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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 | 俞松良 | |
dc.contributor.author | Wen-Hsin Chang | en |
dc.contributor.author | 張文馨 | zh_TW |
dc.date.accessioned | 2021-06-08T00:31:33Z | - |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-07-02 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17695 | - |
dc.description.abstract | 14-3-3家族是一個序列和結構都高度保守相似的蛋白質家族,常藉由與其他蛋白質進行交互作用來調控生物活性。在哺乳動物細胞中,14-3-3家族已被發現有七個家族成員,分別為β、γ、ε、ζ、η、σ和τ,而這些家族成員有六個已經被證實是致癌基因,只有14-3-3σ被定義為是一個腫瘤抑制基因。我們利用非小細胞肺癌進行實驗,發現除了14-3-3σ會抑制細胞的增生,其他六個14-3-3蛋白皆會促進細胞的生長。為了瞭解造成14-3-3σ與其他六個家族成員不同的原因,我們對所有家族成員進行胺基酸序列的比對以及結合基序的預測分析,結果發現14-3-3σ與其他屬於致癌基因的家族成員最主要的差異是在14-3-3σ第180個胺基酸,由可被磷酸化的酪胺酸(Tyrosine)轉變為不能被磷酸化的組胺酸(Histidine),進而導致14-3-3σ喪失了SH2 (Src Homology 2)結合基序(YYEI→HYEI)。因此,我們利用單點突變的方式構築了H180Y突變株,並探討14-3-3σ在獲得SH2結合基序後,會對原來的腫瘤抑制特性產生什麼影響。首先,H180Y突變株獲得與其他家族成員相同的SH2結合基序(YYEI)之後,我們由免疫共沉澱實驗發現,Src和突變株H180Y蛋白之間的交互作用確實比和野生型14-3-3σ強,而且突變株H180Y會大幅促進Src的活化。此外,大量表現14-3-3σ會抑制細胞的生長,然而突變株H180Y蛋白不只會加速細胞的生長也會促進細胞的侵襲,將原有的腫瘤抑制功能轉變成致癌性。顯示His180胺基酸的替換可以使得14-3-3σ從抑癌基因變成致癌基因,也突顯出YYEI結合基序對其他六個14-3-3蛋白之致癌功能的重要性。我們發現14-3-3ζ與Src產生交互作用是透過14-3-3ζ第178個胺基酸與Src SH2 domain結合。此外,YYEI結合基序對於14-3-3ζ促進細胞侵襲和生長的能力很重要。當我們將Tyr178突變之後會使得14-3-3ζ與Src之間的蛋白結合能力下降,而且Src活性不再明顯上升,進而無法再提高細胞侵襲和生長的能力。儘管如此,在臨床上我們並沒有發現非小細胞肺癌病人帶有14-3-3σ之H180Y的單核苷酸多型性。另外,以YYEI結合基序為基礎而設計的合成肽對肺癌細胞也沒有毒殺性。但幸運的是我們發現在演化過程中,14-3-3σ有發生胺基酸的轉變,從YYEI變成HYEI。由以上結果顯示,YYEI結合基序對於14-3-3蛋白與Src之間的交互作用是必要的,進而會影響Src的活性,而且在由Src所調控的訊息傳遞路徑中也扮演著重要的角色。 | zh_TW |
dc.description.abstract | The family of 14-3-3 proteins is implicated with many biological activities by binding to other proteins. It consists of seven highly conserved isoforms (β, γ, ε, ζ, η, σ, and τ) and most of them are identified as oncogenes in various types of cancer except 14-3-3σ, a well-known tumor suppressor. In non-small cell lung cancer, we found that overexpression of 14-3-3 proteins increased cell growth besides 14-3-3σ, which inhibited cancer cell viability. To clarify the suppressor characteristic of 14-3-3σ divergent from others, the protein alignment of 14-3-3 family found that the major difference between the other oncogenic members and 14-3-3σ was a substitution at amino acid 180 from Tyr to His by which a SH2-binding motif (YYEI) is mutated. Thus, we generated an H180Y 14-3-3σ mutant by site-direct mutagenesis and investigated the impact of this amino acid change on tumor suppressive activity. First, we found that overexpression of 14-3-3σ decreased the abilities of cancer cell invasion. Surprisingly, the H180Y mutant not only enhanced cell invasiveness but also promoted cell viability. Meanwhile, the interaction between H180Y mutant and Src was stronger than that of wild type. The fact indicates one amino acid substitution switches 14-3-3σ from tumor suppressor to oncogene. Hence, the YYEI motif might be important for the oncogenic activity of other 14-3-3 member proteins. Indeed, we demonstrated that 14-3-3ζ interacted with Src through Tyr178, which is crucial for the binding of 14-3-3ζ with Src-SH2 domain. Owing to the importance of Tyr178 in the 14-3-3ζ/Src interaction, we introduced the Y178F 14-3-3ζ mutant to lung cancer cells and confirmed that Tyr178 is important for the increase of invasion and viability. Nevertheless, we found no single nucleotide polymorphism (SNP) of 14-3-3σ in clinical samples of NSCLC patients. We also failed to design effective synthetic peptides based on YYEI and HYEI to kill cancer cells. Fortunately, we revealed an amino acid switch of 14-3-3σ from YYEI to HYEI during evolutionary progression, showing the special features of YYEI motif in 14-3-3 family. Taken together, our findings suggested that YYEI motif is essential for 14-3-3 proteins to interact with Src and to regulate Src-mediated cell functions. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T00:31:33Z (GMT). No. of bitstreams: 1 ntu-102-R00424015-1.pdf: 2753120 bytes, checksum: 83e4a9550cd1d9810c3af8add84738a1 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 口試委員會審定書............................................................................................................I
致謝...................................................................................................................................II 中文摘要.........................................................................................................................III 英文摘要..........................................................................................................................V 1. Introduction...............................................................................................................1 1.1 Cancer................................................................................................................2 1.2 Protein family....................................................................................................3 1.3 Src.....................................................................................................................5 1.4 14-3-3 family.....................................................................................................8 1.5 Specific aims...................................................................................................14 1.6 Experimental flow chart..................................................................................15 2. Materials and Methods............................................................................................16 2.1 Materials and reagents....................................................................................17 2.2 Plasmid constructs...........................................................................................17 2.3 Cell culture and transfection...........................................................................20 2.4 Cell viability assay..........................................................................................21 2.5 Cell invasion assay..........................................................................................21 2.6 Scratch wound-healing assay..........................................................................22 2.7 Immunoprecipitation and immunoblotting.....................................................22 2.8 Detection of 14-3-3σ mutation........................................................................23 2.9 Statistical analysis...........................................................................................23 3. Results.....................................................................................................................24 3.1 In non-small cell lung cancers, most of 14-3-3 are identified as oncogenes except for 14-3-3σ, a tumor suppressor..........................................................25 3.2 Identification of the difference between 14-3-3σ and the other oncogenic members by amino acid sequence alignment and computational prediction..25 3.3 Constructs of 14-3-3σ and 14-3-3ζ mutants....................................................27 3.4 YYEI motif in 14-3-3 proteins is critical for the interaction with Src............27 3.5 YYEI motif in 14-3-3 proteins is critical for Src activation...........................28 3.6 YYEI motif in 14-3-3 proteins promotes cell invasion...................................29 3.7 YYEI motif in 14-3-3 proteins promotes cell viability...................................30 3.8 Src inhibition blocks oncogenicity of YYEI motif.........................................31 3.9 14-3-3σ does not mutate at Phe179 and His180 in 100 NSCLC patients...........31 3.10 The synthetic peptides, YYEI and HYEI, have no influence on Src, EGFR, and STAT3 activity.........................................................................................32 3.11 14-3-3σ develops suppressive feature during evolutionary process...............33 4. Conclusions.............................................................................................................35 5. Discussion................................................................................................................37 5.1 The cellular functions of 14-3-3σ in various types of cancer..........................38 5.2 Src is a novel and important binding partner of 14-3-3 family.......................39 5.3 14-3-3σ is different from other members in many aspects besides the dissimilarity of amino acids ...........................................................................40 5.4 Development of peptide drug based on YYEI motif.......................................41 6. Figures.....................................................................................................................44 Figure 1. 14-3-3 proteins increase cell growth except 14-3-3σ in CL1-0 cells........45 Figure 2. 14-3-3 proteins increase cell growth except 14-3-3σ in CL1-5 cells........46 Figure 3. Identification of the unique motifs between 14-3-3σ and the other oncogenic members..................................................................................................47 Figure 4. Constructions of 14-3-3σ and 14-3-3ζ mutants.........................................49 Figure 5. YYEI motif is critical for 14-3-3 proteins to interact with Src.................50 Figure 6. YYEI motif is critical for 14-3-3 proteins to enhance Src activity...........51 Figure 7. YYEI motif has an effect on cell invasion................................................53 Figure 8. YYEI motif has an effect on cell viability.................................................54 Figure 9. Dasatinib inhibits oncogenicity of YYEI motif........................................55 Figure 10. Survey of potential mutations at Phe179 and His180 in 100 NSCLC patients......................................................................................................................57 Figure 11. The effect of synthetic peptides, YYEI and HYEI, on signal transduction..............................................................................................................58 Figure 12. 14-3-3σ is unique in the course of evolution..........................................60 7. References...............................................................................................................62 | |
dc.language.iso | en | |
dc.title | YYEI結合基序對14-3-3蛋白之致癌特性的重要性 | zh_TW |
dc.title | YYEI Motif Is Critical to Oncogenicity of 14-3-3 Proteins | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 李財坤,詹迺立,蘇剛毅 | |
dc.subject.keyword | 癌症,Src蛋白,14-3-3σ蛋白,14-3-3ζ蛋白,YYEI結合基序, | zh_TW |
dc.subject.keyword | Cancers,Src,14-3-3σ,14-3-3ζ,YYEI motif, | en |
dc.relation.page | 75 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2013-07-02 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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