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研究生:徐慧雯
研究生(外文):Shyu Huey-wen
論文名稱:小鼠睪丸專一表現之RING鋅指轉錄因子Trif分子選殖及功能探討
論文名稱(外文):Molecular Cloning and Functional Characterization of a Testis-specific RING-Zinc Finger Transcriptional Factor, Trif
指導教授:李鴻李鴻引用關係
指導教授(外文):Li Hung
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:91
中文關鍵詞:睪丸鋅指轉錄因子退化性引子細胞凋亡
外文關鍵詞:testisRING zinc fingerdegdndrate primersapoptosisround spermatid
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Testis—RING zinc finger (Trif)基因是我們利用退化性引子(degdndrate primers) PCR所發現的一個基因,其核甘酸序列經與NCBI的cDNA庫中比對結果,發現它是一新的基因,基於其睪丸組織表現之特異性,因此將其定名Trif。其mRNA 全長約1.7 kb 而open reading frame (ORF)約1500 bp約可轉錄出500氨基酸,其中含有RING zinc finger、B-box及B30.2 (亦稱rfp)等功能區。經由北方墨點法的分析,我們發現該基因的 mRNA在成鼠的不同組織中只有表現在睪丸。自出生後20天開始表現,並在90天時達到最大量,隨後呈現恆定之表現量。
經由原位雜交分析發現Trif 的mRNA主要表現在round spermatid的階段;在進一步分離出Sertoli細胞、Leydig細胞及germ細胞後証明Trif mRNA僅存在germ cells,且於 缺乏成熟germ cell之小鼠睪丸中並未發現Trif mRNA的表現,更加証實Trif是一個germ cell專一表現的基因。隨後經由染色體原位雜交試驗我們發現Trif基因是位於小鼠第二號染色的F1位置上。此外,我們Trif mRNA在睪丸中的表現可藉由額外施打黃體酮及睪固酮而促進其mRNA的表現,而施打雌二醇則會抑制Trif mRNA的表現。
將Trif基因送入一般細胞株中表現時發現Trif蛋白質會存在於細胞核中並且以斑點狀分佈,並由雙重染色觀察Trif能與promyelocytic leukemia (PML) protein相互鍵結。經由細胞外系統的蛋白質激酶磷酸化實驗,我們發現p38可在試管中直接的對Trif蛋白進行磷酸化;當使用SB203580抑制p38磷酸激的活性時,則發現Trif蛋白會由核轉至細胞質中。
在Trif生理功能的分析方面,我們發現Trif的大量表現可使細胞走向細胞凋亡一途,並且導致DNA的合成速度下降3-4倍,由西方墨點法亦發現,Bax 、caspase 2及RIP等蛋白質表現量均會上升。但在Trif基因轉殖小鼠的睪丸中我們並沒有觀察到如同在表現Trif穩定細胞株中所造成的影響。於性成熟小鼠時期發現,睪丸細胞表現較高量的FasL及FSH receptor之mRNA,並且有較明顯的凋亡細胞現象,且轉殖小鼠的生育能力亦略低於正常小鼠。
經由以上的實驗結果,說明Trif 是一個轉錄因子。同時轉殖小鼠的睪丸中亦發現有多量的凋亡細胞,顯示Trif在精子成熟的發育過程中扮演重要的角色。
In this study, we isolated and characterized a novel RING zinc finger gene, Trif (testis-specific ring finger). This deduced protein from the 1.8 kb Trif cDNA contains several structural motifs such as an N-terminal RING-finger, a B box, and a C-terminal B-30.2 like domain which grouped the trif protein to a RING finger-B box-coiled coil (RBCC) family.
Northern blot analysis of adult mouse multiple tissues indicated that Trif gene is expressed predominately in the testis. Further analysis showed that transcript of Trif became detectable at a prepubertal stage (20 dpp). In situ hybridization showed that Trif is expressed in the round spermatids. Trif transcripts were not detected by Northern blot in the adult testes and epididymis of W/Wv and Wv/Wv germ-cell-deficient mice. We also confirmed that Trif was expressed in the germ cells by fractionated mouse testicular cells. Mammalian spermatogenesis is a complex process and is tightly regulated by hormones. Estradiol treatment during juvenile development results in the suppression of testicular function. Here we also found that the Trif expression is decreased by estradiol treatment.
From the subcellular location analysis, we identified that the Trif protein had a speckled nuclear expression pattern in COS-7 and HEK-293 cells. Trif and promyelocytic leukemia (PML) protein, in part colocalizing in the nucleus, was further detected by double staining analysis. As shown by protein kinas assays in vitro, the Trif protein can be phosphorylated by p38. p38 inhibitor (SB203580) treatment resulted in a translocation of the Trif protein from the nucleus into the cytoplasm.
The biological function of Trif protein in apoptosis was demonstrated by DNA fragmention assay, flow cytometry assay and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling) staining in Trif-transfected cells. To further characterize the molecular mechanism of Trif-induced apoptosis, we examined the levels of apoptosis-associated proteins, Bax, Bcl-2, caspase-2, p53, and RIP. With the increase of Trif level, Bax, caspase-2 and RIP were progressively induced in the cells. However, no significant morphological phenotypes were found in the transgenic mouse testis. Only some elevated levels of FSH receptor, and FasL in adult transgenic testes were observed.
In summary, Trif is a testis-specific transcription factor. Ectopic expression of Trif could induce apoptosis in cells and testis. Trif may play a very important role in the regulation of spermatogenesis.
致謝………………………………………………….………………………………
縮寫表………………………………………………….……………………………
附圖目錄………………………………………………….…………………………
中文摘要………………………………………………………………………………1
英文摘要……………………………………………………………………………2
第一章 Trif 基因選殖及表現………………………………………………....4
第一節、 前言……………………………...……………………………. 4
壹、 戒環鋅指蛋白的特性………………………………………….…4
貳、 戒環鋅指蛋白的種類……………….…………………………..5
參、 戒環鋅指蛋白的生理功能………………….……………………6
肆、 精子的生成………………….………………………………….6
一、雄性性腺發育相關的基因……………….……..………………7
(一) SRY基因…………………………………………………....7
(二) SOX-9基因………………………………....………………7
(三) SF-1基因……………………………….…………………..7
(四) WT-1基因………………………………....………………..8
二、生精過程…………………………………………………………8
(一) 精原細胞期……………………………..………………….9
(二) 精母細胞期…………………………..…………………….9
(三) 精細胞期…………………...…………...………………….9
第二節、 材料與實驗方法……………………………………………...12
第三節、 實驗結果……………………………………………………...17
壹、 Trif基因選殖及表現……………………………………………17
貳、 Trif基因在胚胎及成體時期表現的時間………………………18
參、 Trif基因在胚胎及成體時期表現的位置………………………19
肆、 Trif 基因在c-kit 缺陷小鼠中的表現………………………19
伍、 性荷爾蒙對Trif基因表現的影響………………………………19
陸、 Trif基因在小鼠染色體上的位置………………………………20
柒、 Trif蛋白在體細胞中表現的位置………………………………20
捌、 Trif蛋白的訊息傳遞路徑………………………………………21
第四節、 實驗討論……………………………………………………...21
第二章 Trif 基因生理功能分析………………………………………25
第一節、 前言………………………………………………………….. 25
壹、 細胞壞死及細胞凋亡之區別……………………………………25
一、 細胞壞死…………………………………………………..25
二、 細胞凋亡……………………………….….………………..26
貳、 精子生成參與的細胞凋亡相關系統……………………………26
一、 Bcl-2 family members…………………………………….….27
二、 Fas /FasL系統………………………………………….…...28
第二節、 材料與實驗方法…………………….….………………………28
第三節、 實驗結果………………………………………………………31
壹、 暫時性Trif基因表現於體細胞………………………………..32
貳、 誘發Trif基因表現於體胞…………………………………….33
參、 Trif基因轉殖小鼠的分析………………………………………34
第四節、 實驗討論……………………………………………………….35
圖表……………………………………………………………………………39
參考資料…………………………………………………………………….80
附錄……………………………………………………………………………92
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