitin-proteasome system 3 Cullin-RING ubiquitin ligase family 4 DDB2 6 Aim of this study 7 Result 8 LRH-1 is degraded by ubiquitin-proteasome system 8 Cullin 4-RING ubiquitin ligases regulate LRH-1 proteolysis 9 CUL4-DDB1-DDB2 ubiquitin ligase complexes govern LRH-1 protein levels 10 LRH-1 interacts with DDB2 11 DDB2 facilitates LRH-1 ubiquitination and destabilizes LRH-1 12 Insulin upregulates LRH-1 in HepG2 cells that is repressed by DDB2 13 Effects of DDB2 on LRH-1-mediated functions 15 Discussion 17 Chapter II. Proximal GATA-binding sites are essential for human HSD3B1 gene transcription in the placenta 41 Introduction 41 HSD3B gene 41 Physiological function of HSD3B in placenta 41 GATA2/3 43 Aim of this study 45 Result 46 Promoter activity of human HSD3B1 gene in JEG-3 cells 46 Enhancement of HSD3B1 promoter activity by GATA2 and GATA3 47 Expression of HSD3B, GATA 2, and GATA3 in the placenta 48 Analysis of GATA2 and GATA3 binding to the GATA elements 49 Effects of GATA2 or GATA3 knockdown on HSD3B1 expression 50 Discussion 51 Materials and methods 66 Plasmids 66 Cell culture, transfection and treatment 67 Human tissues and animals 68 shRNA knockdown 69 Cellular extraction, immunoprecipitation, subcellular fractionation, and western blot analysis 69 Electrophoretic mobility shift assay (EMSA) 72 GST pull-down 73 Immunofluorescence 74 Cycloheximide chase experiment 74 Luciferase assay 75 RNA extraction and quantitative reverse transcription PCR (RT-qPCR) 75 Chromatin immunoprecipitation (ChIP) 76 Glucose and lactate assay 78 Statistical analysis 78 References 79 Publication 89 表次 Table 1. Antibodies used in the western blot analysis 72 Table 2. Primer sequences for RT-qPCR 77 圖次 Figure 1. LRH-1 protein is degraded by the ubiquitin-proteasome pathway 23 Figure 2. Lysine 48 linked-ubiquitin promotes LRH-1 protein degradation 24 Figure 3. Cullin-RING ligase inhibitor MLN4924 increases LRH-1 protein 25 Figure 4. CRL4 ubiquitin ligases regulate LRH-1 protein degradation 26 Figure 5. CUL4-DDB1 ubiquitin ligase complex affects LRH-1 protein degradation 27 Figure 6. DDB2 regulates LRH-1 protein degradation 28 Figure 7. CUL4-DDB1-DDB2 complex interact with LRH-1 29 Figure 8. LRH-1 interacts with DDB2 through its DNA binding domain 30 Figure 9. Co-localization of LRH-1 and DDB2 in the nucleus 31 Figure 10. DDB2 promotes LRH-1 ubiquitination 32 Figure 11. DDB2 destabilizes LRH-1 protein turnover 33 Figure 12. Insulin increases LRH-1 protein levels 34 Figure 13. Insulin diminishes LRH-1 ubiquitination 35 Figure 14. DDB2 overexpression reduces insulin-stimulated LRH-1 protein increase 36 Figure 15. DDB2 overexpression affects LRH-1-mediated target genes 37 Figure 16. DDB2 diminishes LRH-1-driven promoter activity 38 Figure 17. Effects of DDB2 on LRH-1-mediated gene expression and glucose metabolism 39 Figure 18. Transcriptional activity of the human HSD3B1 promoter 57 Figure 19. Enhancement of the transcriptional activity of the HSD3B1 promoter by two putative GATA sites 58 Figure 20. Effects of GATA factors on the transcriptional activity of the HSD3B1 promoter 59 Figure 21. Expression of HSD3B, GATA2, and GATA3 in cell lines and tissues 60 Figure 22. Analysis of GATA2 and GATA3 binding to sites at -106/-45 in the HSD3B1 promoter 61 Figure 23. Effects of GATA2 or GATA3 knockdown on HSD3B1 expression 63 Figure 24. Integrative Genomics Viewer shows GATA2 ChIP-seq results using the data set from GEO 64 Figure 25. Analysis of GATA-like binding site between -558 and -547 in HSD3B1 promoter 65 | |
dc.language.iso | en | |
dc.title | 探討轉錄因子LRH-1與GATA2/3的分子細胞機制 | zh_TW |
dc.title | Molecular and cellular mechanisms of transcription factors LRH-1 and GATA2/3 | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 陳小梨(Show-Li Chen),鄭瓊娟(Chung-Jiuan Jeng),王致恬(Chih-Tien Wang),盧主欽(Juu-Chin Lu) | |
dc.subject.keyword | 轉錄因子,泛素連接?,葡萄糖代謝,類固醇生成, | zh_TW |
dc.subject.keyword | Transcription factor,ubiquitin ligase,glucose metabolism,steroidogenesis, | en |
dc.relation.page | 89 | |
dc.identifier.doi | 10.6342/NTU201803646 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-08-16 | |
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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