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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳瑞華(Ruey-Hwa Chen) | |
dc.contributor.author | Tzu-Yin Chen | en |
dc.contributor.author | 陳姿穎 | zh_TW |
dc.date.accessioned | 2021-06-13T02:01:51Z | - |
dc.date.available | 2016-08-10 | |
dc.date.copyright | 2011-08-10 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-08-02 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30352 | - |
dc.description.abstract | The expression of tumor suppressor promyelocytic leukemia (PML) is lost in a wide variety of solid tumors through a proteasome-dependent mechanism. Previous studies in our laboratory identified a KLHL20-based ubiquitin ligase complex that targets CDK1/2-phosphorylated PML for ubiquitination and degradation and in vitro analysis demonstrated PML S518 residue as the prime site for CDK1/2 phosphorylation. In this thesis, we first generated a PML S518-specific antibody and confirmed that both CDK1/2 were capable of phosphorylating PML at S518 in vivo. Next, we explored the effect of hypoxia on KLHL20-mediated PML degradation, because KLHL20 is known to be upregulated in hypoxic cells. We found that PML level was drastically decreased in hypoxia, correlating with a marked elevation of KLHL20 level. This opposite regulations of KLHL20 and PML were also detected by overexpression of a constitutively active HIF-1 in normoxia and were blocked by HIF-1 depletion in hypoxia. Importantly, we presented evidence indicating that CDK1/2 activities were responsible for PML S518 phosphorylation and PML degradation under hypoxia conditions. Thus, CDK1/2 activities are responsible for PML S518 phosphorylation in both hypoxic and normoxic cells and KLHL20 induction by HIF-1 likely contribute to enhanced PML degradation in hypoxia. Finally, we determined the residues flanking S518 that are important for KLHL20-mediated PML degradation. To this end, we generated a panel of PML point mutants. Mutations of S518 and P519 interfered with CDK1/2-induced PML S518 phosphorylation, whereas mutations of A516 and H521 blocked KLHL20-induced PML ubiquitination and degradation without affecting S518 phosphorylation. Taken together, our results suggest that the sequence of AxpSPxH between 516 and 521 of PML may act as a degron for KLHL20 recognition. This finding may aid in future identification of additional KLHL20 substrates. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T02:01:51Z (GMT). No. of bitstreams: 1 ntu-100-R98b46006-1.pdf: 1269681 bytes, checksum: 8443e0f65c8de2ec70daf0428c2d46b1 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | Contents
誌謝 i 摘要 ii Abstract iii Introduction 4 1. The ubiquitin-proteasome system 4 1.1 The E3 ubiquitin ligase enzyme 5 2. The BTB/POZ domain family 8 2.1 The BTB-BACK-Kelch protein KLHL20 10 3. The promyelocytic leukaemia protein 11 4. Hypoxia and hypoxia-inducible factor (HIF) 14 Preface 16 Materials and Methods 17 Plasmid 17 Antibodies and reagents 17 Cell culture and transient transfection 17 Establishment of HIF-1 | |
dc.language.iso | en | |
dc.title | 探討抑癌基因PML中被KLHL20辨認之降解區塊 | zh_TW |
dc.title | Characterization of the degron of KLHL20 on PML | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 張智芬,陳光超,吳君泰 | |
dc.subject.keyword | 磷酸化,CDK,PML,KLHL20,HIF-1a,Degron, | zh_TW |
dc.subject.keyword | Phosphorylation,CDK,PML,KLHL20,HIF-1a,Degron, | en |
dc.relation.page | 54 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-08-02 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-100-1.pdf 目前未授權公開取用 | 1.24 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。