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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 曾賢忠 | |
dc.contributor.author | Chih-Yao Li | en |
dc.contributor.author | 李智堯 | zh_TW |
dc.date.accessioned | 2021-06-13T01:09:53Z | - |
dc.date.available | 2016-10-07 | |
dc.date.copyright | 2011-10-07 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-08-03 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29541 | - |
dc.description.abstract | Programmed Cell Death 5 (PDCD5)又名TFAR19 (TF-1 cell apoptosis-related gene 19),最早被發現在TF-1細胞凋亡時會大量產生,並進入細胞核內執行作用。但是PDCD5如何被活化及其相關訊息分子,目前仍不清楚。此外,在許多的癌症細胞中,PDCD5的表達都比較低,這被認為和癌症細胞克服細胞凋亡增加生長與存活有關。本研究之目的在探討PDCD5是如何被活化和傳導訊息來執行細胞凋亡。我們採用GAL4/UAS系統建立的轉基因果蠅做交配來找尋可能與PDCD5相關的分子,首先建立PDCD5轉基因果蠅,利用dsRNA選擇性在眼睛抑制PDCD5表現,並藉其眼睛潰爛的表現型和不同分子之轉基因果蠅進行交配,再由觀察眼睛表現型的變化來推測PDCD5可能相關的訊息傳導路徑。然後再將篩選結果在人類細胞做進一步驗證和分析,從而找出調節PDCD5與被PDCD5控制的相關分子。由於現有文獻報告指出PDCD5與癌症形成關連,因此我們首先篩選和癌症相關的訊息傳遞路徑。我們發現mTOR訊息傳遞路徑中,TSC高度表達或抑制S6K活性皆可減輕PDCD5轉基因果蠅眼睛之潰爛,顯示mTOR和PDCD5的訊息傳遞頗有關連。另一方面,我們也發現c-Abl作用增強會加重PDCD5被抑制掉所造成的果蠅眼睛潰爛,說明c-Abl也參與PDCD5的訊息傳遞。Hedgehog與Wnt訊息不僅在細胞發育與生長方面扮演重要角色,也和癌症的形成有關。我們發現Hedgehog訊息傳遞路徑下游的轉錄因子Ci高度表達時可以減緩PDCD5轉基因果蠅眼睛之表現型。而Wnt訊息傳遞路徑中的轉錄因子LEF/TCF高度表達時也有類似的現象。綜合上述,利用GAL4/UAS轉基因果蠅系統,我們篩選到mTOR、c-Abl、Hedgehog和Wnt的訊息傳遞路徑和PDCD5的訊息傳導可能有直接或間接的關係。接下來,我們決定先用BJAB淋巴瘤和AGS胃癌這兩種癌症細胞株來深化機轉的研究,希望透過更瞭解PDCD5的作用和訊息傳遞,藉以研發可以調控PDCD5表達和訊息傳導的藥物,提供癌症治療之新標靶和新策略。 | zh_TW |
dc.description.abstract | Programmed cell death 5 (PDCD5), also known as TFAR19 (TF-1 cell apoptosis-related gene 19), is a novel apoptosis-related gene, which was first identified as a gene upregulated in TF-1 cells undergoing apoptosis. During apoptosis, PDCD5 rapidly translocates from cytoplasm where it normally resides to the nucleus for its action and this process occurs much earlier than externalization of membrane phosphatidylserine and nuclear DNA fragmentation, suggesting that PDCD5 might be crucial in the initiation of apoptosis. In addition, a decrease of PDCD5 expression, presumably to suppress apoptosis, has been reported in various human tumors, such as breast cancer, hepatocellular carcinoma, and gastric tumor. Nevertheless, the mechanisms of PDCD5 activation and signaling remain largely unclear and this motivates us to conduct an in-depth investigation. We took advantage of the powerful genetics of Drosophila by phenotypic analysis to unravel the associated molecules and pathways with PDCD5. The UAS/GAL4 ectopic gene expression system was utilized to generate a Drosophila line carrying an eye-specific dsRNA knockdown of PDCD5 gene as a convenient readout for screening. By crossing this fly line with other genetically modified flies of a specific molecule of interest, we can determine its potential relationship with PDCD5 through assessment of changes of the eye phenotype. We started to investigate key pathways in tumorigenesis for PDCD5 is often down-regulated in cancer. We found that both gain-of-function of TSC (tuberous sclerosis) and dominant negative mutation of S6K (ribosomal S6 kinase) genes of mTOR pathway rescued the rough-eye phenotype of PDCD5 gene knockdown. In contrast, over-expression of c-Abl enhanced the rough-eye phenotype of PDCD5 knockdown. Hedgehog and Wnt pathways are known to play an important role in not only growth and development but tumorigenesis. We found that both gain-of-function of Ci (Cubitus interruptus), a transcription factor of Hedgehog pathway, and the dominant negative mutation of LEF/TCF (lymphoid enhancer-binding factor 1/T cell-specific transcription factor) gene of Wnt pathway rescued the rough-eye phenotype of PDCD5 knockdown. The results from this initial screening showed that PDCD5 signaling may crosstalk and interact with intermediaries of mTOR, c-Abl, Hedgehog and Wnt signaling pathways, respectively. To validate these findings from Drosophila crosses in mammals, we decided to use BJAB (human Burkitt's lymphoma) and AGS (human gastric adenocarcinoma) cell lines for further investigation. In summary, our data from screening genetically modified flies have provided insights into the anti-apoptotic mechanisms of cancer cells through modulation of PDCD5 and pointed out a PDCD5-based novel strategy for drug discovery to treat cancers. | en |
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dc.description.tableofcontents | Contents
口試委員審定書 I 中文摘要 II Abstract III List of Abbreviations V Contents IX Contents of Figures XII Contents of Tables XV Chapter 1. Introduction 1 1.1 Apoptosis 2 1.2 PDCD5 gene is a novel apoptosis-related gene 5 1.3 PDCD5 and cancer 6 1.4 MTOR (mammalian target of rapamycin) signaling pathway regulates a wide variety of cellular events 8 1.5 c-Abl is a nonreceptor tyrosine kinase that is linked to growth factor receptor signaling 9 1.6 PI 3-kinases (PI3Ks) regulate many aspects of cellular functions 11 1.7 Yki is a member of hippo pathway that control cell size 12 1.8 The Hedgehog signaling pathway regulates cell growth and cell differentiation in embryos 13 1.9 Wnt signaling pathway in embryogenesis and cancer 15 1.10 Autophagy pathway 16 1.11 Motivation 17 Chapter 2. Materials and Methods 19 2.1 Materials 20 2.2 Generation of plasmid constructs 20 2.3 Cell culture of BJAB and AGS cells 21 2.4 Reverse transcription-polymerase chain reaction (RT-PCR) 22 2.5 Western blotting 22 2.6 Cell viability assay 23 2.7 Immunofluorescence staining (IFS) 24 2.8 Transgenic Drosophilla strains 24 2.9 Statistical analysis 27 Chapter 3. Results 28 3.1 MTOR pathway is involved in PDCD5 signaling pathway 29 3.2 C-Abl pathway is involved in PDCD5 signaling 29 3.3 The rough-eye phenotype of PI3K is not dependent on PDCD5 30 3.4 The rough-eye phenotype of Yki is not dependent on PDCD5 30 3.5 Hedgehog signal is involved in PDCD5 signal pathway 31 3.6 Wnt pathway is associated with PDCD5 signaling pathway 31 3.7 ATG1 and ATG7 are not involved in PDCD5 signal pathway 32 3.8 Both BJAB cells and AGS cells express PDCD5 33 3.9 Cisplatin and H2O2 can induce apoptosis 34 3.10 Cisplatin and H2O2 do not induce PDCD5 mRNA expression 35 3.11 Cisplatin induces PDCD5 protein expression 35 3.12 Exogenous H2O2 activates c-Abl phosphorylation 36 3.13 Exogenous H2O2 decreases the mRNA expression levels of c-Abl 36 3.14 Cisplatin and H2O2 alter the cellular localization of PDCD5 37 Chapter 4. Discussion 38 Figures and Tables 49 References 112 Appendix 124 Contents of Figures Chapter 1 Figure 1-1 A schematic representation of apoptotic triggers 50 Figure 1-2 The conserved DNA binding domain of PDCD5 across species 51 Figure 1-3 An illustration of the mTOR and PI3K/Akt signaling pathways 52 Figure 1-4 The mechanisms of c-Abl to induce cell cycle arrest and apoptosis 53 Figure 1-5 A schematic representation of signal transduction through phosphatidylinositol-3-kinase (PI3K)/AKT 55 Figure 1-6 The Hedgehog signaling pathway 56 Figure 1-7 Wnt signaling pathway 57 Figure 1-8 Autophagy pathway 58 Chapter 2 Figure 2-1 The UAS/GAL4 ectopic expression system 64 Figure 2-2 The rough-eye phenotype of PDCD5 knockdown is triggered by UAS/GAL4 ectopic expression system 65 Figure 2-3 Strategy to generate a stable fly line of PDCD5 dsRNA knockdown for screening 67 Figure 2-4 Strategy to generate a stable fly line of ectopic c-Abl over-expression 68 Chapter 3 Figure 3-1 Gain-of-function of TSC rescues the rough-eye phenotype of PDCD5 knockdown 69 Figure 3-2 Gain-of-function of S6K rescues the rough-eye phenotype of PDCD5 knockdown 71 Figure 3-3 Gain-of-function of c-Abl worsens the rough-eye phenotype of PDCD5 knockdown 73 Figure 3-4 Dominant negative mutant of PI3K enhances the degree of eye roughness of PDCD5 knockdown flies 75 Figure 3-5 The rough-eye phenotype of Yki is not dependent on PDCD5. 77 Figure 3-6 Slimb gain-of-function does not affect the rough eye phenotype of PDCD5 78 Figure 3-7 Gain-of-function of Ci rescues the rough-eye phenotype of PDCD5 knockdown 79 Figure 3-8 Smo gain-of-function does not affect the rough-eye phenotype of PDCD5 knockdown 81 Figure 3-9 The rough-eye phenotype of gain-of-function mutation of Arm is not dependent on PDCD5 82 Figure 3-10 Dominant negative mutant of TCF rescues the rough-eye phenotype of PDCD5 knockdown 84 Figure 3-11 ATG1 knockdown does not change the rough-eye phenotype of PDCD5 knockdown 86 Figure 3-12 ATG7 knockdown does not change the rough-eye phenotype of PDCD5 knockdown 88 Figure 3-13 Both BJAB cells and AGS cells express PDCD5 89 Figure 3-14 Both cisplatin and H2O2 induce cell death 91 Figure 3-15 Cisplatin and H2O2 do not alter mRNA expression levels of PDCD5 93 Figure 3-16 Cisplatin induces PDCD5 expression 95 Figure 3-17 Exogenous H2O2 stimulates c-Abl tyrosine phosphorylation 97 Figure 3-18 Exogenous H2O2 decreases the mRNA expression levels of c-Abl 98 Figure 3-19 Cisplatin and H2O2 alter the cellular localization of PDCD5 100 Chapter 4 Figure 4-1 The speculated relationship of PDCD5 with TSC1 and S6K 102 Figure 4-2 The possible effects of PDCD5 on c-Abl 103 Figure 4-3 The speculated relationship of PDCD5 with Ci 104 Figure 4-4 The speculated relationship of PDCD5 with TCF 105 Figure 4-5 The working model of pathways that interact or crosstalk PDCD5 based on the data from screening transgenic lines of Drosophila 106 Figure 4-6 The interacting proteins of PDCD5 reported in the literature 107 Contents of Tables Table 1-1 Apoptosis, necrosis and autophagy 59 Table 1-2 Currently available fly stocks for pathway-discovery 60 Table 1-3 The key functions of pathways for screening 62 Table 4-1 The results of pathway screenings against PDCD5 110 | |
dc.language.iso | en | |
dc.title | 探討PDCD5在腫瘤及免疫細胞的角色 | zh_TW |
dc.title | The Role of Programmed Cell Death Protein 5(PDCD5, PD-5) in Cancer and Immune Cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳青周,張百恩,吳君泰 | |
dc.subject.keyword | 程序化細胞死亡因子5,癌症,細胞凋亡, | zh_TW |
dc.subject.keyword | PDCD5,Cancer,apoptosis, | en |
dc.relation.page | 129 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-08-03 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
顯示於系所單位: | 藥理學科所 |
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