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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 呂勝春 | |
dc.contributor.author | Yu-Chen Tsai | en |
dc.contributor.author | 蔡宇臣 | zh_TW |
dc.date.accessioned | 2021-06-17T00:45:38Z | - |
dc.date.available | 2014-03-02 | |
dc.date.copyright | 2012-03-02 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2012-01-04 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66601 | - |
dc.description.abstract | SIK3隸屬於AMPK家族一員的SIK次家族,為一被廣泛表現的蛋白激酶。已有報告指出,SIK3在果蠅與人類之中肩負著調控能量平衡以及細胞週期的功能。SIK3由磷酸域,UBA域,PKA催化位址以及富含麩醯胺的C端所組成。SIK3的蛋白激酶活性咸信是由LKB1以及GSK-3β所調控。這兩個上游的蛋白激酶將SIK3位於催化環上的蘇氨酸163給磷酸化,藉此提升SIK3作為激酶的活性。SIK3與SIK1和SIK2在催化域的序列上具有高度的同源性。如同失去活性的SIK2 K49M的突變,SIK3的K41M以及K37M的突變同為失去激酶活性的型態。降低內生性的SIK3將會導致蛋白質組合錯誤反應的上升以及增加內質網的負擔同時損毀內質網蛋白質降解路徑。外源性過表現SIK3和SIK3將加速變性內質網蛋白質降解路徑的進行,反之,降低內生性的SIK2和SIK3將導致此一路經遭到抑制。在這個研究中,我試著去探討SIK2 SIK3以及UBQLN在變性內質網蛋白質降解路徑中的角色。 | zh_TW |
dc.description.abstract | Salt-inducible kinase 3 (SIK3) is a ubiquitously expressed kinase which belongs to member of AMPK family and SIK sub-family. SIK3 has been reported to regulate energy homeostasis and cell cycle in Drosophila and Human. SIK3 is composed of kinase domain, UBA domain, PKA site and Q-rich C-terminal region. The kinase activity of SIK3 is thought to be regulated by LKB1 and GSK-3β. These two kinases could phosphorylate Thr163 in the activation loop to enhance SIK3 kinase activity. SIK3 shares extensive sequence homology with SIK1 and SIK2 in the ATP-binding pocket and catalytic domain. Similar to SIK2 kinase dead mutant SIK2-K49M, SIK3-K37M or K41M mutant is also kinase dead. Knockdown of SIK3 leads to activation of unfolded protein response (UPR) and impaired ER-associated degradation (ERAD). Overexpression of SIK2 or SIK3 can facilitate ERAD process. In contrast, knockdown of SIK2 or SIK3 lead to inhibition of ERAD. In this study, I investigate the potential roles of SIK2, SIK3 and UBQLN1/2 in regulating ERAD. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T00:45:38Z (GMT). No. of bitstreams: 1 ntu-100-R98448012-1.pdf: 2203194 bytes, checksum: bd8f30cf927480e229118e946b8058c4 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | 誌謝………………………………………………………………………………….. I
中文摘要…………………………………………………………………………….. II Abstract……………………………………………………………………………...III Introduction……………………………………………………………………….….1 Materials and Methods……………………………………………………………....5 Plasmid constructs and site-directed mutagenesis………………………………..5 RNA interference………………………………………………………………....7 Cell culture and transfection……………………………………………………...7 Antibodies……………………………………………………………………..…8 Cell lysate preparation……………………………………………………………8 Western blot analysis………………………………………………………..……8 Immunoprecipitation…………………………………………………………..…9 Dual Luciferase assay………………………………………………………...…10 Immunofluorescent staining and confocal microscopy……………………...….10 Results………………………………………………………………………………..11 SIK3-K41 is acetylated…………………………………………………………11 Antibodies to SIK3/QSK……………………………………………………….11 Subcellular distribution of SIK3-WT and mutant………………………………13 Knockdown or overexpression of SIK3 kinase-dead mutant induces ER stress………………………………………………………………..14 Knockdown of SIK2 or SIK3 induces UPR…………………………………….14 SIK3 regulates the degradation of ERAD substrate…………………………….15 SIK3 mediates endogenous UBQLN family protein level…………………...…16 Discussion……………………………………………………………………………18 Reference……………………………………………………………………………20 List of Figures………………………….……………………………………………24 Figure 1. SIK3-K41M abolishes the acetylation of SIK3.. ……………………….....24 Figure 2. Characterization of SIK3 antibodies. ………………………….……….25 Figure 3. Immunoprecipitation of endogenous SIK3 from 293T cells.…………………………………………………………………….………….…27 Figure 4. Kinase dead mutants of SIK2 and SIK3 form aggregate when overexpressed.. ………………………………………………………………….…...28 Figure 5. Knockdown of SIK3 enhances expression of HSP27 protein level. …………………………………………………………………………….…30 Figure 6. Overexpression of kinase dead SIK2 or SIK3 or knockdown of SIK3 stimulates ER loading activity. …………………………………….………………31 Figure 7. Knockdown of SIK2 and SIK3 enhances the transcription level of GRP78.………………………………………………..……….……………….…….33 Figure 8. Knockdown of endogenous SIK3 cause the accumulation of CD-3δ in 293Tcells.………………………………………………………….……….34 Figure 9. Overexpression of SIK2 and SIK3 affect CD-3δ level in 293T cells. ………………………………………………………………………35 Figure 10. SIK2 and SIK3 are required for CD-3δ degradation. ……………………………………………….…………………………36 Figure 11. Knockdown of SIK2 or SIK3 causes little changes in UBQLN1/2 level……………………………………………………………………………....…..38 Figure 12. Co-immunoprecipitation of SIK3 and UBQLN2.. ……………………....39 Figure 1S. Expression of SIK2 and SIK3 in different cell-lines. ……………………40 Figure 2S. SIK3-K41M mutant is predominantly in the insoluble fraction.……………………………………………………………………….………41 Figure 3S. SIK2 knockdown lead to accumulation of UBQLN2.…………………....42 | |
dc.language.iso | en | |
dc.title | SIK3 的功能研究 | zh_TW |
dc.title | Functional study of SIK3 | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 施修明,周祖述 | |
dc.subject.keyword | SIK3,內質網蛋白質降解,SIK2,UBQLN,內質網壓力, | zh_TW |
dc.subject.keyword | SIK3,ERAD,SIK2,UBQLN,ER stress, | en |
dc.relation.page | 42 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-01-05 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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