臺灣博碩士論文加值系統

肌醇磷酯酶(phospholipase C, PLC)為一重要的訊息傳遞酵素, 它的功能為將細胞外的刺激轉化為細胞內的訊息。共有四種肌醇磷酯同功酶被在生物體內被發現,分別為乙型(beta),咖嗎型(gamma),丁型(delta)及戊型(epsilon)。其中除了丁型肌醇磷酯酶外, 餘亞型酵素本身都具有調節功能的區段(domain), 因此對於丁型肌醇磷酯酶的調節的認知, 也就相對地較其它亞型為少。截至目前, 共有四種哺乳類的丁型肌醇磷酯酶(PLC delta)在文獻中被報導, 其中第一丁型肌醇磷酯酶(PLC delta1)是被研究最多的。它可以被鳥糞漂呤鏈結蛋白質所活化GTP-binding protein),而且被認為是細胞內鈣離子的增幅酵素。然而在其它丁型肌醇磷酯酶的亞型的研究其所知較少。因此在這論文中我們選殖一新的亞型肌醇磷酯酶, 第三丁型肌醇磷酯酶(PLC delta3), 並探討其特性。我們首先檢視此第三丁型肌醇磷酯酶在人體不同組織的表現, 除此之外, 我們也更進一步的探討其在不同細胞株內的表現調節。我們發現第三丁型肌醇磷酯酶在人體的組織中, 在訊息核醣核酸(mRNA) 與蛋白質層次上, 有不同的特異分佈表現。另外研究結果也發現此第三丁型肌醇磷酯酶基因是由15個表現子(exon) 所組成, 且在其轉錄起動區(promoter region)有一典型的環腺核咁單磷酸反應序列(cyclic AMP response element), 藉由研究此特異的啟動區位置, 我們分別探討的三個訊息傳遞路徑, 包括了環腺核咁酸, 鈣離子與C型蛋白激酶(protein kinase C) 對此第三丁型肌醇磷酯酶的表現影響。研究結果發現第三丁型肌醇磷酯酶的訊息核醣核酸表現會受到環腺核咁單磷酸及細胞內鈣離子的調節。在肺胚胎雙套體細胞株WI38及星狀細胞瘤U373細胞株中, 均可見到其抑制性的調節。然而卻沒有受到其下游的訊息接受體C型蛋白激酶的回饋性調節。本研究明白的展示出第三丁型肌醇磷酯酶的基因表現受到環腺核咁單磷酸與鈣離子的調控。此為一新穎原創的發現,相信對於了解其它肌醇磷酯同功酶在細胞內如何被調控,有所助益。

Phospholipase C (PLC) is one of the major enzymes that transmits extracellular signals across membrane into cells. When activated, the PLC anchors to the membrane and hydrolyze the phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1, 4, 5-triphsphate (IP3) to activate protien kinase C and release the intracellular calcium store, respectively. There are four isozymes in PLC family including beta, gamma and delta forms. Among them, PLC delta is the most ancient and conserved form with four common domains found in all PLC isozymes. Without other surplus regulatory domains as the other family members, the regulation of PLC delta is least known. Four different isoforms of mammalian PLC delta have been described. PLC delta1, the best understood isoform, can be activated by an atypical GTP-binding protein. It has been suggested that PLC delta functions as a calcium signal amplifier. However, very less is known about other subtypes, including PLC delta3. Therefore, in the present study, we examined the expression of PLC delta3 in different human tissues. Moreover, the cellular underlying regulation for PLC delta3 was studied in different cell lines. Our study showed the mRNA and protein levels differed significantly among human tissues. The human PLC delta3 gene was composed of 15 exons and one putative cAMP response element in the 5' end promoter region. The PLC3 mRNA expression was down-regulated by cAMP and calcium in both human normal embryonic lung tissue diploid WI38 cell line and glioblastoma/astrocytoma U373 cell line. However, the mRNA expression showed no impact by PKC activators or inhibitors. This study shows human PLC delta3 expression pattern and is the first report that the PLC delta3 gene expression is down regulation by cAMP and calcium.

Contents Page
Abbreviations Used in Thesis6.
中文摘要9.
English Abstract11.
Chapter 1. Introduction
1.1. Cellular response and PLC isozymes12.
1.2. Physiological function of PLC isoenzyms13.
1.2.1. Tissue Distribution and Expression 13.
1.2.2. Required for fertilization.14.
1.2.3. Brain disease14.
1.2.4. Hypertension15.
1.3. Regulation of PLC isozymes15.
1.3.1. Regulation of PLC beta15.
1.3.2. Regulation of PLC gamma
1.3.3. Regulation of PLC delta
1.3.4. Regulation of PLC activity through protein phosphorylation18.
1.4. Structure of PLC delta18.
1.4.1. Primary structures of PLC Isozymes18.
1.4.2. PH Domain19.
1.4.3. EF Hand Domain19.
1.4.4. Catalytic Domain20.
1.4.5. C2 Domain20.
1.5. Catalysis of PI-PLC20.
1.6. PLC and Ca2+ Oscillation.21.
Chapter 2. Material and Method
2.1. Cloning of human PLC delta3 cDNA23.
2.2. Subcloning of human PLC delta3 cDNA23.
2.3. Construction of expression vector23.
2.4. Expression of human PLC delta3 in E. coli23.
2.5. Purification of recombinant human PLC delta3 24.
2.6. Protein determination24.
2.7. Measurement of PLC activity 24.
2.8. RNA analysis of PLC delta3 tissue expression25.
2.9. Preparation of PLC delta3 monoclonal antibodies25.
2.10. Immunoblotting analysis of human PLC delta3 tissue expression26.
2.11. Immunoblotting analysis of rat PLC delta3 tissue expression26.
2.11.1 Extraction of rat tissue protein26.
2.11.2. Preparation of sodium dodecyl sulphate poly acrylamide gel electrophoresis (SDS-PAGE) 27.
2.11.3 Transfer protein onto PVDF membrane27.
2.11.4 Competition test.28.
2.12. Comparison of human PLC delta3 cDNA with genomic sequence28.
2.13. Electrophoretic mobility shift assay29.
2.13.1. Preparation of probes for electorphoretic mobility shift assay29.
2.13.2. Preparation of nuclear extract from U373 cells29.
2.13.3 Electrophoretic mobility shift assay29.
2.14. Luciferase assay30.
2.14.1. Construction of PLC delta3 promoter-luciferase plasmids30.
2.14.2. Transient DNA transfection 30.
2.14.3. Luciferase assay30.
2.15. Cell culture and chemical reagents treatment31.
2.16. Cell RNA extraction and Northern blot analysis of PLC delta3 expression31.
2.16.1 Total Cell RNA Extraction31.
2.16.2 RNA transfer onto Nylon membrane32.
2.16.3. Probe preparation32.
2.16.4. Nothern blot hybridization 32.
2.16.5. Quantification of the Northern blot results33.
2.17. Statistical analysis33.
Chapter 3. Results
3.1. Isolation and the sequence of human PLC delta3 cDNA34.
3.2. Expression of human PLC delta3 in E. coli34.
3.3. Mapping of anti-PLC delta3 antibodies epitope region34.
3.4. Human tissue expression of PLC delta335.
3.5. Rat tissue expression of PLC delta335.
3.6. Genomic structure of human PLC delta335.
3.7. Electrophoretic mobility shift assay36.
3.8. Determination of the promoter region of the human PLC delta3 gene36.
3.9. Down-regulated expression by treatment of dibutyl cAMP 37.
3.10. Down-regulated expression by Ca2+ 38.
3.11. PKC Role on PLC delta3 mRNA expression38.
Chapter 4. Discussions
4.1. Primary Gene structure40.
4.2. PLC delta Specific tissue expression40.
4.3. cAMP pathway and the PLC delta expression control40.
4.4. cAMP pathway, p53 and PLC delta3 expression control41.
4.5. cAMP and PLC isozyme activity41.
4.6. Calcium signal and regulation on PLC delta isoform42.
4.7. Roles of calcium on PLC deltaactivity and expression42.
4.8. Shut off control of IP3/calcium releasing43.
4.9. Further study44.
Reference45.
Table and Figure List
Table 1. Exons and introns of human PLC delta3 gene57.
Fig. 1. Nucleotides and deduced amino acid sequence of human PLC delta3 cDNA.58.
Fig. 2. Recombinant PLC delta3 purified from E. Coli.63.
Fig. 3. PLC delta3 expression in human tissues and cell lines. 64.
Fig. 4. Western blot analysis of rat PLC delta3.65.
Fig. 5. Eletrophoretic mobility-shift assay of the cMYC and CRE sites in
PLC delta3 promoter region.66.
Fig. 6. Eletrophoretic mobility-shift assay of cre site in PLC delta3 promoter
region.67.
Fig. 7. Promoter activity analysis of PLC delta3 gene.68.
Fig. 8. Effects of dibutyl cAMP on PLC delta3 mRNA expression.69.
Fig. 9. Effects of A23187 on PLC delta3 mRNA expression.70.
Fig. 10. Effects of the PKC modulators and A23187 on PLC delta3 mRNA
xpression.71.
Appendix 1. pTZ19R vector map72.
Appendix 2. pRSETA vector map73.
Appendix 3. pGL3-Basic vector map74.
Appendix 4. pRL vector map75.

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