臺灣博碩士論文加值系統

p53在調控人類細胞的生長、分化、代謝及凋亡中扮演著重要的角色。文獻顯示，在腸道上皮細胞中，調節糖轉運蛋白 (Sodium-dependent glucose cotransporter) SGLT1的表達能夠調節葡萄糖的吸收作用。先前的研究指出，p53表達可抑制GLUT1、GLUT2、GLUT3與GLUT4等葡萄糖轉運蛋白之表現量或活性，但是對於SGLT系列糖轉運蛋白之影響則不明瞭。為了瞭解p53在調控人類攝取葡萄糖至體內及其在系統代謝之角色，我們研究p53對SGLT1基因表現之影響與機制。以表達WTp53與SGLT1基因的人類腸道細胞HCT116為研究模式。研究方法：（1）分別利用Doxorubicin與5-Fluorouracil、或以WT/mutant p53表達載體誘導WT或mutant p53的表達、或以Pifithrin α抑制WTp53的活性。（2）使用Western Blot及qPCR分析p53的誘導或抑制下，SGLT1蛋白質與mRNA表現量的變化。（3）分析p53對細胞葡萄糖吸收之影響。（4）使用promoter Luciferase assay分析參與p53 調節SGLT1表現之序列、轉錄因子及機轉。我們發現，不論在蛋白質或mRNA層次，SGLT1的基因表現量會隨著p53蛋白質的誘導而穩定上升；相反地，當p53蛋白質受到抑制時，會弱化下游SGLT1的表現量。顯示p53對SGLT1基因表現之影響與基因轉錄有關，因此 分析SGLT1基因啟序列，以瞭解p53的調控機制。p53對糖吸收之效應也在進行中。本研究顯示p53在SGLT1基因表現扮演著相當重要的角色，並且直接調節細胞的糖吸收與代謝，此研究將延伸我們對p53在生物系統窘迫壓力下對代謝所扮演的角色之瞭解。

The tumor suppressor p53 plays an important role in the regulation of proliferation, apoptosis, and metabolism in human cells. The sodium-dependent glucose cotransporter 1 (SGLT1) play a crucial role in glucose uptake in intestinal and kidney tubular epithelial cells, respectively. Previous studies indicate that p53 protein significantly down-regulates the expression and activity of the facilitate glucose transporter proteins, including GLUT1, GLUT2, GLUT3, and GLUT4. However, the effect and mechanisms of p53 on regulation of SGLTs expression are still not understood. To understand the metabolic role of p53 protein in the active absorption of glucose from exterior environments, the effect of p53 on the function and gene expression of SGLT1 was investigated. In this study, the cultured human intestinal cell HCT116, which are known to express WT-p53 protein were used. To investigate the effect of p53 protein on SGLT1 gene expression, the p53 protein was induced in using doxorubicin, 5-fluorouracil, and the inhibited by pifithrin-α. The wild type (WT) or mutant p53 protein were also overexpressed using WT- or mutant-p53 vectors. In addition, the p53-KO HCT116 cells were also used. Western blot and Q-PCR analysis were used to analyze the induction and inhibition of p53 mRNA and protein levels in these cells. Moreover, the effect of different p53 status on glucose uptake were examined. Transient transfection analysis further used to analyze a series of SGLT1 promoter constructs to investigated the sequence elements and transcription factors that are involved in the p53-mediated effects. Our results showed that the expression of SGLT1 is increased with increasing p53 protein level. In addition, quantitative PCR also revealed a pronounced increase in SGLT1 mRNA levels following p53 induction. Further studies using the luciferase reporters showed that the similar induction of SGLT1 promoter activities by p53 protein. These results suggest that the p53-mediated induction of SGLT1 is regulated primarily at the transcriptional level. Further studies are performed to identify the promoter elements and transcription factors that are involved in p53-mediated induction. In conclusion, we demonstrate that p53 palys a significant role in the expression of SGLT1. Our results also extended the metabolic significance of p53 to whole body glucose homeostasis.

目錄 I
表目錄 V
圖目錄 VI
縮寫表 VIII
中文摘要 X
Abstract XII
第一章 緒言 1
壹、腫瘤抑制蛋白p53 1
一、腫瘤抑制蛋白p53簡介與功能 1
二、突變p53之結構與功能 2
貳、糖代謝作用 3
一、細胞機轉 3
二、糖質新生(Gluconeogenesis) 4
三、肝醣的合成 (Glycogenesis)與分解 (Glycogenlysis) 4
四、p53與糖代謝之關係 5
五、癌細胞與糖代謝之關係 6
參、葡萄糖轉運蛋白 6
一、葡萄糖轉運蛋白家族 (GLUTs) 6
二、鈉依賴型葡萄糖轉運蛋白家族 (SGLTs) 8
肆、實驗使用之各類細胞系 10
一、HCT116 (Human Intestinal Epithelial Cells) 10
二、HT-29 (Human Colorectal Adenocarcinoma Cell Line) 10
伍、研究動機 12
第二章 材料與方法 18
壹、主要儀器及藥品試劑 18
一、儀器及器材 18
二、藥品試劑 19
三、抗體 21
四、細胞來源 21
貳、方法 21
一、HCT116(WT)、HCT116(Mut)、RPTECs細胞培養(Cell culture) 21
二、葡萄糖轉運分析 (Glucose transport assay) 25
三、蛋白質濃度測定（Protein assay） 26
四、西方墨點法（Western blotting） 27
五、萃取細胞RNA（RNA extraction） 34
六、反轉錄聚合酶連鎖反應（RT-PCR） 36
七、定量聚合酶連鎖反應（Q-PCR） 37
八、轉形作用 38
九、小量質體的備製 40
十、大量質體的備製 42
十一、細胞轉染 43
十二、相對螢光酶（Luciferase）活性分析 44
第三章 結果 45
壹、p53的活化與SGLT1訊息路徑影響之分析 45
一、Dox誘導p53的活化與SGLT1蛋白質生合成之連動性分析 45
二、5-Fu誘導p53的活化與SGLT1蛋白質生合成之連動性分析 45
貳、抑制p53的活化對SGLT1訊息路徑影響之分析 46
Dox或5Fu誘導p53後給予抑制對SGLT1蛋白質連動性之分析 46
參、p53的活化與SGLT1 基因表現之連動性分析 47
一、Dox誘導p53的活化與SGLT1 基因表現連動性之分析 47
二、5-Fu誘導p53的活化與SGLT1 基因表現連動性之分析 47
肆、活化不同細胞系的p53對SGLT1訊息路徑影響之分析 48
一、5-Fu誘導各細胞系的p53與SGLT1蛋白合成之連動性分析 48
二、5-Fu誘導各細胞系的p53對SGLT1基因調控之連動性分析 48
伍、不同p53基因型對SGLT1訊息路徑影響之分析 49
轉染WT-p53或Mut-p53基因對SGLT1蛋白質連動性之分析 49
陸、p53的活化對SGLT1轉錄活性影響之分析 50
一、SGLT1上游啟動子的構築 50
二、5-Fu誘導p53的活化對SGLT1 promoter轉錄活性影響之分析 50
柒、p53的活化與人類腸道上皮細胞葡萄糖運輸影響之分析 51
一、Dox藥物誘導內源性p53的活化與糖吸收效率影響之分析 51
二、5-Fu藥物誘導內源性p53的活化與糖吸收效率影響之分析 51
第四章 討論 53
壹、p53的活化與SGLT1訊息路徑影響之分析 53
貳、p53的活化與SGLT1 基因表現之連動性分析 54
參、p53的活化與人類腸道上皮細胞葡萄糖運輸影響之分析 55
第五章 結論 56
第六章 參考文獻 73

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