Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/97775
DC FieldValueLanguage
dc.contributor洪慧芝zh_TW
dc.contributorHui-Chih Hungen_US
dc.contributor.author李倩筠zh_TW
dc.contributor.authorChien-Yun Leeen_US
dc.contributor.other生物科技學研究所zh_TW
dc.date2018zh_TW
dc.date.accessioned2019-03-22T06:05:11Z-
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dc.identifier.urihttp://hdl.handle.net/11455/97775-
dc.description.abstract瓜胺酸化 (citrullination)是由胜肽精胺酸脫亞胺酶 (peptidylarginine deiminases, PAD)於精胺酸 (Arginine)上催化的蛋白後轉譯修飾 (post-translational modification, PTM)。雖然瓜胺酸化在蛋白分子量上僅增加0.98 Da,胺基酸正電荷的損失可能造成蛋白結構和功能的改變。目前研究已顯示瓜胺酸化參與了許多生理機制,例如發炎、細胞凋亡、中樞神經系統的穩定性、角質細胞的成熟等等。瓜胺酸化在病理機制中扮演的角色首先在類風濕性關節 (Rheumatoid arthritis, RA)中建立,在RA中,不正常瓜胺酸化的蛋白會誘導自體免疫抗體的產生,並導致患者關節的慢性發炎。近年來,在許多癌症中也發現了失調的瓜胺酸化蛋白,因此瓜胺酸化在腫瘤學中的病理機制也被廣泛討論,例如PAD4催化的組蛋白 (Histones)瓜胺酸化參與了癌細胞中的與致癌基因相關的表觀遺傳調控。因此,PAD已成為近年來治療類風濕性關節炎和癌症的新興治療標靶。儘管目前在研究PAD和瓜胺酸化在生理、病理機制上有許多發展,我們仍然缺乏了PAD受質的相關研究,藉由了解PAD受質可以幫助我們探討PAD瓜胺酸化調控的生理機制,進而對病理機制有更清楚的了解。在本論文中,我報告了兩種新的瓜胺酸化蛋白,抗酶和p53蛋白,並透過生化和細胞的功能性分析,研究瓜胺酸化後蛋白的結構與功能。第一部分,闡明了第四型胜肽精胺酸脫亞胺酶 (PAD4)如何藉由瓜胺酸化抗酶蛋白,參與細胞多元胺生合成的調控。第二部分,藉由研究全長p53與PAD4的四級結構,提供了PAD4和p53相互作用的直接證據與分子化學計量 (stoichiometry),以及PAD4透過瓜胺酸化p53參與p53下游基因調控的可能機制。zh_TW
dc.description.abstractCitrullination is a post-translational modification (PTM) on arginine catalyzed by peptidylarginine deiminases (PAD). The mass increment of citrullination is only 0.98 Da but the loss of a positive charge causes the alteration on the structure and function of modified proteins. Citrullination has been shown to involve in various physiological pathways such as inflammation, apoptosis, stability of central nervous system, and keratinocyte maturation. Its role in pathogenesis has been firstly established in rheumatoid arthritis (RA), in which autoantibodies against citrullinated proteins were identified and led to chronic inflammation of patients' joints. Recently, the pathological role of citrullination has also been widely discussed in oncology since deregulated citrullination level was found in many cancers. PAD4-catalyzed histone citrullination involves in the epigenetic regulation during carcinogenesis. Hence, PAD has emerged as a therapeutic target of both RA and cancer. Despite the great efforts in studying the role of PADs and citrullination in pathogenesis, many of PAD-regulating pathways are still unclear due to the lack of the mechanistic study of PAD substrates. In this dissertation, I report two novel citrullinated proteins, antizyme and p53 protein, and their functional consequences after citrullination by biochemical- and cell-based analyses. The findings on these proteins indicate that citrullination has a tremendous impact on the protein structure and function.en_US
dc.description.tableofcontentsPART 1. Introduction of citrullination and PADs 1 1.1 Citrullination and its role in physiology 2 1.2 Peptidylarginine deiminase (PAD) family and PAD4 3 1.3 Deregulation of PAD4 expression and activity has been correlated with various diseases 3 1.3.1 Rheumatoid arthritis (RA) 4 1.3.2 Cancer 5 1.4 Specific aim 6 PART 2. AZ citrullination and its functional consequences 7 2.1 Abstract 8 2.2 Introduction 9 2.2.1 Polyamines in physiology 9 2.2.2 Regulation of polyamine metabolism 9 2.2.3 Antizyme 10 2.2.4 Polyamines and rheumatoid arthritis (RA) 11 2.2.5 Polyamines, ODC, and cancer 12 2.2.6 Specific aim 13 2.3 Materials and methods 14 2.3.1 Jurkat T cell activation by TPA and ionomycin stimulation 14 2.3.2 Inducible expression of PAD4 using Tet-on system 14 2.3.3 Cell proliferation assay 14 2.3.4 Immunoblotting analysis 15 2.3.5 Expression and purification of human PAD4, AZ, ODC and AZI proteins 16 2.3.6 Purification of the citrullinated AZ protein 16 2.3.7 Site-directed mutagenesis 17 2.3.8 Spectrophotometric assay for PAD4 enzyme activity (for in vitro assay) 17 2.3.9 Colorimetric assay for PAD4 enzyme activity (for cell-based assay) 18 2.3.10 ODC enzymatic activity assay and AZ inhibition assay 19 2.3.11 Measurement of cellular putrescine level and ODC activity 20 2.3.12 Generation of anti-citrullinated AZ antibody 21 2.3.13 In vitro citrullination and immunoblotting of citrullinated AZ protein 21 2.3.14 Measurement of in vitro degradation of ODC and AZI in a reticulocyte lysate-based system 22 2.3.15 Size distribution analysis by analytical ultracentrifugation 22 2.3.16 Mass spectrometry (LC-MS/MS) 23 2.3.17 Statistical analysis 24 2.4 Results 25 2.4.1 PAD4 is expressed during Jurkat T cell activation 25 2.4.2 Overexpression of PAD4 in activated Jurkat T Cells increases cellular putrescine levels without promoting cell proliferation 25 2.4.3 A natural ornithine decarboxylase inhibitor, antizyme (AZ), can be citrullinated by PAD4 in vitro and in cells 26 2.4.4 Accumulation of citrullinated AZ proteins in PAD4-expressing activated Jurkat T cells increases ODC protein level 28 2.4.5 Functional analysis of citrullinated AZ proteins in binding, inhibition, and degradation of ODC and AZI binding 28 2.4.6 Identification of the critical citrullinated residues that impair the function of AZ protein 31 2.5 Discussions 34 2.5.1 Physiological and pathological significances of AZ citrullination 34 2.5.2 Implications of citrullination sites on AZ-ODC complex structure 35 2.5.3 Putrescine level and cell growth 36 2.5.4 Interaction of citrullinated AZ and other interacting proteins 37 2.5.5 Identifying citrullinated AZ in cells 37 2.5.6 Protein stability of citrullinated AZ 39 Tables 40 Figures 44 PART 3. Identification of p53 citrullination and its role in the structure and function 62 3.1 Abstract 63 3.2 Introduction 64 3.2.1 PAD4-regulated gene expression in carcinogenesis 64 3.2.2 Post-translational modifications in regulating the structure and function of p53 64 3.2.3 The interaction of p53, PAD4, HDAC1, and HDAC2 66 3.2.4 Identifying citrullination by mass spectrometry (MS) 67 3.2.5 Specific aim 68 3.3 Materials and methods 70 3.3.1 Expression and purification of human PAD4, p53, ubiquitin, and Mdm2 proteins 70 3.3.2 Purification of the citrullinated p53 protein 71 3.3.3 Spectrophotometric assay for PAD4 enzyme activity (in vitro assay) 71 3.3.4 In vitro citrullination and immunoblotting of citrullinated p53 protein 72 3.3.5 Generation of anti-citrullinated p53 antibody 72 3.3.6 In vitro ubiquitylation assay 72 3.3.7 Size distribution analysis by analytical ultracentrifugation 73 3.3.8 DNA-binding affinity measurement by electrophoretic mobility shift assay (EMSA) 73 3.3.9 Cell culture and PAD4 activation 74 3.3.10 Immunoprecipitation of endogenous p53 74 3.3.11 Sample preparation for MS analysis 75 3.3.12 Mass spectrometry (LC-MS/MS) 75 3.3.13 Parallel-reaction monitoring (PRM) assay (Targeted MS) 76 3.4 Results 78 3.4.1 Interaction of p53 and PAD4 can be observed in the presence of DNA 78 3.4.2 Tumor suppressor p53 can be citrullinated by PAD4 in vitro and in MCF 7 cells 79 3.4.3 Citrullination on p53 alters its quaternary structure and ability to form a complex with DNA 81 3.4.4 Citrullination on p53 weakens its DNA-binding ability 82 3.4.5 Citrullinated p53 is less susceptible to Mdm2-dependent ubiquitylation 82 3.4.6 Identification of endogenous p53 citrullination sites from MCF 7 cells by MS 83 3.5 Discussions 87 3.5.1 Biological significances of p53 citrullination 87 3.5.2 The importance of p53 tetramerization in its function and proteins interactions 87 3.5.3 Difficulties of identifying endogenous p53 citrullination sites 88 3.5.4 Possible implications from identified citrullination sites 89 3.5.5 Protein stability of citrullinated p53 91 Tables 92 Figures 102 PART 4. Conclusions and future prospects 125 References 129zh_TW
dc.language.isoen_USzh_TW
dc.rights同意授權瀏覽/列印電子全文服務,2021-08-20起公開。zh_TW
dc.subject瓜胺酸化zh_TW
dc.subject胜肽精胺酸脫亞胺酶zh_TW
dc.subject蛋白後轉譯修飾zh_TW
dc.subject抗酶zh_TW
dc.subjectp53蛋白zh_TW
dc.subjectCitrullinationen_US
dc.subjectpeptidylarginine deiminaseen_US
dc.subjectpost-translational modificationen_US
dc.subjectantizymeen_US
dc.subjectp53en_US
dc.title人類第四型胜肽精胺酸脫亞胺酶瓜胺酸化人類抗酶與p53蛋白之功能性研究zh_TW
dc.titleFunctional Roles of PAD4-catalyzed Citrullination on the Human Antizyme and p53 Proteinsen_US
dc.typethesis and dissertationen_US
dc.date.paperformatopenaccess2021-08-20zh_TW
dc.date.openaccess2021-08-20-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.openairetypethesis and dissertation-
item.cerifentitytypePublications-
item.fulltextwith fulltext-
item.languageiso639-1en_US-
item.grantfulltextrestricted-
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