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系統識別號 U0026-0812200910344035
論文名稱(中文) 人體與老鼠中multidrug resistance-associated protein 7 之探討
論文名稱(英文) Study on a new human transporter, multidrug resistance-associated Protein 7 (MRP7), and its mouse homologue
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 91
學期 1
出版年 92
研究生(中文) 高馨馨
研究生(英文) Hsin-Hsin Kao
學號 s5884105
學位類別 博士
語文別 英文
論文頁數 121頁
口試委員 指導教授-黃金鼎
口試委員-張明熙
口試委員-施桂月
召集委員-賴明德
口試委員-呂增宏
口試委員-黃銓珍
口試委員-戴明泓
口試委員-莊麗月
中文關鍵字 多重抗藥基因 
英文關鍵字 multidrug resistance  ABCC10  MRP7  ABC transpor 
學科別分類
中文摘要   Multidrug resistance (MDR) 指癌症治療中對於不相關的藥物,所伴隨產生的抗藥性。至今已有兩類人類的MDR基因被發現,包括MDR-associated protein (MRP) and P-glycoprotein (Pgp)基因,兩者均屬於ATP-binding cassette (ABC) transporter family。MRP 可能運送疏水性抗癌藥物及陰離子性藥物之結合物,其生理功能也許與異質性抗藥性的發生有關。
  多種化合物(chemosen-sitizing agents)會干擾MRP的功能,同時服用這些藥物也許可以增加傳統治療的效果。決定是否在chemosensitizing agents存在的情況下治療仍舊失敗的病人體內有其它MDR mechanisms將會非常有意義。瞭解較多ABC transporters的機制在化學治療的進步推展上有其重要性。我們已由人體小腸中定序出有機陰離子運輸者基因,MRP7A (multidrug resistance-associated protein 7A). MRP7A為MRP7之 alternatively splicing variant, 其cDNA序列共4,389 bp,經由一段退化性聚合脢連鎖反應 (degenerate PCR)及一系列重疊的反轉聚合脢連鎖反應 (inverse PCR) , 由人體小腸中被定序出來。此一cDNA序列可被轉印成一含1,462個氨基酸,分子量約158.8 kD之蛋白質。經北方點墨法 (Northern Blotting)檢測,顯示此一運輸者基因的組織分布以心臟及骨骼肌較多。經由MRP7之cDNA序列與一人體基因組序列 (accession number AC021391)之比較,顯示MRP7僅有20個表現序列, 與其它MRP家族之基因結構有30-31個表現序列大為不同。在極化的MDCK cells (polarized Madin-Darby canine kidney cells)中,MRP7之 promoter的luciferase activity為 SV40 promoter的四倍至五倍。基礎的MRP7基因表現 (basal MRP7 gene expression) 由兩段位於5' 側端 –1780 bp 到 –1287 bp, 和 –611 bp 到 –208 bp 的序列所調控。在MDCK細胞中, MRP7 promoter 的活性分別會被2-acetylaminofluorene (2-AAF) 及 trichostatin A (TSA) 刺激,增加到原來的226% 和347%. 另外,藉由西方點墨法 (Western Blotting),MRP7能在MDCK細胞中表現一大小約160 kD 之蛋白質,與預測值相符合,且表現在分離後之細胞膜的部份。
  為了經由transgenic mice或gene knockout的方法來了解MRP7的生物功能,我們由老鼠體內定序出mrp7A, 以及它的alternatively splicing variant, mrp7B。mrp7A、mrp7B之cDNA序列分別為4383 bp及4506 bp,可被轉印成含1,460、1501個氨基酸之蛋白質。 老鼠mrp7基因包含至少21個表現序列,及20個插入序列,總長約20 kb,與人類之MRP7基因幾乎相同,但與其它家族的基因差距甚大。mrp7之 promoter的luciferase activity為 SV40 promoter的二倍以上。老鼠mrp7A基因和mrp7B基因在某些特定的組織中之表現量有所差別。
英文摘要   The multidrug resistance-associated protein (MRP) subfamily transporters associated with anticancer drug efflux are attributed to the multidrug-resistance in cancer cells. The genomic organization of human multidrug resistance-associated protein 7 (MRP7) was identified. The human MRP7 gene, consisting of 22 exons and 21 introns, is quite different from other members of the human MRP subfamily. A splicing variant of human MRP7, MRP7A, expressed in most human tissues, is also characterized. The 1.93-kb promoter region of MRP7 was isolated and shown to support luciferase activity four- to five-fold greater than SV40 promoter. Basal MRP7 gene expression was regulated by two regions in the 5'-flanking region at –1780 bp to –1287 bp, and –611 bp to –208 bp. In Madin-Darby canine kidney (MDCK) cells, MRP7 promoter activity was increased to 226% by genotoxic 2-acetylaminofluorene (2-AAF) and 347% by the histone deacetylase inhibitor trichostatin A (TSA). The protein was expressed in the membrane fraction of the transfected MDCK cells.
  To understand the mechanism of biological functions of MRP7 through the generation of transgenic mice or gene knockout, a new MRP subfamily gene, mrp7A and its splicing variant, mrp7B, were isolated from mouse. The lengths of the open reading frames (ORF) of mouse mrp7A and mrp7B are 4383 bp and 4506 bp, respectively. Estimated polypeptide sequences of mrp7A and mrp7B are 1460 and 1501 amino acids. The mouse mrp7 gene consists of at least 21 exons and 20 introns spanning around 20 kb that is almost the same as the one in human MRP7 gene, but different with the other MRP subfamily genes. The promoter region was isolated from the genomic clone and shown to support the luciferase activity seven fold over the promoterless negative control and two fold activity higher than the positive control of SV40 promoter. The analysis of tissue expression of mouse mrp7A and mrp7B showed that these two transcripts express differentially in specific tissues.
論文目次 1. Index of Tables I
2. Index of Figures II
3. Abbreviations IV
4. Introduction 1
5. Materials and Methods 23
6. Results 45
7. Discussion 83
8. References 93
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