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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59041完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 曾賢忠 | |
| dc.contributor.author | Tze-Ting Su | en |
| dc.contributor.author | 蘇子婷 | zh_TW |
| dc.date.accessioned | 2021-06-16T08:46:17Z | - |
| dc.date.available | 2023-08-19 | |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-08-20 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59041 | - |
| dc.description.abstract | Programmed cell death 5 (PDCD5) 最早是自人類紅白血病細胞TF-1中分離出的基因。當TF-1細胞因缺乏生長因子而導致細胞凋亡時，PDCD5 蛋白質會高度表現。目前研究指出PDCD5在某些癌細胞的基本表達量較少，像是前列腺癌、胃癌和軟骨肉瘤等。而有研究指出若在癌細胞中過度表達PDCD5，可以增加癌細胞對於抗癌藥物的敏感度。由於PDCD5可能與腫瘤的增生與惡化相關，因此進一步探討其與腫瘤抑制基因p53之間的相關性。目前已知p53藉由調控細胞凋亡與細胞週期的停止來影響腫瘤的增生與惡化以及腫瘤對於抗癌藥物的敏感性。研究指出PDCD5可藉由組蛋白乙醯轉移酶Tip60作用於p53第120個胺基酸而活化細胞凋亡途徑。再者，PDCD5蛋白質可能藉由和p53蛋白質作用來影響p53下游基因的表現。因此，本研究的目標是進一步釐清PDCD5和p53在轉錄與轉譯過程中是否相互影響。藉由轉錄因子分析軟體我們預測出PDCD5啟動子區域中具p53結合區,但p53的角色是促進或抑制PDCD5的表達仍未知。當在人類腎臟細胞HEK293T過度表達PDCD5與p53時，發現p53可能降低PDCD5在轉錄與轉譯層面的表現。在人類大腸癌細胞株HCT116中，發現PDCD5在沒有p53的細胞株中表達較高。此外，由於PDCD5具DNA的結合區，因此經由染色質免疫沉澱法和核酸定序分析PDCD5可能直接調節的基因。過度表達PDCD5，發現和肌肉萎縮症相關的基因DUX4L4的表達在轉錄層面增加。由於之前有研究指出在心肌細胞過度表達PDCD5的基因轉殖鼠中，會藉由另一種細胞死亡的途徑－細胞自噬造成心臟肥大最後導致心臟衰竭。PDCD5在心臟細胞的表現量又高於其他身體組織，因此我們希望可以在後續的實驗進一步分析PDCD5是否會在心肌細胞中調節DUX4L4。另一可能基因為CCDC88C，能負調控Wnt的訊息傳遞，均有待進一步研究。 | zh_TW |
| dc.description.abstract | Programmed cell death 5 (PDCD5) is a protein identified from TF-1 cells during apoptosis process induced by growth factor deprivation. PDCD5 has been shown down-regulated in many cancer tissues. Overexpression of PDCD5 sensitizes cancer cells to chemotherapeutic agents. The tumor suppressor gene p53 induces apoptotic cell death and causes cell cycle arrest. P53 plays an important role in controlling the cellular response to DNA damage. Loss of p53 function causes increased resistance to chemotherapeutic agents, and p53 mutation is an important determinant of clinical outcome in cancer. Previously PDCD5 was shown to interact with Tip60, a histone acetyltransferase, and increase Tip60-dependent K120 acetylation of p53, which is essential for p53-dependent apoptosis. PDCD5 was also shown to interact with p53 and serves as a co-activator of p53 to regulate gene transcription, resulting in cell cycle arrest upon DNA damage. In this study, we focused on the relationship between PDCD5 and p53. Since the binding sites for p53 were predicted in PDCD5 promoter, we reasoned that PDCD5 might be a target gene of p53. We found that the mRNA and protein levels were decreased in HEK293T cells over-expressing p53. In the p53-deficient HCT116 colon cancer cells PDCD5 was also higher constitutively. Over-expression of PDCD5 in HEK293T cells had no significant effects on the expression of p53. By ChIP-Seq, we also identified DUX4L4 and mRNA expression was increased when PDCD5 was overexpressed in HEK293T cells. The double homeobox protein 4-like protein 4 (DUX4L4) gene was associated with facioscapulohumeral muscular dystrophy (FSHD) and the DUX4 mRNAs can be translated and localizes to the cell nuclei. DUX4L4 is a nuclear protein and it belongs to DUX4 family. This raised the possibility that PDCD5 might regulate DUX4 in the heart. DUX4 expression in cell culture alters the inner-nuclear envelope distribution of emerin and leads to cell death via apoptosis. In summary, the regulation of PDCD5 expression was mediated by p53 and DUX4L4 and perhaps CCDC88C as potential target genes of PDCD5. | en |
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| dc.description.tableofcontents | 口試委員審定書………………………………………………………………………I
中文摘要...........................................................II Abstract………………………………………………………………………………III List of abbreviation………………………………………………………………….V Contents……………………………………………………………………………...VII Contents of Figures………………………………………………………………..IX Contents of Tables…………………………………………………………………...X Chapter1. Introduction………………………………………………………1 1.1 Programmed cell death 5………………………………………………………...2 1.1.1 PDCD5 description…………………………………………………………….2 1.1.2 PDCD5 expression and localization……………………………………………2 1.1.3 The structure and function of PDCD5 protein…………………………………3 1.1.4 PDCD5 and apoptosis………………………………………………………….6 1.1.5 PDCD5 and autophagy…………………………………………………………7 1.1.6 PDCD5 and cancers…………………………………………………………….8 1.2 TP53………………………………………………………………………………..10 1.2.1 P53 description…………………………………………………………………10 1.2.2 P53 activation and regulation of downstream targets…………………………..10 1.2.3 The structure and function of p53………………………………………………11 1.2.4 Post-translational modification of p53………………………………………….11 1.2.5 Relationship between PDCD5 and p53………………………………………...12 1.3 DNA damage response…………………………………………………………….13 1.4 Tip60……………………………………………………………………………….13 1.4.1 Tip60 description……………………………………………………………….13 1.4.2 Tip60 and PDCD5 in the p53 pathway…………………………………………14 1.4.3 Tip60 and DNA double strand break response…………………………………14 1.5 Doxorubicin………………………………………………………………………..14 1.5.1 Drug description………………………………………………………………..14 1.5.2 Drug mechanism………………………………………………………………..15 1.5.3 The anticancer effect of drug…………………………………………………..16 1.5.4 The drug side effect……………………………………………………………16 1.6 Motivation…………………………………………………………………………17 Chapter2. Materials and Methods…………………………………….19 2.1 Cell lines and culture conditions………………………………………………..20 2.2 Cell treatments…………………………………………………………………..20 2.3 Plasmid constructs for overexpression and knockdown……………………...20 2.3.1 PDCD5 knockdown…………………………………………………………..20 2.3.2 PDCD5 overexpression………………………………………………………..21 2.3.3 P53 overexpression…………………………………………………………….21 2.3.4 Cell sorting…………………………………………………………………….22 2.4 Immunoblot and antibodies……………………………………………………...22 2.5 RNA extraction and semi-quantitative PCR…………………………………....23 2.6 Taqman Q-PCR…………………………………………………………………...24 2.7 Immunoprecipitation……………………………………..……………………….25 Chapter3. Results…………………………………………………………...…26 3.1 Putative binding sites of p53 transcription factor in human PDCD5 gene promoter…………………………………………………………………………..27 3.2 Over-expression of p53 in HEK293T cells down-regulated transcription and translation of human PDCD5gene………………………............................30 3.3 PDCD5 expression is induced following doxorubicin treatment in HCT116 cells……………..…………………………………………......................31 3.4 Over-expression of PDCD5 had no significant effects on the expression of p53 in HEK293T cells……………………..….………………………….….....33 3.5 Genetic knowdowns of PDCD5 resulted in increased susceptibility to DNA damage…………………………………………………………………………......34 3.6 The potential target genes of PDCD5……………………………………………35 Chapter4. Discussions…………………….………..........................…………37 Figures and Tables……………………………………………………………..45 References…………………………………………………………………………74 Appendix…………………………………………………………………………...83 Contents of figures Figure 3-1. A schematic diagram of human PDCD5 gene and cross-species sequence alignment………………………………………………………47 Figure 3-2. Human PDCD5 promoter region contains multiple binding sites for p53 transcription factor……………………………………………..51 Figure 3-3. Overexpression of p53 in HEK293T cells resulted in a decrease of PDCD5 expression at transcriptional and translational levels……….54 Figure 3-4. Co-immunoprecipitation of PDCD5 and p53 in HEK293T cells transiently transfected with Flag-p53 and EGFP-PDCD5 / PDCD5-EGFP…………………………………………………………..57 Figure 3-5. The mRNAs and proteins of PDCD5 increased in HCT116 cells in response to doxorubicin in a dose-dependent manner………………..60 Figure 3-6. Expression of p53 and PDCD5 was inversely correlated following doxorubicin treatment……………………………………………………61 Figure 3-7. Overexpression of PDCD5 reduced the expression level of p53 in HEK293T cells…………………………………………………………...64 Figure 3-8. Genetic knockdown of PDCD5 by shRNA enhanced the levels of phospho-γH2AX in response to doxorubicin in HEK293T cells……...67 Figure 3-9. Validation of potential target genes identified by chromatin immunoprecipitation-sequencing (ChIP-Seq) of overexpressed PDCD5……………………………………………………………………69 Figure 3-10. The cDNA alignment of DUX4 and DUX4L4…………………………72 Contents of tables Table 2-1 Primers used in Q-PCR analysis to detect the gene expression of human…………………………………………………………….…...73 | |
| dc.language.iso | en | |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | PDCD5 | en |
| dc.title | 探討PDCD5和p53在細胞中的分子機制 | zh_TW |
| dc.title | Molecular relationship between programmed cell death 5 and p53 | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林淑華,俞松良 | |
| dc.subject.keyword | 細胞凋亡, | zh_TW |
| dc.subject.keyword | PDCD5, | en |
| dc.relation.page | 84 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-08-20 | |
| 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 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-102-1.pdf 未授權公開取用 | 3.97 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。