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研究生：	曾淑貞 Tzeng, Shwu-Jen
論文名稱：	大白鼠有機陰離子轉送器之分子調控機制 Transcriptional Regulation of Rat Multidrug-Resistance Protein 3 (Mrp 3) Gene Expression
指導教授：	黃金鼎 Huang, Jin-ding
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2005
畢業學年度：	93
語文別：	英文
論文頁數：	120
中文關鍵詞：	轉錄因子、大白鼠、有機陰離子轉送器
外文關鍵詞：	C/EBPbeta, Sp1, Rat, Multidrug-Resistance Protein 3 (Mrp 3), C/EBPalpha
相關次數：	點閱：110 下載：1
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　　在正常生理狀況下，由於MRP2 在肝臟的表現量較在腸或其他組織的表現量高 (位於 canalicular 或 apical site)，MRP3 在肝臟的表現量較在腸或其他組織的表現量低 (位於 basolateral site)；因此肝臟中大多數結合後的有機陰離子是經由 MRP2 排至膽道。當 Mrp2 轉送器有缺陷或缺乏的老鼠或因 MRP2 轉送器有缺陷而患Dubin-Johnson症候群的人，其肝臟會代償性的誘使 MRP3 表現增加，進而將原本因應自膽道排除的有害化合物轉送至血液中再經腎臟排除，以便減少因阻塞性黃膽造成肝臟中有害肝細胞的物質淤積。除了膽汁阻滯的情況會誘導 MRP3 表現增加外，也有報導指出 phase II 酵素誘導劑，如： TSO 和 DAS，可經由與 CAR 和 PXR 等這些 nuclear receptor 無關的途徑增加 MRP3 的表現。此外外生素 (xenobiotics) 如：omeprazole， β-naphthoflavone，和 2-acetylaminofluorene (2-AAF)，也可增加人類肝癌細胞株 (Hep G2) 表現 MRP3。然而，這些藥物誘導肝臟中 MRP3 表現增加的機制仍有待進一步探討。本實驗的目的是探討大白鼠 Mrp3 基因在肝臟及腸中的調控機制，並建立一 in vitro 模式來研究 TSO ，DAS和 2-AAF 等藥物誘導大白鼠肝癌細胞株 (H4IIE) 表現 MRP3 的調控機制，並進一步找出參與調控的轉錄因子。首先利用部份已知的 cDNA 序列設計基因特異引子 (primers) 配合 GenomeWalker 試劑所附的引子，分別於五個由不同限制酵素切割的基因庫中選植特異性片段，轉接至 pCRII 載體並作序列分析，再將此片段 (2723bp) 轉接至不含啟動序列的報告基因 (pGL3-Basic 載體) 。利用不同 5’ 端段切長度的 Mrp3 啟動區的報告基因轉染至腸 (IEC-18) 或肝癌 (H4IIE) 細胞株作分析，發現重要的 Mrp3 啟動區是在相對於轉譯起始點 (ATG) 上游157 bp 處。進一步將此區間內轉錄因子的結合序列，如： C/EBP，COUP，及Sp1，作單點或多點的突變修飾，並藉報告基因活性變化，分析發現將這些在 C/EBP，Sp1 (3)， Sp1 (4) 轉錄因子的結合序列作單點或多點的突變修飾後的載體送入 H4IIE 細胞，顯示報告基因活性有顯著降低，證實這些轉錄因子的結合序列它們的重要性。經凝膠電泳位移 (EMSA) 及 supershift 實驗，顯示轉錄因子 Sp1/Sp3 及 C/EBPα， C/EBPβ 和 C/EBPδ，分別結合在Mrp3 啟動區的 GC boxes (–122/–106) 和 C/EBP (–157/–140) 結合序列。為進一步探討C/EBPα， C/EBPβ 和 C/EBPδ在大白鼠 Mrp3 基因表現的影響，我們利用CMV啟動子 (promoter) 啟動C/EBPα， C/EBPβ 和 C/EBPδ 的載體與報告基因一同轉染至各種肝 (H4IIE C3，clone 9， BRL 3A等) 或纖維母 (Rat 2 fibroblast) 細胞株，藉報告基因活性變化發現 C/EBPα 和 C/EBPδ對活化 Mrp3 啟動序列較 C/EBPβ顯著。而不具轉錄活性區 (transactivation domain) 的 A-C/EBP 轉錄因子(僅具與 DNA結合序列)，與其它 C/EBP分子組成 heterodimer方式來降低內生性 C/EBPα 和 C/EBPβ 對 Mrp3 啟動區的活性，並以此方式抑制外送的 C/EBPα， C/EBPβ 和 C/EBPδ對大白鼠 Mrp3 基因的活化。也證實 C/EBPs 轉錄因子的結合不需鄰近序列的幫忙；並具有組織特異性的只活化肝細胞株的Mrp3 啟動序列。將利用果蠅 actin 5C啟動子啟動 Sp1 和 Sp3 的載體分別送入不含 Sp 轉錄因子的果蠅細胞 (SL2 cells)，證實 Sp1 和 Sp3 轉錄因子依轉染量的增加而活化Mrp3 啟動報告基因的活性，並分別與 C/EBPα 或C/EBPδ 產生協同性的活化Mrp3 啟動報告基因的作用，然而Sp1 或 Sp3與 C/EBPδ 產生協同性的活化Mrp3 啟動序列作用會因 C/EBPβ 的共同存在而降低。TSO依藥物濃度的增加而誘導大白鼠肝癌細胞株 (H4IIE) 表現內生性 Mrp3 的 mRNA 及活化 Mrp3 啟動報告基因活性，也找出參與調控的序列是位於 (–157/–106) 的Mrp3 啟動區。在 C/EBP，Sp1 (3)， Sp1 (4) 轉錄因子的結合序列作單點或多點的突變修飾後載體送入 H4IIE 細胞，於 TSO 誘導活化 Mrp3 啟動報告基因活性亦有顯著的影響。凝膠電泳位移 (EMSA) 及染色質免疫沉澱 (ChIP) 實驗結果，顯示 TSO 的誘導Mrp3基因表現量增加，是藉由抑制 C/EBPβ 及促進 Sp3 和CBP 結合至Mrp3 啟動序列來誘導Mrp3基因轉錄。共同轉染的實驗也顯示 C/EBPα 轉錄因子和CBP可協同性增加Mrp3 啟動報告基因的轉錄活性。綜合以上的結果得知，不同 C/EBP 和 Sp1/Sp3 轉錄因子共同參與 rat Mrp3 基因的組織特異性的調控；且因不同 C/EBP 轉錄因子對Mrp3 啟動報告基因的轉錄活性不同，再者，不同 C/EBP 轉錄因子又依不同的組合方式或轉譯後修飾而有不同的轉錄活性，提供另一個在肝細胞中調控rat Mrp3 基因的機制。

　　Mrp3 is expressed in rat intestine, but not in the liver at normal circumstance. MRP3 is highly up-regulated in the livers of rats made cholestatic by bile duct ligation or in cholestatic human liver. In addition to cholestasis, induction of Mrp3 mRNA and protein expression in rat liver can occur by treatment with microsomal enzyme inducers that induce cytochrome P450 2B1/2 (Cyp2B1/2), such as trans-stilbene oxide (TSO) and diallyl sulfide (DAS). However, the precise mechanism of rat Mrp3 upregulation by these drugs in the liver is still unknown. Therefore, the goals of this study are to explore the basal and inducible regulation mechanism of rat Mrp3 gene in intestine and liver, and to test whether pretreatment with phase II enzyme inducers can up-regulate Mrp3 mRNA expression in hepatoma H4IIE cells, and determine the response elements of Mrp3 promoter by these drugs. In the present study we identified molecular elements involved in the transcriptional regulation of rat Mrp3 in intestine and liver cells. The sequence of the 5’-flanking region of the rat Mrp3 gene was determined up to 2723 bp upstream of the translation start site. Regulatory regions crucial for Mrp3 promoter activity were characterized between –157 and –106 bp in intestine (IEC-18) and hepatoma (H4IIE) cells. In this region, one C/EBP-binding site (–157/ –140) and two GC boxes (–122/ –106) were involved in specific DNA-protein interaction. EMSAs and supershift assays demonstrated that Sp1 and Sp3 transcription factors bound to these GC boxes and the C/EBP proteins bound to the C/EBP-binding site. Mutagenesis studies demonstrated that these binding contributed at least 85% of Mrp3 promoter (pWT-157) activity. In Drosophila SL2 cells, both Sp1 and Sp3 transactivated the Mrp3 minimal promoter (pWT-157). Whereas overexpression of C/EBPδ had synergistic effect on Sp1 or Sp3 in SL2 cells, the activation of Mrp3 promoter due to C/EBPδ was countered by C/EBPβ overexpression. Structural and functional analysis demonstrated that binding sites for C/EBPs, Sp1 and Sp3 are essential for transcription of the rat Mrp3 gene in Mrp3-expressing cells (including: H4IIE C3, BRL 3A, clone 9, and Rat 2). Cotransfection assays demonstrate that C/EBP transcription factors modulate the basal and tissue specific activity of the Mrp3 gene promoter by recognition of the C/EBP (−157/−140) element and through functional cooperation with factors interacting with the Sp1 (3) and Sp1 (4) (−140/−106) cis-acting elements. TSO stimulated Mrp3 mRNA levels as determined by RT-PCR and elevated the activity of a transfected (–2723) Mrp3 promoter reporter gene construct in a dose-dependent manner. Functional 5’deletion and point-mutation analysis mapped the TSO response element of rat Mrp3 promoter to the sequence –157/–106. Gel shift assays showed that treatment of the cells with TSO resulted in a time-dependent decrease in the binding of Sp1 and short form of Sp3 compared with nuclear extract from untreated cells, but not affected in the binding of long form of Sp3. C/EBP binding activity increased 12-24 hours after TSO treatment. Further ChIP assays reveal that TSO is capable of preventing the association of C/EBPβ with the Mrp3 promoter, while somewhat unexpectedly inducing the recruitment of Sp3 and CBP. Coexpression of C/EBPα and CBP showed a synergistic effect on the Mrp3 promoter activity. Meanwhile, the expression of E1A inhibited the transactivation of C/EBPα as well as CBP on Mrp3 promoter activity with or without TSO treatment in a dose-dependent manner. Cotransfection of C/EBPα and CBP expression vectors were reduced or abrogated when the Sp1- and C/EBP-binding sites were individually mutated with or without TSO treatment. At the concentration utilized in ChIP assay, TSO dramatically increases Mrp3 mRNA. Taken together, these results suggest that inhibition of C/EBPβ association and recruitment of CBP and Sp3 to the Mrp3 promoter is a critical step to initiate transcriptional activation. In this study, we found C/EBPs and Sp1/Sp3 can cooperatively regulate the basal and inducible promoter activity of rat Mrp3 gene through proximal (−157/−106) region suggested another fine-tune regulation mechanism may involve in Mrp3 gene expression.

Contents

Abstract  ………………………………………………………………………	V
Abstract in Chinese …………………………………………………………	VII
Table Index  ……………………………………………………………………	IX
Figure Index  …………………………………………………………………	X
Abbreviations …………………………………………………………………	XII
	
Introduction	
I.	Efflux Mechanisms as Barriers  …………………………………………	1
II.	ABC Protein and Gene Organization  ……………………………………	2
III.	Substract Specificity   ……………………………………………………	3
IV.	Functional Role of MRPs   ………………………………………………	3
V.	Induction of Rat Mrp3 Gene Expression under Cholestasis  ……………	5
VI.	Induction of Rat Mrp3 Gene Expression by Phase II Enzyme Inducers and Genotoxic Drugs  …………………………………………………………	6
VII.	Aim  ………………………………………………………………………	7
		
Materials and Methods	
I.	Materials	
	1.	Chemicals and reagents   ……………………………………………	8
	2.	Kits   …………………………………………………………………	11
	3.	Enzymes   ……………………………………………………………	12
	4.	Bacterial culture accessories and antibiotics   ………………………	12
	5.	Antibodies   …………………………………………………………	13
	6.	Cell culture accessories   ……………………………………………	14
	7.	Instruments   …………………………………………………………	16
	8.	Others   ………………………………………………………………	16
	7.	Instruments   …………………………………………………………	16
II.	Methods	
	1.	Cell culture   …………………………………………………………	17
	2.	Cloning of the 5’-flanking region of rat Mrp3 gene  …………………	17
	3.	RT-PCR and 5’-RACE analysis   ……………………………………	18
	4.	Effector plasmids    …………………………………………………	18
	5.	Reporter plasmids    …………………………………………………	19
	6.	Transient transfection and luciferase assay    ………………………	21
	7.	Preparation of nuclear extracts    ……………………………………	23
	8.	Electrophoretic mobility shift assays (EMSAs)   ……………………	23
	9.	Western Blot Assays    ………………………………………………	24
	10	Chromatin immunoprecipitation assays (ChIP assays)   ……………	25
			
Result and Discussion	
Chapter 1	
I.	Clone the 5’-flanking region of rat Mrp3 gene from rat genomic library by a genomic walker method     ………………………………	27
II.	Basal regulation of rat Mrp3 gene in intestine (IEC-18) cells  ………	
	1.	Identification of the core regulatory region within the rat Mrp3 promoter in intestine (IEC-18) cells   ………………………………	
28
	2.	Site-directed mutagenesis of putative Sp1 binding sites between –443 and –19 of rat Mrp3 gene upstream    ………………………………	
29
	3.	Identification of the transcription factors acting on the putative Sp1 binding sites between –157 and –106 by EMSA and supershift assays   ………………………………………………………………	

29
III.	Discussion	30
		
Chapter 2	
I.	Identification of the core regulatory region within the rat Mrp3 promoter in hepaoma (H4IIE) cells	
	1.	Identification of the transcriptional initiation site of rat Mrp3 gene in liver cells by 5’ rapid amplify cDNA end (5’RACE) assay  …………	32
	2.	Identification of the core regulatory region within the rat Mrp3 promoter in hepatoma (H4IIE) cells  …………………………………	32
	3.	Identification of the transcription factors acting on Mrp3 promoter between –122 and –106 by EMSA and supershift assays   …………	33
	4.	Site-directed mutagenesis of putative Sp1, C/EBP and COUP-binding sites on Mrp3 Promoter   ……………………………………………	34
	5.	Identification of the transcription factors acting on Mrp3 promoter between –157 and –140 by EMSA and supershift assays   …………	34
	6.	C/EBP proteins modulates Mrp3 promoter activity in H4IIE cells  …	36
	7.	C/EBPα or A-C/EBP induce or inhibit Mrp3 promoter activity in a sequence-dependent manner    ………………………………………	37
II.	Sp1/Sp3 and C/EBP proteins cooperatively modulate Mrp3 promoter activity in SL2 cells	
	1.	Sp1 and Sp3 activate Mrp3 promoter in a dose-dependent manner …	37
	2.	C/EBPs as well as Sp1 or Sp3 to activate Mrp3 promoter in SL2 cells  …………………………………………………………………	38
III.	Tissue-specific regulation of Mrp3 promoter by C/EBP proteins	39
IV.	Discussion	40
		
Chapter 3	
I.	Stimulation of Mrp3 gene expression by phase II enzyme inducers	
	1.	TSO stimulate Mrp3 mRNA levels in H4IIE cells with a dose-dependent manner  ………………………………………………	
45
	2.	TSO stimulate Mrp3 promoter activity in H4IIE cells with a dose-dependent manner  ………………………………………………	
45
II.	Analysis of TSO response elements in Mrp3 promoter	
	1.	Comparison of the Mrp3 promoter activity under different serum-content medium     ……………………………………………	
45
	2.	Proximal C/EBP- and Sp1-binding sites differentially contribute to Mrp3 promoter regulation   …………………………………………	
46
	3.	Role of C/EBP family proteins in Mrp3 induction by TSO  …………	47
	4.	Effect of TSO on the binding of Sp1/Sp3 and C/EBPs to Sp1(3, 4)- and C/EBP-binding sites    …………………………………………	
48
III.	Functional roles of Sp1, Sp3, C/EBPα, C/EBPβ, p300 and CBP in Mrp3 promoter by TSO treatment 	
	1.	TSO promotes Sp3, C/EBPα and CBP binding in vivo. ………………	48
	2.	Cooperation of C/EBPα and CBP in upregulation of the Mrp3 promoter.   ……………………………………………………………	49
	3.	Mutation of Mrp3 promoter at Sp1- or C/EBP-binding sites abrogates transcriptional activity with or without TSO treatment.  ……………	
49
V.	Discussion   ………………………………………………………………	51
		
Conclusion   …………………………………………………………………	54
Tables   …………………………………………………………………	57
Figures   …………………………………………………………………………	61
Referrences   ………………………………………………………………………	102
Publication    …………………………………………………………………	112


                                    

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