Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/97810
標題: 探討GCIP在癌症細胞中的調控機制
Investigation of regulation mechanism of GCIP in cancer cell
作者: 黃琳倫
Lin-Lun Huang
關鍵字: 癌症;GCIP;MEK2;c-Myc;ITGAV;cancer;GCIP;MEK2;c-Myc;ITGAV
引用: 1. Ledent, V. and M. Vervoort, The basic helix-loop-helix protein family: comparative genomics and phylogenetic analysis, in Genome Res. 2001. p. 754-70. 2. Toledo-Ortiz, G., E. Huq, and P.H. Quail, The Arabidopsis basic/helix-loop-helix transcription factor family. Plant Cell, 2003. 15(8): p. 1749-70. 3. Massari, M.E. and C. Murre, Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol, 2000. 20(2): p. 429-40. 4. Ma, W., et al., GCIP/CCNDBP1, a helix-loop-helix protein, suppresses tumorigenesis. J Cell Biochem, 2007. 100(6): p. 1376-86. 5. Xia, C., et al., GCIP, a novel human grap2 and cyclin D interacting protein, regulates E2F-mediated transcriptional activity. J Biol Chem, 2000. 275(27): p. 20942-8. 6. Huang, Y., et al., Ccndbp1 is a new positive regulator of skeletal myogenesis. J Cell Sci, 2016. 129(14): p. 2767-77. 7. Seto, A., et al., Crystallization and preliminary X-ray diffraction analysis of GCIP/HHM transcriptional regulator. Acta Crystallogr Sect F Struct Biol Cryst Commun, 2009. 65(Pt 1): p. 21-4. 8. Sonnenberg-Riethmacher, E., et al., Maid (GCIP) is involved in cell cycle control of hepatocytes. Hepatology, 2007. 45(2): p. 404-11. 9. Chen, K.Y., et al., GCIP functions as a tumor suppressor in non-small cell lung cancer by suppressing Id1-mediated tumor promotion. Oncotarget, 2014. 5(13): p. 5017-28. 10. Roberts, P.J. and C.J. Der, Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 2007. 26(22): p. 3291-310. 11. Lin, Y.W., S.M. Chuang, and J.L. Yang, ERK1/2 achieves sustained activation by stimulating MAPK phosphatase-1 degradation via the ubiquitin-proteasome pathway. J Biol Chem, 2003. 278(24): p. 21534-41. 12. Caunt, C.J., et al., MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nature Reviews Cancer, 2015. 15: p. 577. 13. Rolland, T., et al., A proteome-scale map of the human interactome network. Cell, 2014. 159(5): p. 1212-1226. 14. Giancotti, F.G. and E. Ruoslahti, Integrin Signaling. Science, 1999. 285(5430): p. 1028-1033. 15. Desgrosellier, J.S. and D.A. Cheresh, Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer, 2010. 10(1): p. 9-22. 16. Jin, H. and J. Varner, Integrins: roles in cancer development and as treatment targets. Br J Cancer, 2004. 90(3): p. 561-5. 17. Agrez, M.V. and R.C. Bates, Colorectal cancer and the integrin family of cell adhesion receptors: current status and future directions. Eur J Cancer, 1994. 30a(14): p. 2166-70. 18. Waisberg, J., et al., Overexpression of the ITGAV gene is associated with progression and spread of colorectal cancer. Anticancer Res, 2014. 34(10): p. 5599-607. 19. Lu, J.G., et al., Overexpression of osteopontin and integrin alphav in laryngeal and hypopharyngeal carcinomas associated with differentiation and metastasis. J Cancer Res Clin Oncol, 2011. 137(11): p. 1613-8. 20. Wang, J.T., et al., Cilengitide, a small molecule antagonist, targeted to integrin alphanu inhibits proliferation and induces apoptosis of laryngeal cancer cells in vitro. Eur Arch Otorhinolaryngol, 2014. 271(8): p. 2233-40. 21. Schwickert, A., et al., microRNA miR-142-3p Inhibits Breast Cancer Cell Invasiveness by Synchronous Targeting of WASL, Integrin Alpha V, and Additional Cytoskeletal Elements. PLoS One, 2015. 10(12): p. e0143993. 22. Liu, J., et al., Genetic variants in the integrin gene predicted microRNA-binding sites were associated with the risk of prostate cancer. Mol Carcinog, 2014. 53(4): p. 280-5. 23. Luo, Z., et al., Decreased Expression of miR-548c-3p in Osteosarcoma Contributes to Cell Proliferation Via Targeting ITGAV. Cancer Biother Radiopharm, 2016. 31(5): p. 153-8. 24. Symonds, J.M., et al., PKCdelta regulates integrin alphaVbeta3 expression and transformed growth of K-ras dependent lung cancer cells. Oncotarget, 2016. 7(14): p. 17905-19. 25. Raimo, M., et al., miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization. Mol Cancer Res, 2016. 14(6): p. 548-62. 26. Cabarcas, S.M., et al., The differentiation of pancreatic tumor-initiating cells by vitronectin can be blocked by cilengitide. Pancreas, 2013. 42(5): p. 861-70. 27. van der Horst, G., et al., Targeting of alpha-v integrins reduces malignancy of bladder carcinoma. PLoS One, 2014. 9(9): p. e108464. 28. Liu, H., et al., MYC suppresses cancer metastasis by direct transcriptional silencing of alphav and beta3 integrin subunits. Nat Cell Biol, 2012. 14(6): p. 567-74. 29. Tian, T., et al., Determination of metastasis-associated proteins in non-small cell lung cancer by comparative proteomic analysis. Cancer Sci, 2007. 98(8): p. 1265-74. 30. Deveraux, Q.L. and J.C. Reed, IAP family proteins--suppressors of apoptosis. Genes Dev, 1999. 13(3): p. 239-52. 31. Rosette, C., et al., Role of ICAM1 in invasion of human breast cancer cells. Carcinogenesis, 2005. 26(5): p. 943-50.
摘要: 
GCIP (Grap2 and CyclinD1 interacting protein)是一個helix-loop-helix leucine zipper蛋白質,但是缺乏基本的DNA結合區域,在過去文獻指出GCIP是一個抑癌蛋白,不論在體外或體內的實驗中可以抑制癌細胞生長、增殖以及轉移。在我們先前實驗發現,GCIP和MEK2 (Mitogen-activated protein kinase kinase 2)會直接互相作用,我們的數據中再次證實MEK2會使GCIP的蛋白穩定度下降,MEK2也會磷酸化GCIP在serine上。
  在過去文獻指出GCIP會抑制癌細胞的轉移,而我們先前實驗發現GCIP抑制轉移並不是透過epithelial-mesenchymal transition (EMT),也不是透過轉移相關基因,如Rac1、Rho A,而GCIP蛋白可以負調控ITGAV (Integrin αv) 基因的表現,因此,我們利用luciferase assay觀察到GCIP和c-Myc會共同負調控ITGAV的轉錄,這些研究結果可以提供GCIP可以抑制癌細胞生長及轉移,有助於設計新的癌症治療策略來治療癌細胞。

GCIP (Grap2 and CyclinD1 interacting protein) is a helix-loop-helix leucine zipper protein without DNA-binding domain. Recent studies had been demonstrated that GCIP is a tumor suppressor that suppress cell growth, proliferation, migration in vitro and in vivo. In our previous studies, it suggested GCIP and MEK2 (Mitogen-activated protein kinase kinase 2) will interact directly. Our data also confirmed MEK2 would reduce the protein stability of GCIP and phosphorylate GCIP on serine site.
GCIP was reported the ability of inhibition of cancer cell metastasis. Based on that, our past research demonstrated GCIP-mediated metastatic inhibition is through neither epithelial - mesenchymal transition (EMT) nor the metastasis related genes, such as Rac1, Rho A. Importantly, GCIP protein can regulate ITGAV (Integrin αv) gene expression negatively. Therefore, we used the luciferase assay observed GCIP and c-Myc will jointly mediate the transcription of ITGAV on negative regulation. These results indicate GCIP can inhibit the growth and metastasis of cancer cells, and it can be designed as a new cancer treatment strategy of cancers.
URI: http://hdl.handle.net/11455/97810
Rights: 不同意授權瀏覽/列印電子全文服務
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