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研究生： 高國勝
Kao, Gour-Shenq
論文名稱： KIAA1866基因在人類細胞功能的分析研究
Functional characterization of the KIAA1866 gene in human
指導教授： 孫孝芳
Sun, Hsiao-Fang Sunny
蘇益仁
Su, Ih-Jen
學位類別： 碩士
Master
系所名稱： 醫學院 - 分子醫學研究所
Institute of Molecular Medicine
論文出版年： 2004
畢業學年度： 92
語文別： 英文
論文頁數： 79
中文關鍵詞： 第六號染色體長臂 、假設性蛋白質 、DNA片段缺失 、膀胱癌細胞株
外文關鍵詞： functional domain/ motif, Hypothetical protein, chromosome 6q25.3, KIAA1866
相關次數： 點閱：109  下載：2 
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    • 　　隨著人類基因序列的解讀完成，科學家們期待從基因組中尋找癌症的發生原因及機制。在本實驗室先前針對鼻腔自然殺手暨T細胞淋巴瘤的基因體分析研究報告中，發現第六號染色體長臂有重要的缺失區域，其中有2.6Mb區域的DNA片段缺失率更高達86%。此外，鄰近的區域也有相當高的DNA片段缺失現象，如位於6q25.3的KIAA1866即有43%的DNA片段缺失率。KIAA1866基因是2001年日本人由胎兒腦部的cDNA基因庫中選殖出。而在目前的資料庫中仍歸類為生物功能未知的假設性蛋白質(Hypothetical protein)。本實驗的目的是想探討KIAA1866基因產物在細胞內所扮演的生物功能。我們利用聚合酶鏈反應檢定KIAA1866在不同正常組織以及癌症組織中的基因表現。所得結果發現KIAA1866在所測的組織中均呈現相當低的表現量。相較於正常睪丸、膀胱、腦組織以及胸腺癌組織可測得KIAA1866表現，其相對應的組織則不表現。另外利用不同分級的膀胱癌細胞株進行cDNA即時定量的實驗發現，KIAA1866在細胞株J82有微量的表現，其餘則否(RT4, TSGH8301, T24)。但相對於正常膀胱組織，J82細胞株KIAA1866的表現量也只有正常膀胱組織的1/10。我們也成功的將KIAA1866重組蛋白表現於原核細胞表現系統。此外，KIAA1866融合綠色螢光蛋白(GFP, green fluorescence protein)，在HeLa及HEK293細胞株中均可表現融合蛋白，且由螢光顯微鏡觀察發現此融合蛋白表現於細胞漿質中。依照生物資訊學的預測，KIAA1866蛋白存有許多功能特定區域(functional domain/ motif)，但它真正的細胞功能為何，仍需藉由更近一步的實驗來探討證明。

    　　Deletions of the chromosome 6 q were observed in several human tumor types, especially in many different types of lymphoma. Our previous study in nasal NK/T cell lymphomas has mapped the smallest region of overlapping (SRO) deletion to a 2.6Mb region on 6q25.3 interval with 86% deletion rate. The neighbor regions also have high frequency of DNA copy number loss; for example, the KIAA1866 gene located in 6q25.3 exist 43% loss in examined nasal NK/T cell lymphoma cases. The KIAA1866 gene has been cloned from the human fetal brain cDNA library. The role of this hypothetical protein remains unknown. We had examined the expression profiles in human normal and tumor tissues and results indicate a low abundance in all tested tissues with relatively higher expression in normal heart, bladder, testes, brain, and thymus tumor. Quantitative measurement of expression in cDNAs of bladder cancer cell lines (RT4, TSGH8301, J82, and T24) demonstrated that the KIAA1866 expresses trace amount in J82 cells and this only counts 1/10 of the expression of normal bladder tissue. The constructed KIAA1866 fusion proteins were successfully expressed in E. coli system as well as in mammalian cell lines (HeLa and HEK293). The KIAA1866ORF-EGFP protein showed cytoplasm localization but not in the nuclear as predicted by pSORT II program. Bioinformatics predications have revealed many functional domains in KIAA1866 protein including phosphorylation sites, N-myristoylation sites, cleavage sites, interaction motifs and binding motifs. However, the exact physiological role of KIAA1866 protein in human cells remains to be determined empirically.

    ABSTRACT IN CHINESE………………………………………I ABSTRACT IN ENGLISH………………………………………II LIST OF TABLES……………………………………………VII LIST OF FIGURES…………………………………………VIII Chapter 1 – Introduction.........................1 1.1 Genetic alterations in human cancers......1 1.1.1 Oncogenes.................................3 1.1.2 Tumor suppressor genes....................4 1.1.2.1 Loss of heterozygosity (LOH)..............5 1.1.2.2 Microsatellite instability (MSI)..........6 1.1.3 Epigenetic alteration in cancers..........7 1.1.3.1 DNA methylation...........................8 1.1.3.2 Chromatin remodeling......................9 1.2 Chromosome 6q deletion and tumorigenesis.11 1.3 The extranodal nasal NK or T Cell lymphomas........................................15 1.4 The KIAA1866 protein.....................17 1.4.1 Molecular cloning of KIAA1866 gene.......17 1.4.2 Functional characterization of the serial KIAA genes.......................................18 1.5 Specific aim of this study...............19 Chapter 2 - Materials and Methods................20 2.1 Bioinformatics programs used to annotate KIAA1866 gene....................................20 2.2 Cell lines...............................24 2.3 PCR screening of cDNA panels.............24 2.3.1 Primer design............................24 2.3.2 The multiple tissue cDNA panels..........26 2.3.3 PCR amplification........................26 2.4 The full length KIAA1866 mRNA clone from the Kazusa DNA Research Institute in Japan.......27 2.5 E. coli expression system................30 2.5.1 Generation of cloning fragment...........30 2.5.2 KIAA1866ORF3’mut/pET21b construction....30 2.5.3 Expression the T7-KIAA1866ORF-6xHis fusion proteins.........................................32 2.5.4 Detection of recombinant protein.........32 2.6 To define the cellular localization of the KIAA1866 protein.................................33 2.6.1 KIAA1866ORF3’mutB fragment..............33 2.6.2 KIAA1866ORF3’mutB/pCR®II construction...34 2.6.3 Rapid colony screening...................34 2.6.4 KIAA1866ORF3’mutB/pEGFP-N1 construction.....................................36 2.6.5 Transient transfection...................36 2.6.6 Fluorescence microscope..................37 2.6.7 RNA isolation, reverse transcription and PCR..............................................37 2.6.8 Western blotting.........................38 2.7 KIAA1866ORF3’mut/pcDNA3.1 myc-His A(+) construction.....................................38 2.7.1 Transient transfection...................39 2.7.2 Western blotting.........................39 2.8 Real-Time Quantitative RT-PCR analysis...39 2.8.1 In vitro transcription...................39 2.8.2 Reverse transcription....................40 2.8.3 Quantitative real-time PCR...............40 Chapter 3 – Results.............................43 3.1 Sequence annotation of the KIAA1866 gene by the use of bioinformatics........................43 3.1.1 Gene structure of KIAA1866...............43 3.1.2 Expression pattern in EST database.......43 3.1.3 KIAA1866 protein information.............48 3.1.4 Localization prediction by pSORT II program..........................................49 3.2 Establishment of expression profile of the KIAA1866 gene in normal and cancer tissues.......49 3.2.1 The PCR screening results using coding region specific primer...........................49 3.2.2 The PCR screening results using 3’ untranslated region specific primer..............49 3.3 E. coli expression system................53 3.4 To define the cellular localization of the KIAA1866 protein by microscope observation.......55 3.5 The overexpression of KIAA1866ORF myc-His fusion protein...................................60 3.6 To quantify the expression of KIAA1866 gene in bladder cancer cell lines by quantitative RT-PCR...........................................60 3.6.1 The endogenous KIAA1866 expression in bladder cancer cell lines........................60 3.6.2 The KIAA1866 expression in transfected cell lines............................................60 Chapter 4 – Discussions.........................65 4.1 The different bioinformatics annotation in KIAA1866 gene....................................65 4.2 Compare the expression profile in normal and tumor tissues................................65 4.3 The localization between predicted and recombinant GFP fusion protein...................66 4.4 Chromosome 6 alteration and bladder cancer progression......................................67 4.5 Study on tumorigenesis...................67 Chapter 5 – References..........................69

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