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研究生:王書品
研究生(外文):Wang, Shu-Ping
論文名稱:p53可經由MDM2及Slug之複合體而控制癌細胞之侵襲能力
論文名稱(外文):p53 controls cancer cell invasion by forming a complex with MDM2 and Slug and mediates Slug degradation
指導教授:楊泮池楊泮池引用關係
指導教授(外文):Yang, Pan-Chyr
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:89
中文關鍵詞:癌轉移蛋白質降解肺癌
外文關鍵詞:cancer metastasisp53SlugMDM2E-cadherin
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抑癌因子p53可以藉由抑制腫瘤細胞增生以及誘使其發生細胞凋亡來制止惡性腫瘤的發展; 然而對於p53如何調控腫瘤侵襲以及轉移的功能卻仍不清楚。 Slug是一個促腫瘤侵襲因子, 它可以透過壓制E-cadherin基因轉錄表現來執行促進腫瘤侵襲的功能。 在本篇研究中, 我們發現wild-type (wt) p53可以促使Slug 蛋白降解; 然而mutant p53卻可以穩定Slug蛋白。 我們於非小細胞肺癌 (Non Small Cell Lung Cancer,NSCLC) 病患的腫瘤檢體中發現, p53 基因突變與低的MDM2蛋白表現量、 高的Slug蛋白表現量以及低的E-cadherin蛋白表現量呈現正相關性; 此表現圖譜同時與肺癌病人低整體存活率以及低無轉移存活率有關。 我們同時發現wtp53可以促進MDM2表現, 並且與MDM2和Slug形成wtp53-MDM2-Slug複合體進而協同調控Slug蛋白降解。 Slug蛋白表現受p53或是MDM2抑制的結果可以促使E-cadherin的表現提升並且抑制腫瘤細胞侵襲能力。相反地,mutant p53可以抑制Slug蛋白降解的能力,進而累積腫瘤細胞內的Slug蛋白量並強化腫瘤細胞的侵襲能力。因此,我們的研究顯示wtp53與mutant p53可能以不同的方式透過p53-MDM2-Slug這條路徑來調控腫瘤侵襲以及癌轉移。
The tumor suppressor p53 prevents cancer progression by inhibiting proliferation and inducing apoptosis of tumor cells. Little is known about the function of p53 in regulating cancer invasion and metastasis. Slug is an invasion promoter that exerts its effects by repressing E-cadherin transcription. Here, we find that wild-type p53 (wtp53) suppresses cancer invasion by inducing Slug degradation, whereas mutant p53 may stabilize Slug protein. In non-small-cell lung cancer (NSCLC), p53 mutation correlates with low MDM2, high Slug and low E-cadherin expression. This expression profile is associated with poor overall survival and short metastasis-free survival in NSCLC patients. wtp53 upregulates MDM2, and forms a wtp53-MDM2-Slug complex that facilitates MDM2-mediated Slug degradation. Downregulation of Slug by wtp53 or MDM2 enhances E-cadherin expression and represses cancer cell invasiveness. In contrast, mutant p53 inhibits Slug degradation and leads to Slug accumulation and increased cancer cell invasiveness. Our findings indicate that wtp53 and p53 mutants may differentially control cancer invasion and metastasis through the p53-MDM2-Slug pathway.
Table of Contents: page
Abstract of Chinese..............................................1
Abstract.........................................................2
Chapter 1: Introduction..........................................3
1.1 Cancer invasion and metastasis..............................4
1.2 E-cadherin, an invasion and metastasis suppressor...........5
1.3 Slug, an invasion and metastasis promoter...................6
1.4 The tumor suppressor p53....................................7
1.5 Mutations in the p53 gene...................................8
1.6 p63 and p73, the tumor suppressors analogous to p53.........10
1.7 MDM2, an E3-ubiquitin ligase downstream of p53..............11
Chapter 2: Materials and Methods.................................14
2.1 Sample collection, p53 mutation analysis and immuno- histochemical staining...........................................15
2.2 Plasmids and transfection...................................16
2.3 Viruses and transduction....................................17
2.4 Cell culture................................................18
2.5 UV treatment................................................19
2.6 Semiquantitative reverse transcription-PCR analysis.........19
2.7 Quantitative real-time PCR..................................20
2.8 Cell lysate preparation, immunoprecipitation and immunoblotting...................................................21
2.9 Antibodies..................................................23
2.10 Pulse-chase analysis.......................................23
2.11 RNA interference...........................................24
2.12 In vivo ubiquitination assay...............................25
2.13 Matrigel invasion assay....................................25
2.14 Statistical analysis.......................................26
Chapter 3: Results...............................................27
3.1 p53 mutation correlates with outcomes of NSCLC patients.........................................................28
3.2 p53 mutation is associated with high Slug and low E-cadherin
expression in NSCLC tumor specimens..............................28
3.3 Wild-type p53 inhibits Slug protein expression..............29
3.4 Wild-type p53 is required for Slug protein degradation......30
3.5 Wild-type p53 induces MDM2-mediated ubiquitination and degradation of Slug..............................................31
3.6 Wild-type p53 forms a complex with Slug and MDM2............35
3.7 Mapping the binding domains of the p53-MDM2-Slug complex....36
3.8 The wtp53-MDM2-Slug complex facilitates Slug degradation....37
3.9 Wtp53-mediated Slug degradation represses Slug-mediated cancer cell invasion.............................................38
3.10 Mutant p53 upregulates Slug and enhances cancer cell invasion.........................................................40
3.11 The signature of p53 mutation, low MDM2, high Slug, (and low E-cadherin) expression is associated with poor overall survival and early metastasis in NSCLC patients...........................42
Chapter 4: Discussion............................................45
Chapter 5: Figures and Tables....................................52
Figure 1. p53 mutation is associated with poor clinical outcome in NSCLC patients and correlates with low MDM2, high Slug and low E-cadherin expression in NSCLC tumor specimens...............53
Figure 2. p53 can regulate Slug protein expression..............54
Figure 3. RNAi knockdown of p53 reverses p53-mediated Slug down-
regulation.......................................................55
Figure 4. Slug is unstable in p53+/+ cells and is regulated by the 26 S proteasome..................................................56
Figure 5. MDM2 ubiquitin E3-ligase is involved in p53-induced Slug degradation......................................................57
Figure 6. MDM2 acts downstream of p53 to mediate Slug degradation......................................................59
Figure 7. The p53-MDM2-Slug complex facilitates Slug degradation......................................................60
Figure 8. Mapping regions of Slug that interact with p53 and MDM2.............................................................62
Figure 9. Mapping the region of p53 that interacts with Slug....63
Figure 10. Mapping the region of MDM2 that interacts with Slug..64
Figure 11. p53 assists and enhances the MDM2-mediated degradation of Slug..........................................................65
Figure 12. The effects of wild-type (wt) p53 on Slug-mediated cancer cell invasion.............................................66
Figure 13. The effects of mutant p53 on Slug-mediated cancer cell invasion.........................................................67
Figure 14. The effects of mutant p53 silencing on MDM2, Slug, E-cadherin, and cancer cell invasiveness MDA-MB-231 and SW620 cells............................................................69
Figure 15. The signature of p53 mutation, low MDM2, high Slug, and low E-cadherin expressions correlates with poor overall survival and early metastasis in NSCLC patients..................70
Figure 16. Correlation of p53 activation, Slug expression, and p21 and Mdm2 induction with apoptosis in UV-irradiated HFB(p53+/+)cells............................................................72
Table 1. The relationship between p53 mutation status and the protein expression of p53, MDM2, Slug, and E-cadherin in tumor specimens from 79 NSCLC patients.................................73
Table 2. The p53 mutation status as well as the MDM2, Slug, and E-cadherin expression profiles with relation to clinical and pathologic characteristics.......................................74
Table 3. The p53 mutation status and protein expression pattern of MDM2 and Slug in 79 NSCLC patients...............................75
Table 4. The p73 targets, p21 and MDM2, were significantly downregulated in mutant p53- and Slug-expressing NSCLC tumors....76
Table 5. The relationship between MDM2 and Slug expression in tumor specimens from 79 NSCLC patients...........................77
Table 6. Sequence information for gene silencing and RT-PCR analysis.........................................................78
References.......................................................79
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