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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳瑞華 | |
dc.contributor.author | Li-Ting Lu | en |
dc.contributor.author | 呂立婷 | zh_TW |
dc.date.accessioned | 2021-06-15T04:54:32Z | - |
dc.date.available | 2015-08-05 | |
dc.date.copyright | 2010-08-05 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-07-30 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/46118 | - |
dc.description.abstract | 抑癌基因PML(promyelocytic leukemia)已被報導在許多人類腫瘤細胞株中有表現量降低的情形。目前認為會導致異常蛋白質降解的後轉譯機制是造成PML蛋白質表現量降低的主因。PML蛋白質表現量以及穩定性受到許多後轉譯修飾作用(post-translational modifications)的調控。根據本實驗室最近的研究指出,PML在蛋白酶體降解作用(proteasome degradation)的過程中主要受到三種後轉譯修飾作用的調控;CDK1/2會對PML蛋白的Ser518-Pro519 motif進行磷酸化(phosphorylation),此磷酸化會促進Pin1對PML的異構化(isomerization)以及KLEIP-Cullin3泛素連接酶(E3 ligase)對PML進行的多次泛素化(polyubiquitination)。本實驗室利用干擾型核醣核酸篩檢(siRNA screening),找到三個可能調控PML蛋白穩定性的去泛素酶(deubiquitinating enzymes),分別是USP3、USP16以及USP40。本篇論文的第一部分主要在檢驗這三個去泛素酶調控PML蛋白質穩定性的能力;然而,我們發現需要更多的研究才能釐清這些去泛素酶在PML蛋白酶體降解作用中所扮演的角色。本篇論文的第二部分,我們發現SCP1(small C-terminal domain phosphatase 1)為一針對PML Ser518位置進行去磷酸化(dephosphorylation)的去磷酸酶(phosphatase);失去酵素催化能力的SCP1則無法對PML Ser518進行去磷酸化。FCP/SCP家族的其他成員,像是SCP2和SCP3也可以對PML進行去磷酸化作用,而FCP1則不具有此能力。此外,我們發現透過對PML的去磷酸化,SCP1可以減少Pin1-KLHL20媒介的多次泛素化,進而增加PML蛋白的穩定性。綜合以上,在本篇論文中,我們除了發現去泛素酶對PML調控的複雜性,也找到了去磷酸酶SCP的新受質PML。 | zh_TW |
dc.description.abstract | Downregulation of tumor suppressor PML has been reported in various human tumor cell lines. The decrease of PML protein level in tumor cells was thought to result from post-translational mechanisms, such as aberrant degradation. PML expression and stability has been shown to be regulated by various posttranslational modifications. We recently discovered that targeting PML to proteasome degradation requires three posttranslational modifications at the PML Ser518-Pro519 motif. CDK1/2 can phosphorylate PML at Ser518 and then promote the prolyl cis/trans isomerization by Pin1 and polyubiquitination by KLHL20-Cullin3 ubiquitin ligase. In the first part of this thesis, we try to find deubiquitinating enzymes that may regulate PML stability. However, we need more effort to improve the siRNA knockdown efficiency and to clarify the regulatory mechanism of DUBs on PML protein. In the second part of this thesis, by using functional genomic approach, we identified the small C-terminal domain phosphatase 1 (SCP1) as a specific phosphatase for PML dephosphorylation at Ser518. A catalytically inactive mutant (SCP1 DN) had no effect on PML phosphorylation in vivo and in vitro. Of the other FCP/SCP family members SCP2 and SCP3, but not FCP1, could also dephosphorylate PML at Ser518. Through this dephosphorylation, SCP1 decreased Pin1-KLHL20 mediated PML polyubiquitination and increased PML stability. Taken together, this study implies the complexity of PML regulation by DUBs and reveals an important new substrate for SCPs. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T04:54:32Z (GMT). No. of bitstreams: 1 ntu-99-R97b46003-1.pdf: 1207204 bytes, checksum: 3815f99e99217aa9c32cb7f72c58d812 (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | 口試委員審定書
誌謝 ..............................................................................................................i 大綱 …………………………………………………………………….....ii Abstract ......................................................................................................iii Introduction ................................................................................................4 1. Ubiquitination system ..........................................................................................4 2. PML .....................................................................................................................4 2.1 The PML nuclear body and PML protein ............................................................5 2.2 PML function .......................................................................................................6 2.3 Regulation of PML expression and stability .......................................................7 3. Deubiquitinating enzymes .................................................................................10 4. Protein serine/threonine phosphatases ...............................................................13 4.1 C-terminal domain phosphatases ............................................................14 4.2 Small C-terminal domain phosphatases .................................................14 Preface .......................................................................................................16 Materials and Methods ............................................................................17 Cell culture and transient transfection .....................................................................17 Plasmids ...................................................................................................................17 Antibodies and reagents ..........................................................................................17 Establishment of DUB knockdown cell lines by lentivirus system ........................18 Western blotting .......................................................................................................19 RT-PCR ....................................................................................................................19 Quantitative Real-Time PCR ...................................................................................20 Immunoprecipitation ...............................................................................................20 Immunofluorescence and microscopy .....................................................................20 In vivo degradation assay ........................................................................................21 In vitro phosphatase assay .......................................................................................21 In vitro ubiquitination assay ....................................................................................22 Results ........................................................................................................23 USP3 siRNAs did not significantly increase PML protein level ............................ 23 USP40 siRNAs could not affect PML protein level ................................................24 The effects of USP16 on PML may be complex .....................................................24 SCPs are widely expressed in various human cell lines ..........................................25 SCP1, SCP2 and SCP3 can all dephosphorylate PML at Ser518 ............................26 All three SCP isoforms interact with PML in vivo ..................................................27 SCP1 dephosphorylates PML in vitro .....................................................................27 Dephosphorylation of PML by SCP1 blocks its interaction with Pin1 ...................28 Dephosphorylation of PML by SCP1 attenuates KLHL20-mediated PML ubiquitination ...........................................................................................................28 SCP1 increases the protein stability of PML ...........................................................29 Ectopic expression of SCP1 increases the number of PML-NBs ............................29 Discussion ..................................................................................................31 Figures .......................................................................................................35 References .................................................................................................47 Appendix ...................................................................................................56 | |
dc.language.iso | en | |
dc.title | 探討後轉譯修飾作用對PML降解機制之調控 | zh_TW |
dc.title | Role of post-translational modifications in PML degradation | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 孟子青,施修明 | |
dc.subject.keyword | PML,KLHL20,去泛素酶,SCP,後轉譯修飾作用,去磷酸化, | zh_TW |
dc.subject.keyword | PML,KLHL20,DUB,SCP,posttranslational modification,dephosphorylation, | en |
dc.relation.page | 57 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2010-07-30 | |
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 |
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