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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 周子賓(Tze-Bin Chou) | |
dc.contributor.author | Yu-Hsien Tung | en |
dc.contributor.author | 童宇賢 | zh_TW |
dc.date.accessioned | 2021-06-07T17:53:24Z | - |
dc.date.copyright | 2012-08-27 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-17 | |
dc.identifier.citation | Aberle H, Bauer A, Stappert J, Kispert A, Kemler R (1997) beta-catenin is a target for the ubiquitin-proteasome pathway. The EMBO journal 16: 3797-3804
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/15842 | - |
dc.description.abstract | 在果蠅中的人類高基氏體蛋白GOLPH3同源物Rti 是一個在高基氏體中負責調控EXT蛋白群的回送運輸的蛋白質。EXT蛋白群是生合成HSPG支鏈所需要的酵素群。當Rti增量或缺失時皆會導致HSPG 表現量減少以及Hh訊息傳導路徑的失常。
在果蠅中Wnt/Wingless (Wg) 調控翅脈以及翅膀周圍剛毛的形成。在翅碟上,EXT缺失的細胞會造成Wg的表現量減少,但此現象並未在Rti異常表現的細胞中觀察到。相反地在Rti增量表現時會導致Wg累積在原本合成Wg的細胞內,而Rti缺失時則不會影響Wg的表現量。因此Rti影響Wg的分佈表現並非源自於HSPG的缺失。此外,當Rti增量表現時,Wg會被限制在細胞內而無法送至細胞膜上,因此 Wg訊息傳導的下游的目標無法被誘發,最後造成翅膀周圍的剛毛缺失。 Wntless (Wls) 是一個膜蛋白,負責將Wg由高基氏體送往細胞膜,而自身由retromer回收至高機氏體以利進行下一循環。文獻指出當retromer缺失時,會造成Wg累積在細胞內以及細胞外的Wg量減少,這些現象皆與Rti增量表現時類似。考量Rti與retromer在免疫沈澱中有交互作用,且在細胞中坐落在一起,推測Rti增量表現時會阻斷retromer回收Wls,細胞內Wls不足而導致Wg無法正常被運輸至細胞膜上。 在另一方面,分別將同源rti突變以及野生型果蠅的卵巢萃取蛋白純化後以二維電泳分析。結果顯示有些許的蛋白質表現量異常,經質譜分析鑑定這些蛋白質身分,其中包含一個Tor complex2 (TORC2)的成員Sin1。 文獻中GOLPH3已知會透過未明機制參與Tor訊息傳導路徑,此外在 Rti增量表現時所引起的果蠅眼睛皺縮性狀與Tor突變的果蠅眼睛性狀類似。推測Rti 是否透過透過調控Sin1參與Tor訊息傳導路徑。因此我們在S2細胞中證實Rti的表現會負調控Sin1的表現。 此外,TORC2的下游訊息傳導目標Akt及其磷酸化 (pAktS505) 也受Rti所調控。Rti的表現量正調控Akt及pAktS505的量,而因此我們推測Rti正向調控Akt及其磷酸化,引起Tor下游訊息傳導活化而最終負回饋抑制Sin1的表現量。 | zh_TW |
dc.description.abstract | Drosophila homologue of human Golgi protein GOLPH3, Rotini (Rti), regulates the retrograde trafficking of EXT proteins, which are required for the polymerization of Heparan Sulfate Proteoglycans (HSPGs) GAG chains. Both loss- and gain-of-function rti causes the reduction of HSPGs expression and Hedgehog signaling. In other words, both loss- and gain-of-function rti represent the loss-of-function of EXTs.
Drosophila Wnt/Wingless (Wg) is required in a wide range of patterning events, including defining the wing blade and specifying the wing margin. In wing margin, the expression of Wg is reduced in EXT clone but not in rti mutant cells. Instead, Wg accumulates inside the Wg producing cells in rti gain-of-function condition, and expressed normally in rti loss-of-function condition. For instance the way Rti affects the expression pattern of Wg is HSPG independent. In addition, when Rti is overexpressed, Wg was restricted inside the producing cells but not secreted to the cell surface. Wg downstream signaling targets are not induced consequently. For example, the bristles on the wing margin are lost because of the defect of Wg signaling pathway. Wntless (Wls), a multipass transmembrane protein, is required for sending Wg from Golgi onto the cell surface. Wls are recycled back to trans-Golgi by an essential regulator called retromer. The failure of retromer will cause the accumulation of Wg inside the cell and the reduction of extracellular Wg secreted. These phenotypes are similar to those found in Rti gain-of-function. Considering that Rti interacts and colocalizes with the cargo recognition complex of the retromer, and Wg accumulation occurs in Rti gain-of-function condition, we postulated that overexpressed Rti may interrupt the retromer dependent retrograde recycling of Wls resulting in the restriction of Wg inside the Wg producing cells. On the other hand, we purified total proteins of rti GLC and OR ovaries to perform two-dimensional gel electrophoresis. We observed that some proteins with abnormal expression level between ovaries of rti GLC and OR. After in gel trypsin digestion and LC-MS/MS analysis, we identified these proteins including a protein named Sin1, which is a component of Tor complex 2 (TORC2). Since GOLPH3 was reported involving in the Tor signaling pathway with unknown mechanism, and the reduced eye phenotype is similar between rti and tor mutant condition, we were interested in whether Rti involved in Tor pathway through modulating Sin1. In S2 cells, we demonstrated that Rti negatively regulated Sin1, and the expression of Sin1 was dosage dependence on the expression of Rti. In addition, Akt and pAktS505, which are the downstream signal targets of TORC2, were also modulated by the expression of Rti. Rti positively regulates the expression of Akt and pAktS505 in vivo. In conclusion we postulate that Rti may facilitate the phosphorylation of Akt on S505, and the down-stream signaling pathway triggers the negative feedback to negatively regulate Sin1. | en |
dc.description.provenance | Made available in DSpace on 2021-06-07T17:53:24Z (GMT). No. of bitstreams: 1 ntu-101-R99b43006-1.pdf: 3069944 bytes, checksum: d54a5eb9ca280cc162b65eace0593273 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | Table of contents
Abstract iv List of table and figures xi Abbreviations xiii Introduction 1 I. Rti, Golgi proteins evolution homologues involve Vps74p, GMx33, and GPP34 1 1. Vps74, Rti homologue in yeast, is involved in protein sorting and interacts with retromer 1 2. Gmx33, Homologue of Rti in mouse, is involved in several endomembrane trafficking pathways 2 3. GPP34, Homologue of Rti human, is predicted to be involved in Golgi trafficking and regulate biogenesis of mitochondria 3 II. GOLPH3 has high affinity with phosphoinositide lipids 5 1. The synthesis of phosphoinositide lipid 5 2. The spatial distributions of phosphoinositide lipids are tightly regulated 5 3. Vps74P/GOLPH3 is newly identified PI(4)P binding protein 6 III. Rotini is required for HSPGs biogenesis 8 1. The rotini gene is identified as a segment polarity gene in Drosophila 8 2. Rotini protein does not have any conserved domain 8 3. Rotini is confirmed to be a Golgi protein 9 IV. The Drosophila wing imaginal disc as a model for studying morphogens 13 V. Hedgehog and Wingless signal transduction in wing discs 15 1. Hedgehog pathway 15 2. Wingless pathway 18 3. The mechanisms of Wingless processing and secretion 20 4. Proteoglycans regulate developmental signal molecules 22 5. HSPG affects the distribution of Wg 24 6. Retromer influences Wg secretion 27 VI. The components and function of retromer 29 1. Cargo recognition complex 30 2. Sorting nexin complex 31 VII. Tor signaling in growth and metabolism 33 1. Two Tor complexes 34 2. TORC1 is sensitive to rapamycin and regulates temporal aspects of cell growth 34 3. TORC2 is insensitive to rapamycin and regulates spatial aspects of cell growth 36 4. Function of TORC2 in regulating cell growth and metabolism 37 Materials and Methods 39 1. Fly stocks and maintenance 39 2. The autosomal FLP-DFS technique 39 3. Heat shock treatment 40 4. GAL4-UAS system 41 5. Drosophila S2 cells maintenance 42 Thawing S2 cells 42 Freezing S2 cells 43 6. Transient transfection of S2 cells 44 A. Plate cells 44 B. Prepare TransIT-2020 reagent:DNA complex (immediately before transfection) 44 C. Distribution the complexs to cells in complete growth medium 45 8. Proteomics 48 1. Sample preparation of two-dimensional electrophoresis 48 2. First dimension-Iso Electric Focusing (IEF) 49 3. Second dimension-SDS PAGE 49 4. In-Gel digestion 49 5. LC-MS/MS analysis 50 9. Cloning constructs 51 10. Immunohistochemistry 55 Fluorescence antibody staining of disc - conventional staining 55 Fluorescence antibody staining of disc – Wg extracellular staining 56 Fluorescence antibody staining of S2 cells 57 10. Western blotting analysis 58 11. Membrane stripping 59 12. Micro-injection and transgenic fly 60 13. Co-immunoprecipitation 61 Results 62 I. Rti regulates the expression of Wg in HSPG independent pathway 64 1. Both rti clone and rti GOF in wing disc represent EXTs LOF 64 2. Abnormal Rti level interferes the expression and distribution pattern of Wg in a HSPGs independent pathway 64 II. GOF Rti restricts the secretion of Wg in Wg producing cells 66 1. The transcription of Wg is normal in rti GOF condition 66 2. Extracellular Wg is reduced in abnormal level of Rti in wing disc 67 3. Wg is restricted inside the Wg producing cells in rti GOF condition 68 4. Wg down-stream signaling target is interrupted in rti GOF cells but not in rti mutant clones 69 5. The bristles on the wing margin is lost in rti GOF cells 71 6. There is no effect on the wing margin in rti knocked down cells 71 7. GOF Rti interrupted the secretion of Wg 72 III. rti is highly related to components of retromer complex 73 1. Rti co-immunoprecipitates with Vps26, Vps29, and Vps35, which are cargo recognition complexs of retromer 73 2. Rti co-localizes with Vps26, Vps29, and Vps35 in S2 cells. 74 IV. The difference in protein expression level between wild-type and rti germ-line clone ovaries 76 1. 21 proteins with different expression level between Rti germ-line clone and wild-type ovaries 77 2. 21 protein spots were identified through LC-MS/ MS 79 V. Rti may play a role in Tor pathway through modulating Sin1 in Tor complex II 81 1. The ablation of eye phenotype was similar in rti GOF and Tor LOF background 81 2. Sin1, a member of Tor complex II, is a candidate effector of Rti 82 3. Sin1 does not act in the upstream of Rti 82 4. Rti negatively regulates the expression of Sin1 in S2 cells 83 5. The expression of Akt, a TORC2 substrate, is positively regulated by Rti 84 6. The phosphorylation of Akt was positively related with the expression of Rti 85 Discussion 87 I. rti may act as a negative regulator to interrupt retromer dependent retrograde recycling 89 1. Rti involved in the secretion of Wg in HSPG independent pathway 89 2. GOF rti interrupted the secretion of Wg 90 3. The defect on Wg secretion in rti GOF condition is similar to that in retromer mutant condition 91 II. Rti involves in Tor pathway 94 1. Rti may regulate Sin1 at Golgi 94 2. Rti may regulate Sin1 at ER 97 Reference 102 List of table and figures Table 1. Proteins with abnormal expression in rti GLC ovaries Figure 1. Rotini, a Golgi resided protein, which is required for HSPGs biogenesis to regulate Hh behaviors Figure 2. Cartoon of synthesis and distribution of phosphoinositide lipids Figure 3. Cartoon of a Drosophila wing imaginal disc at third larval instar Figure 4. Models of HSPG function in cell signaling Figure 5. Composition of retromer in yeast Figure 6. The mTor signaling pathway in mamalian Figure 7. Abnormal Rti level interferes the expression and distribution pattern of Wg Figure 8. The level of extracellular Wg is reduced in Rti gain-of-function cells Figure 9. Wg is retained inside cells in Rti gain-of-function cells Figure 10. Wg is retained inside cells in Rti gain-of-function cells Figure 11. The expression level of Neur-lacZ is reduced in Rti gain-of-function cells. Figure 12. The expression level of Neur-lacZ is normal in Rti clones Figure 13. The bristles on wing margin is patchily lost in Rti gain-of-function cells Figure 14. The development of bristles on the wing margin are not affected in Rti knock down condition Figure 15. Rti co-IPs with the retromer complex Figure 16. Rti partially co-localizes with the retromer complex in S2 cells Figure 17. Two-dimensional gel electrophoresis of rti GLC and OR ovary extracts Figure 18. Master gel of two-dimensional gel electrophoresis stimulates rti GLC and OR ovary extracts Figure 19. Quantity graph report of the result of two-dimensional gel electrophoresis Figure 20. The ablation of eye phenotype was similar in rti GOF and Tor LOF Figure 21. The matched peptides of amino acid sequence of Sin1 in LC-MS/ MS analysis Figure 22. Rti expressed equally between serial doses of the expression of Sin1-V5 Figure 23. Rti negatively regulates the expression of Sin1 in S2 cells Figure 24. The expression of Akt and its phosphorylation on S505 is positively related with the expression of Rti Figure 25. The working hypothesis: Figure 26. The working hypothesis: Figure S1. Abnormal Rti reduces the expression of EXT Figure S2. The expression of HSPGs is reduced in rti clone and rti GOF condition Figure S3. The expression of Wg is reduced in ttv524botv510 clones Figure S4. Dvps35 is required for Wg secretion and signaling Figure S5. rti clone on eye | |
dc.language.iso | en | |
dc.title | "果蠅高基氏體蛋白GOLPH3,Rotini,調控Wingless,及Tor訊息傳導路徑中Sin1的表現" | zh_TW |
dc.title | The Drosophila Golgi protein GOLPH3, Rotini, modulates the Wingless signaling, and Sin1 in Tor pathway | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 黃偉邦(Wei-Pang Huang),溫進德(Jin-Der Wen),董桂書(Kuei-Shu Tung) | |
dc.subject.keyword | wg型態控制素,回收機制,Tor蛋白,Sin1蛋白,Akt蛋白, | zh_TW |
dc.subject.keyword | wingless,retromer,Tor,Sin1,Akt, | en |
dc.relation.page | 155 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2012-08-18 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
顯示於系所單位: | 分子與細胞生物學研究所 |
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