尿嘧啶雙磷酸葡萄糖去氫酶基因驅動子之分析與調控

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研究生：	韋婕亞 Jaya Vatsyayan
論文名稱：	尿嘧啶雙磷酸葡萄糖去氫酶基因驅動子之分析與調控 Transcriptional Regulation of Human Gene Encoding UDP-Glucose Dehydrogenase
指導教授：	張晃猷 Hwan-You Chang
口試委員:
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生命科學系 Department of Life Sciences
論文出版年：	2005
畢業學年度：	94
語文別：	英文
論文頁數：	112
中文關鍵詞：	UGDH 、promoter analysis 、Sp1 、PPRE 、Transcriptional regulation 、Xenobiotics
外文關鍵詞：	UGDH, promoter analysis, Sp1, PPRE, Transcriptional regulation, Xenobiotics
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尿嘧啶雙磷酸葡萄糖去氫酶(UDP-Glc Dehydrogeneas, UGDH) 是生物體唯一催化尿嘧啶二磷酸葡萄糖(UDPGlc)氧化反應變成尿嘧啶雙磷酸葡萄糖醛酸(UDPGlcA)的酵素。尿嘧啶雙磷酸葡萄糖醛酸扮演很多重要的生理角色，在肝臟中可經由第二階段藥物解毒酶作用，結合眾多外生性及內生性物質，增加它們的可溶性以便於後續分泌排出。另外，尿嘧啶雙磷酸葡萄糖醛酸提供醣胺多醣體，玻尿酸，軟骨素硫酸及硫酸肝素的重要成分。

我們分析人類表現序列標記，如同5’RACE實驗結果，證明之前利用北方墨點法的發現，此基因有二個轉錄起始點，相隔約160核苷酸。利用生物資訊軟體分析UGDH5’端附近區域的基因序列，預測出許多有轉錄因子結合的位置。相當獨特的是，有14個可能的Sp1結合位在調控子前面632核苷酸的片段，除此還有一個非典型的TATA區塊的存在。為了探討在UGDH調控子區域對基因表現的調控，尤其是較長的mRNA，我們在2.1kbUGDH調控子區域建立序列性刪除片段及利用螢火蟲冷光報告基因分析不同驅動子區域的調控活性。我們的結果顯示，從-486到-632核甘酸位置可能與此基因的正調節有關。我們也發現SP1轉錄因子的抑制物MithramycinA，可以降低此基因驅動子的活性，說明SP1很可能參與UGDH的基因表現調控。我們在這個區域利用定點突變分析了3個可能與Sp1結合片段的功能。在-564位置的突變，在HepG2 及HeLa細胞實驗中，證實此區域是提供UGDH基因表現增強的片段。另外，經由核酸帶遲滯電泳移動分析以及抗Sp1抗體的超移動分析，證實此GC區塊的確是Sp1的結合單元。總結而言，我們的結果確認一個選擇性的UGDH轉錄起始位置，以及找到了可提高加強UGDH基因基本轉錄活性的cis-element。
我們除了定出在UGDH基因5’端附近714核苷酸為此基因的主要的調控子外，也進行分析UGDH 調控子前面1057-957區域與抑制基因表現有關的區域。突變位在-1003包含於被預測為過氧化酶體接受器的反應片段（PPRE）的核甘酸，可破壞此區域的抑制功能。我們也利用親合性管柱層析搜尋可與此段類似PPRE抑制單元交互作用的蛋白質。利用生物素標定此區域的DNA與細胞核萃取物混合後，經由帶有 streptavidin的顆粒進行純化，找到兩個蛋白質。隨後經MALDI-TOF確認純化之蛋白為一62 kDa的鋅拇指蛋白及42kDa 的肌動蛋白。
另外，由於外生性物質是否可以調控UGDH基因表現仍不清楚，因此我們也嘗試回答這個問題。用藥物處理肝癌細胞HepG2後，利用同步定量PCR方法分析UGDH基因的表現，以及調控子報告基因的分析，我們發現1.23 kb的UGDH驅動子會受到抗生素rifampicin的活化。而-632至-1050的片段是受 rifampicin影響所作用的位置。我們進一步將PPAR及RXR表現載體一同送入細胞之後，再處理PPAR活化物，發現不論是否加入rifampicin， UGDH驅動子的活性，都會受到明顯的抑制。總結而言，我們的研究，第一次說明UGDH基因會受到外生性物質的調節，同時也找出受到rifampicin調控的UGDH基因驅動子單元。

The prominence of UDP-Glc Dehydrogenase (UGDH, EC1.1.1.22) is in its unique and pivotal role in catalyzing the oxidation of UDP-Glc to UDP-GlcA accompanied with the reduction of two molecules of NAD. UDP-GlcA plays many important physiological roles in liver by conjugating with a variety of xeno- and endobiotic compounds to aid in their solubilization and excretion through the action of phase II drug detoxifying enzymes. UDP-GlcA serves as a critical component of the glycosaminoglycans, proteoglycans, hyaluronan, chondroitan sulfate and heparan sulfate.

Analysis of a human EST database, as well as the results of a 5’-RACE experiment revealed the presence of two transcription start sites approximately 160 bp apart in the human UGDH gene confirming previous Northern hybridization results. An extensive bioinformatics analysis of the gene sequence of the UGDH 5’-flanking region revealed many interesting putative transcription factor-binding sites. The most unique fact was the prediction of fourteen putative Sp1 sites upto –632 bp region of the promoter, besides the presence of an atypical TATA box. To delineate the regions in the UGDH promoter required for regulating the expression of the gene, in particular the synthesis of the large transcript, serial deletions of the 2.1-kb UGDH promoter region were constructed and their activities determined by the firefly luciferase reporter gene assay. Our results indicated that the region from nucleotide position –486 to –632 relative to the start of the small transcript contains positive regulatory elements that contribute to gene expression. Mithramycin A, an inhibitor of transcription factor Sp1, abrogated the promoter activity, suggesting the involvement of this specific protein in UGDH expression. By using site-directed mutagenesis, we analyzed the functional contribution of three putative Sp1 binding elements within this region. A mutation at position –564 demonstrated that this site serves as an enhancing element in both HepG2 and HeLa cells. The complex formation pattern revealed by an electrophoretic mobility shift assay as well as an anti-Sp1 antibody-mediated supershift assay confirmed the identity of this GC box as an Sp1 binding motif. Our results thus identified an alternative transcription start site on the UGDH promoter, and located the cis-element that greatly enhances the basal transcriptional activity of UGDH gene.

Besides defining the 714 bp 5’-flanking region of the UGDH gene as the core promoter, in another study, we delineated the region from nucleotide positions –1057 to –957 on the UGDH promoter to be responsible for the repression of the promoter activity. A mutation at nucleotide –1003, which is contained within a motif predicted as the response element for peroxisome proliferator receptor a□ (PPARa), abolished the suppression effect. The proteins interacting with the PPRE-like repressor motif were purified by biotin labeled DNA affinity purification with streptavidin-coated beads. Subsequently MALDI-TOF identified the purified proteins as a 62-kDa zinc finger and a 42-kDa b-actin protein.

In addition, it is not known whether xenobiotics can modulate the UGDH gene expression. An attempt to answer this question was made by treating the human hepatoma cells HepG2 with several medicinal compounds and the UGDH gene expression was analyzed by using Real time-PCR. Through promoter-reporter gene assays, we found that rifampicin showed multiple folds activation of a 1.23-kb UGDH promoter construct, and the region likely to respond to rifampicin treatment is located within the region –632 to –1050. A bioinformatics search for xenobiotic response element in this region predicted a binding motif for the PPAR at position –1003. A mutation at the predicted PPAR recognizing motif eliminated normal suppression as well as the rifampicin activation effect on the UGDH promoter activity. Cotransfection with the PPARa and RXRa expression vectors and subsequent treatment with the PPARa agonist led to the suppression of the UGDH promoter activity either in the presence or absence of rifampicin. Our study for the first time showed the UGDH gene to be under xenobiotic regulation and delineated a motif responsible for rifampicin response and transcriptional repression of the UGDH gene.

Abstract (English) ……………………………………………………………...    II
Abstract (Chinese)………………………………………………………………    V
Acknowledgments……………………………………………………………….    VII
Dedication……………………………………………………………………......    IX
Abbreviations…………………………………………………………………….    X
Table of contents………………………………………………………………...    XII
Chapter 1: General Introduction
1 Background and Significance…………………………………………………    2
2 Regulation of Gene Expression………………………………………………..    10
2.1 Cis-acting DNA Elements…………………………………….……………..    11
2.2 Trans-acting Factors………………………………………………………    13
2.2 (a) General Transcription Factors…………………………………………    13
2.2 (b) Transcriptional Activators……………………………………………….    13
2.2 (c) The Sp-family of Transcription Factors…………….…………………    14
Chapter 2: Analysis of human UDP-Glucose Dehydrogenase promoter: Alternative transcription start site mapping and identification of an Sp1 binding site crucial for the expression of the large transcript
1 Abstract……………………………………………………………………….    18
2 Introduction…………………………………………………………………..    19
3 Materials and Methods
3.1 Mapping of the Ttranscription Start Site of Human UGDH Gene…………    20
3.2 Plasmid Construction and Site-directed Mutagenesis………………………    21
3.3 Cell Culture, Transient Transfection, and Luciferase Assay……………….    22
3.4 Bioinformatics Analyses…………………………………………………….    23
3.5 Electrophoretic Mobility Shift Assay (EMSA)…………………….……….    24
4 Results and Discussion    25
4.1 Identification of Possible Start Sites for UGDH Transcripts……….………    25
4.2 Deletion Analysis of the Human UGDH Promoter…………………………    29
4.3 Identification of Sp1 Binding Motifs that Contributes to UGDH Promoter Activity……………………………………………………………………………    32
4.4 Effects of Mutation of the Putative Sp1 Binding Sites on UGDH Promoter Activity……………………………………………………………………………    36
4.5 Electrophoretic Mobility Shift Assay (EMSA) of Oligonulceotides Spanning the SP#3 GC box………………………………………………………    39
5 Conclusion…………………………………………………………………….    44
Chapter 3: Identification of a Cis-acting element responsible for negative regulation of the human UDP-glucose Dehydrogenase gene expression
1 Abstract……………………………………………………………………….    46
2 Introduction…………………………………………………………………..    47
3 Materials and Methods
3.1 Construction of Promoter-reporter Plasmids………………………………..    48
3.2 Cell Culture and Transfection Analysis……………………………………..    49
3.3 Bioinformatics Analyses …………………………………………………...    50
3.4 Site-directed Mutagenesis  ………………………………………………...    50
3.5 Nuclear Protein Preparation and Electrophoretic Mobility Shift Assay……    51
3.6 Affinity Purification of Protein Binding to the DNA Probe ………………..    53
3.7 Mass Spectrometric Analysis of the Proteolytic Peptides……….…………    54
4 Results and Discussion
4.1 Delineation of Repressor Binding Cis-regulatory Region…………………..    54
4.2 Bioinformatics Analyses for Ppotential Regulatory Sites within –1050 to –632   bp on UGDH Promoter……………………………………….……………..    57
4.3 Mutational Analysis of the Putative PPRE in the Region –1050 to –957…    59
4.4 Electrophoretic Mobility Shift Analysis (EMSA) of the DNA-protein Interaction at the Negative Regulatory Motif ………………………………….…    61
4.5 Purification of the Protein Interacting With the Inhibitory Cis-regulatory Element at –1003 …………………………………………………………………    64
4.6 Mass Spectrometry Identification of the Proteins…………………………..    68
5 Conclusion…………………………………………………………………….    71
Chapter 4: Effects of xenobiotics and peroxisome proliferator receptor-alpha on the human UDP-glucose Dehydrogenase gene expression
1 Abstract………………………………………………………………………..    73
2 Introduction……………………………………………………………………    74
3 Materials and Methods
3.1 RNA Isolation…………………………………………………………………    76
3.2 Reverse Transcription (RT) and Quantitative Real Time (Q) PCR…………...    76
3.3 Construction of Promoter-Reporter Plasmids ………………….……………..    78
3.4 Cell Culture and Transient Transfection Analysis…………………………….    78
3.5□ Bioinformatics Analyses………………………………………………………    80
3.6 Site-Directed Mutagenesis …………………………………………………...    80
3.7 Nuclear Protein Preparation and Electrophoretic Mobility Shift Assay………    81
4 Results and Discussion
4.1 Effect of Xenobiotics on UGDH Expression in the HepG2 Cells…………….    82
4.2 Effect of Rifampicin on the activity of UGDH promoter–reporter constructs..    85
4.3 Bioinformatics Analyses for Potential Regulatory Sites within –1050 to –632 on Human UGDH Promoter………………………………………………….……..    87
4.4 Mutational Analysis of the Putative PPRE at –1003…………………………    88
4.5 DNA-Protein Interaction at the PPRE-like Motif…………………………….    91
4.6 Effect of PPARa Agonist on UGDH Expression…………………………….     93
4.7 Effect of PPARa Agonist on pJR004 Promoter Activity…………………….    95
5 Conclusion……………………………………………………………………...    98
Chapter 5: Conclusions and Future Perspectives………………………………..    99
References ……………………………………………………………….…………    103
List of Publications ………………………………………………………………...    114

                                

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LIST OF PUBLICATIONS

1. Vatsyayan J, Peng HL, Chang HY. 2005 Analysis of human UDP-glucose dehydrogenase gene promoter: identification of an Sp1 binding site crucial for the expression of the large transcript. Journal of Biochemistry. 137(6):703-9
2. Vatsyayan J, Lee SJ, Chang HY. 2005 Effects of xenobiotics and peroxisome proliferator receptor- alpha on the human UDPglucose dehydrogenase gene expression. Journal of Biochemical and Molecular Toxicology (accepted).
3. Vatsyayan J, Lin CT, Peng HL, Chang HY. 2005 Identification of a cis-acting element responsible for negative regulation of the human UDP-glucose dehydrogenase gene expression. Bioscience, Biotechnology, and Biochemistry (revised).

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