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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 曾賢忠(Shiang-Jong Tzeng) | |
| dc.contributor.author | Kai-Li Lin | en |
| dc.contributor.author | 林凱莉 | zh_TW |
| dc.date.accessioned | 2021-06-16T17:19:07Z | - |
| dc.date.available | 2017-09-18 | |
| dc.date.copyright | 2012-09-18 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-08-17 | |
| dc.identifier.citation | Bassing CH., Suh H., Ferguson DO., Chua KF., Manis J., and Eckersdorff M. (2003) Histone H2A.X: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114, 359–370.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/63786 | - |
| dc.description.abstract | Programmed cell death 5 (PDCD5)是細胞在執行凋亡過程中扮演促進性角色的一個分子，最早是在TF-1細胞因失去生長因子而開始凋亡的過程中被發現。正常生理狀態下，細胞在遭受外在環境壓力時，欲維持內部恆定而選擇走向程序性凋亡的過程中該分子的活化被視為是早期訊號。先前的研究報導指出，多數的癌細胞為促進生長與存活，會透過降低PDCD5的表達來達成，此一現象凸顯出PDCD5的作用除了調控細胞生理恆定，亦在腫瘤細胞的惡化與增生扮演不可或缺的角色。但活化PDCD5的分子機制以及其下游的標的分子，目前仍不清楚。本研究之目的在於釐清PDCD5的活化調控方式以及與其一同參與細胞凋亡過程的相關作用分子。我們同時採用化學合成藥物以及分子生物技術分別來提高或抑制PDCD5分子在細胞內的表現程序，藉以研究PDCD5細胞凋亡的重要性。我們發現無論是在DNA損傷或細胞遭受氧化壓力的情況下導致的細胞凋亡，均會顯著提升PDCD5蛋白質的表達，並伴隨著活化caspase的連鎖效應。此外，經由RNA干擾技術抑制內生性PDCD5的生合成，顯示能非常有效地抑制因DNA損傷或者是過氧化自由基的破壞而引發的細胞凋亡，意味著PDCD5在細胞凋亡不可或缺。另外，我們也發現經由轉譯後修飾PDCD5蛋白本身離胺酸的乙醯化為該分子活化與執行細胞凋亡功能所必須。有關PDCD5基因和其蛋白質的調控和功能仍持續在解碼與釐清，我們希望透過發現與瞭解調控PDCD5表達與活化的相關作用分子作為開發藥物治療的標的。 | zh_TW |
| dc.description.abstract | Programmed cell death 5 (PDCD5) is a human apoptosis related molecule, which was first identified as TF-1 cell apoptosis related gene-19 (TFAR19) under growth factor or serum deprivation. The PDCD5 gene encodes a protein which shares significant homology across species ranging from yeast to mice. Under physiological conditions, the protein is thought to play an early and pivotal role in cells undergoing apoptosis prior to activation of the caspase cascade. PDCD5 exhibits a ubiquitous expression pattern and a decreased level of PDCD5 expression is associated with tumorigenesis such as in prostate cancer, colorectal carcinoma as well as ovarian cancer. However, the molecular mechanisms of PDCD5-mediated cell death and its downstream targets remain poorly understood. This prompted us to study the regulatory machinery of PDCD5 in cell death with respect to its triggers, partners and targets. We used both genetic and chemical approaches to address the functional role of PDCD5 in cells undergoing apoptosis. We found that both cisplatin and oxidative stress induced an up-regulation of PDCD5 levels in a dose-dependent and time-dependent fashion during apoptosis. Furthermore, the induction of PDCD5 was accompanied by activation of caspase cascades, leading to cleavage of PARP-1. PDCD5 was essential for apoptosis induction since small hairpin RNAs specific for silencing PDCD5 markedly rescued cell death in response to cisplatin and oxidative stress. When PDCD5 was activated in response to cisplatin and ROS, a portion of PDCD5 translocated from cytoplasm into nucleus, where activation of PDCD5 was linked to its lysine acetylation. Detailed analyses of post-translational modifications of PDCD5 and the identification of proteins responsible for such modifications for propagation of downstream signaling through PDCD5 are under investigation. In summary, our data have provided new insights into the molecular basis of PDCD5 in mediating apoptosis in response to DNA damage agents. More understanding of PDCD5’s actions should pave the way for the development of new targeted therapeutics that aimed to sensitize tumors to chemotherapeutic drugs. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T17:19:07Z (GMT). No. of bitstreams: 1 ntu-101-R99443003-1.pdf: 4848955 bytes, checksum: adbb7ba1f4274fb8bd970b3881664589 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | Contents
口試委員審定書……………………………………………………………………I 中文摘要……………………………………………………………………………II Abstract……………………………………………………………………………III List of Abbreviations……………………………………………...........V Contents……………………………………………………………………………VIII Contents of Figures and Tables……………………....................XI Chapter 1. Introduction…………………………………………...........1 1.1 Gene ontology and general profile of PDCD5…..................2 1.2 PDCD5 is a early signal for cell death……..…................3 1.3 Phosphorylation of PDCD5 in accelerating cell apoptosis……...3 1.4 Potential link of PDCD5 and death receptor pathway………………4 1.5 PDCD5 as a pro-apoptotic signal for cell death in multiple carcinomas……5 1.6 Programmed cell death (PCD or apoptosis)………................6 1.7 DNA damage induced cell death…………………………………….....7 1.8 Role of reactive oxygen species (ROS) in apoptosis induction..8 1.9 Endoplasmic reticulum stress-induced apoptosis…………………..9 1.10 Apoptosis related post-translational modifications of histones…………..11 1.11 Statement of the Motive……………………………………………….12 Chapter 2. Materials and Methods…………………....……….........14 2.1 Materials 2.1.1 Generation of plasmid constructs……………………...........15 2.1.2 RNA interference…………………………………………….........15 2.1.3 Cell culture………………………………………………….........16 2.2 Methods 2.2.1 Cell viability assay……………………………………...........16 2.2.2 Reverse transcription-polymerase chain reaction(RT-PCR)…..16 2.2.3 Western Blotting……………………………………………………….17 2.2.4 Immunofluorescence staining (IFS)…………………............17 2.2.5 Immunoprecipitation…………………………………………………..18 2.2.6 Chromatin Immunoprecipitation……………………………........18 2.2.7 Statistical analysis………………………………………………….19 Chapter 3. Results……………………………..………………………….…20 3.1 PDCD5 expression and cellular localization in BJAB B lymphoma cells and 293T human embryonic kidney cells……....21 3.2 Activation of PDCD5 in response to cisplatin induced DNA damage and apoptosis in 293T cells………………………....22 3.3 Reactive oxygen species (ROS) can augment PDCD5 expression .....................................24 3.4 PDCD5 is essential for cisplatin- and ROS-induced apoptosis………………...….....................................26 3.5 Knockdown of PDCD5 gene by specific short hairpin RNAs abolishes cisplatin-induced cell death in 293T cell...……28 3.6 Effects of over-expression of wild-type and S119A mutant constructs of PDCD5-EGFP and PDCD5-DsRed on 293T cells…30 3.7 Post-translational modification of PDCD5 through acetylation.....................................................32 3.8 Potential PDCD5 interacting proteins at basal state in 293T cells…...…………...................................34 Chapter 4. Discussion……………………………...……………………….37 Figures and Tables…………….…………………...…….…………………41 References……………………………………………………...………………79 | |
| dc.language.iso | en | |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | 程序性細胞凋亡因子5 | zh_TW |
| dc.subject | DNA損傷 | zh_TW |
| dc.subject | PDCD5 | en |
| dc.subject | apoptosis | en |
| dc.subject | DNA damage | en |
| dc.subject | ROS | en |
| dc.title | 探討PDCD5引致細胞凋亡之分子機制 | zh_TW |
| dc.title | Molecular mechanisms of programmed cell death 5-mediated cell death: triggers, partners and targets | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄧述諄(Shu-Chun Teng),李財坤(Tsai-Kun Li),俞松良(Sung-Liang Yu) | |
| dc.subject.keyword | 程序性細胞凋亡因子5,細胞凋亡,DNA損傷, | zh_TW |
| dc.subject.keyword | PDCD5,apoptosis,DNA damage,ROS, | en |
| dc.relation.page | 84 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-08-17 | |
| 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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