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研究生:梁瑞岳
研究生(外文):Ruei-Yue Liang
論文名稱:GCIP蛋白在癌症發展中所扮演的角色
論文名稱(外文):The role of GCIP in cancer progression
指導教授:莊秀美莊秀美引用關係
口試委員:闕斌如李月君蕭乃文王翊青
口試日期:2016-07-28
學位類別:博士
校院名稱:國立中興大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:84
中文關鍵詞:GCIPMEK2磷酸化蛋白質降解轉移
外文關鍵詞:GCIPMEK2Phosphorylationprotein degradationmetastasis
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GCIP (Grap2 and CyclinD1 interacting protein)是一個helix-loop-helix leucine zipper 蛋白質但是缺乏去氧核醣核酸的結合區域(DNA-binding domain)。先前的研究指出GCIP是一個抑癌蛋白,在活體內和活體外的實驗中可以抑制癌細胞的生長,腫瘤的生成和癌症的轉移。因此,抑癌功能的GCIP在癌症細胞中是如何受損的研究更顯重要。在我們的研究當中,我們利用胃癌和肺癌細胞株來探討GCIP的表現和其調控的生理功能。我們的數據顯示,晚期胃癌的GCIP蛋白表現量比早期胃癌有著顯著的降低。此外,利用lentiviral shRNA所導致的內生性GCIP降低技術會促進A549和AGS細胞株細胞的增殖。另外,在活體外和活體內的實驗中我們也證明了MEK2和GCIP之間的直接相互作用。我們還發現,MEK2可直接在GCIP的Thr328位置磷酸化,從而促進GCIP泛素化和蛋白酶體降解。再者,和野生型GCIP相比,模擬磷酸化的 T328D突變株顯著增加細胞的生長,然而模擬非磷酸化的 T328A突變株則明顯地降低細胞生長。除此之外,GCIP蛋白抑制癌細胞的轉移是透過何種機制,到目前為止還不清楚。利用小RNA干擾技術降低GCIP的表現量在胃癌和肺癌細胞中,可以發現這樣的處理會增加細胞的侵襲和轉移能力。另外,我們利用cDNA微陣列技術發現GCIP可以負調控EREG,ICAM-1和ITGAV基因的表現。此外,我們設計了一個可誘導式的shRNA lentivirus,細胞加入強力黴素(Dox)時可降低GCIP的表現量。在強力黴素處理下會抑制GCIP蛋白並同時伴隨著ITGAV蛋白表現的增加。綜合這些結果,我們發現MEK2可能在GCIP的Thr328位置磷酸化,然後降低GCIP的蛋白質穩定性以及壓制GCIP的抑制功能。此外,GCIP能夠抑制癌細胞的侵襲和轉移有可能是透過抑制ICAM-1和ITGAV基因的表現。這些研究結果對於抑癌蛋白在癌細胞中是受到如何調控提供了一些新的見解,並有助於設計新的癌症治療策略來治療癌症。

GCIP (Grap2 and CyclinD1 interacting protein) is a helix-loop-helix leucine zipper protein without DNA-binding domain. Recent studies had demonstrated that GCIP is a tumor suppressor that suppress cell growth, tumorigenesis, and migration in vitro and in vivo. Thus, it is important to study how the tumor suppressive function of GCIP is impaired in cancer. In this study we investigated the expression and the biological function of GCIP in human gastric and lung cancer cells. Our data showed that the protein level of GCIP was significantly lower in advanced stage gastric tumor than early stage ones. Moreover, silenced endogenous GCIP in A549 and AGS cells using a lentiviral shRNA-mediated approach promote cell proliferation. Further, we demonstrated a direct interaction between MEK2 and GCIP in vitro and in vivo. We also showed that MEK2 may directly phosphorylate GCIP at Thr328, thus promoting GCIP ubiquitination and proteasomal degradation. In addition, phosphomimetic T328D mutant GCIP remarkably increased, whereas phosphosinsensitive T328A mutant GCIP significantly decreased cell proliferation as compared to wild-type GCIP. Besides, GCIP suppresses cell migration by which mechanism is still not clear. Knock-down of GCIP expression by siRNA induced cell invasion and migration in gastric and lung cancer cell lines. In addition, we indicated that GCIP negatively regulate EREG, ICAM-1 and ITGAV gene expression by cDNA microarray analysis. Furthermore, we design an inducible shRNA lentiviurs that allows GCIP silencing on doxycycline (Dox) treatment. Dox treatment led to stable inhibition of GCIP expression along with increasing ITGAV expression. In conjunction with these results, we found that MEK2 may phosphorylate GCIP at Thr328, then decreasing its protein stability and inhibiting the suppressed function of GCIP. Moreover, GCIP suppress cell invasion and migration may result from inhibiting ICAM-1 and ITGAV gene expression. These results may provide new insights into understand how tumor suppressor be regulated in cancer cells, and contribute to designing new cancer therapeutic strategies to treat cancer cells.

中文摘要 ….……………………………………………………………………..……..i
Abstract ...…..……………………………………………………………………..……ii
Chapter 1. Research background and aims…………………………………………..1
1. The helix-loop-helix(HLH) protein family ….……………………...………...…..1
2. The classification and structure of GCIP …………………………………......…..1
3. The role of GCIP in cancers ...……………….………….…....…………...….…...2
4. Mitogen-activated protein kinase (MAPK) involved in protein degradation ….....3
5. Ubiquitin-Proteasome System (UPS) ……………………………………….……3
6. The role of Integrin family …………………………………………...……...……4
7. Aims ………………………………………………………………………..……..4
Chapter 2. Materials and Methods……………………………………………………6
1. Cell culture ……………….……………………………………………….………6
2. Chemicals and Antibodies ……………………………………………….…...…..6
3. Tissue specimens and immunohistochemistry…………………………………….7
4. Plasmids and Mutagenesis …….………………………………………………….7
5. Construct pINDUCER10-shGCIP and lentiviral infection ……………………….8
6. Treatment …………………………………………………………………...…….9
7. Transfection and RNA interference ………………………………..……………..9
8. Immunopricipitation and Western Blot………………………………………..…10
9. In vitro kinase assay …………………………………………………..…………10
10. Quantitative real-time PCR ………………………………………….…………..11
11. cDNA microarray analysis …………………………………………………..…..12
12. Proliferation assay ……………………………………………………...………..12
13. Cell matrigel invasion and migration assay ……………………………...……...12
14. Impedance measurement with the xCELLigence system(RTCA) …………..….13
15. Immunofluorescence microscopy …………………………….…………...…….13
16. RhoA activity assay ………………………………………………...……..…….14
17. Statistical Analysis …………………………………………..……………..……14
Chapter 3. Results……………………………………………………………………..15
1. GCIP expression is significantly down regulated in aggressive tumor and cancer cell lines …………………………………………………………………………15
2. Knock down of GCIP increases cell proliferation ….…………………………...15
3. GCIP associated with MEK2 in vivo and in vitro ……………………………….16
4. MEK2 negatively regulates GCIP protein stability……………………...............17
5. Phosphorylation at T328 of GCIP decreases GCIP stability …………………….17
6. MEK2 mediates poly-ubiquitination of GCIP and decreases its stability ………18
7. T328 phosphorylation of GCIP increases cell proliferation …….........................19
8. GCIP inhibits gastric and lung cancer cells invasion and migration ……………19
9. GCIP regulates ITGAV and ICAM-1 gene expression …………………………..20
10. GCIP negatively regulates ITGAV expression by inducible shRNA lentivirus system …………………………………………………………………………...21
Chapter 4. Discussion ………………………………...…………………………........22
Figures ……………………...………………………………………………………....25
References ……………………………………………………………………………..49
Publication……………………………………………………………………………..60


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