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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊泮池(Pan-Chyr Yang) | |
| dc.contributor.author | Shih-Han Kao | en |
| dc.contributor.author | 高詩涵 | zh_TW |
| dc.date.accessioned | 2021-06-16T16:06:10Z | - |
| dc.date.available | 2018-09-24 | |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-06-18 | |
| dc.identifier.citation | 1. Herbst, R.S., J.V. Heymach, and S.M. Lippman, Lung cancer. N Engl J Med, 2008. 359(13): p. 1367-80.
2. Cagle, P.T., et al., Revolution in lung cancer: new challenges for the surgical pathologist. Arch Pathol Lab Med, 2011. 135(1): p. 110-6. 3. Collins, L.G., et al., Lung cancer: diagnosis and management. Am Fam Physician, 2007. 75(1): p. 56-63. 4. Jemal, A., et al., Global cancer statistics. CA Cancer J Clin, 2011. 61(2): p. 69-90. 5. Langer, C.J., et al., The evolving role of histology in the management of advanced non-small-cell lung cancer. J Clin Oncol, 2010. 28(36): p. 5311-20. 6. Mao, L., et al., Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst, 1997. 89(12): p. 857-62. 7. Spira, A., et al., Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci U S A, 2004. 101(27): p. 10143-8. 8. Westra, W.H., Early glandular neoplasia of the lung. Respir Res, 2000. 1(3): p. 163-9. 9. Tang, X., et al., EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients. Cancer Res, 2005. 65(17): p. 7568-72. 10. McCarthy, N., Metastasis: Route master. Nat Rev Cancer, 2009. 9(9): p. 610. 11. Cagle, P.T. and L.R. Chirieac, Advances in treatment of lung cancer with targeted therapy. Arch Pathol Lab Med, 2012. 136(5): p. 504-9. 12. Janne, P.A., Challenges of detecting EGFR T790M in gefitinib/erlotinib-resistant tumours. Lung Cancer, 2008. 60 Suppl 2: p. S3-9. 13. Nguyen, D.X., P.D. Bos, and J. Massague, Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer, 2009. 9(4): p. 274-84. 14. Fidler, I.J., The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer, 2003. 3(6): p. 453-8. 15. Joyce, J.A. and J.W. Pollard, Microenvironmental regulation of metastasis. Nat Rev Cancer, 2009. 9(4): p. 239-52. 16. Ramesh, R., et al., Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. Mol Ther, 2004. 9(4): p. 510-8. 17. Desmarais, V., et al., N-WASP and cortactin are involved in invadopodium-dependent chemotaxis to EGF in breast tumor cells. Cell Motil Cytoskeleton, 2009. 66(6): p. 303-16. 18. Ghosh, M., et al., Cofilin promotes actin polymerization and defines the direction of cell motility. Science, 2004. 304(5671): p. 743-6. 19. Mouneimne, G., et al., Spatial and temporal control of cofilin activity is required for directional sensing during chemotaxis. Curr Biol, 2006. 16(22): p. 2193-205. 20. Brown, N.S. and R. Bicknell, Hypoxia and oxidative stress in breast cancer. Oxidative stress: its effects on the growth, metastatic potential and response to therapy of breast cancer. Breast Cancer Res, 2001. 3(5): p. 323-7. 21. Trelstad, R.L., E.D. Hay, and J.D. Revel, Cell contact during early morphogenesis in the chick embryo. Dev Biol, 1967. 16(1): p. 78-106. 22. Thiery, J.P., et al., Epithelial-mesenchymal transitions in development and disease. Cell, 2009. 139(5): p. 871-90. 23. Chaffer, C.L. and R.A. Weinberg, A perspective on cancer cell metastasis. Science, 2011. 331(6024): p. 1559-64. 24. Peinado, H., D. Olmeda, and A. Cano, Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer, 2007. 7(6): p. 415-28. 25. Kemler, R., From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet, 1993. 9(9): p. 317-21. 26. Takeichi, M., Morphogenetic roles of classic cadherins. Curr Opin Cell Biol, 1995. 7(5): p. 619-27. 27. Tepass, U., et al., Cadherins in embryonic and neural morphogenesis. Nat Rev Mol Cell Biol, 2000. 1(2): p. 91-100. 28. Birchmeier, W. and J. Behrens, Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta, 1994. 1198(1): p. 11-26. 29. Larue, L. and A. Bellacosa, Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene, 2005. 24(50): p. 7443-54. 30. Hirohashi, S., Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol, 1998. 153(2): p. 333-9. 31. Mann, M. and O.N. Jensen, Proteomic analysis of post-translational modifications. Nat Biotechnol, 2003. 21(3): p. 255-61. 32. Alves, C.C., et al., Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers. Front Biosci, 2009. 14: p. 3035-50. 33. Seo, J. and K.J. Lee, Post-translational modifications and their biological functions: proteomic analysis and systematic approaches. J Biochem Mol Biol, 2004. 37(1): p. 35-44. 34. Wolf-Yadlin, A., M. Sevecka, and G. MacBeath, Dissecting protein function and signaling using protein microarrays. Curr Opin Chem Biol, 2009. 13(4): p. 398-405. 35. Schulz, K.R., et al., Single-cell phospho-protein analysis by flow cytometry. Curr Protoc Immunol, 2007. Chapter 8: p. Unit 8 17. 36. Fournier, F., et al., Biological and biomedical applications of two-dimensional vibrational spectroscopy: proteomics, imaging, and structural analysis. Acc Chem Res, 2009. 42(9): p. 1322-31. 37. Faley, S.L., et al., Microfluidic single cell arrays to interrogate signalling dynamics of individual, patient-derived hematopoietic stem cells. Lab Chip, 2009. 9(18): p. 2659-64. 38. Dwek, M.V., H.A. Ross, and A.J. Leathem, Proteome and glycosylation mapping identifies post-translational modifications associated with aggressive breast cancer. Proteomics, 2001. 1(6): p. 756-62. 39. Olsen, J.V., et al., Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell, 2006. 127(3): p. 635-48. 40. Hunter, T., The age of crosstalk: phosphorylation, ubiquitination, and beyond. Mol Cell, 2007. 28(5): p. 730-8. 41. Mao, J.H., et al., FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science, 2008. 321(5895): p. 1499-502. 42. Nieto, M.A., et al., Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Science, 1994. 264(5160): p. 835-9. 43. Carl, T.F., et al., Inhibition of neural crest migration in Xenopus using antisense slug RNA. Dev Biol, 1999. 213(1): p. 101-15. 44. Hajra, K.M., D.Y. Chen, and E.R. Fearon, The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res, 2002. 62(6): p. 1613-8. 45. Nieto, M.A., The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol, 2002. 3(3): p. 155-66. 46. Shih, J.Y., et al., Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma. Clin Cancer Res, 2005. 11(22): p. 8070-8. 47. Shioiri, M., et al., Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Br J Cancer, 2006. 94(12): p. 1816-22. 48. Wang, S.P., et al., p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol, 2009. 11(6): p. 694-704. 49. Shih, J.Y. and P.C. Yang, The EMT regulator slug and lung carcinogenesis. Carcinogenesis, 2011. 32(9): p. 1299-304. 50. Yang, L., et al., Inhibition of epidermal growth factor receptor signaling elevates 15-hydroxyprostaglandin dehydrogenase in non-small-cell lung cancer. Cancer Res, 2007. 67(12): p. 5587-93. 51. Chen, Y.C., et al., Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS One, 2008. 3(7): p. e2637. 52. Willems, A.R., et al., SCF ubiquitin protein ligases and phosphorylation-dependent proteolysis. Philos Trans R Soc Lond B Biol Sci, 1999. 354(1389): p. 1533-50. 53. Karin, M. and Y. Ben-Neriah, Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol, 2000. 18: p. 621-63. 54. Zhou, B.P., et al., Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol, 2004. 6(10): p. 931-40. 55. Taylor, C.T., et al., Phosphorylation-dependent targeting of cAMP response element binding protein to the ubiquitin/proteasome pathway in hypoxia. Proc Natl Acad Sci U S A, 2000. 97(22): p. 12091-6. 56. Vernon, A.E. and C. LaBonne, Slug stability is dynamically regulated during neural crest development by the F-box protein Ppa. Development, 2006. 133(17): p. 3359-70. 57. Wu, Z.Q., et al., Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression. Proc Natl Acad Sci U S A, 2012. 109(41): p. 16654-9. 58. Buss, H., et al., Phosphorylation of serine 468 by GSK-3beta negatively regulates basal p65 NF-kappaB activity. J Biol Chem, 2004. 279(48): p. 49571-4. 59. de Groot, R.P., et al., Negative regulation of Jun/AP-1: conserved function of glycogen synthase kinase 3 and the Drosophila kinase shaggy. Oncogene, 1993. 8(4): p. 841-7. 60. Yada, M., et al., Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J, 2004. 23(10): p. 2116-25. 61. Busino, L., et al., Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. Nature, 2003. 426(6962): p. 87-91. 62. Kitagawa, M., et al., An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. EMBO J, 1999. 18(9): p. 2401-10. 63. Wei, W., et al., The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell, 2005. 8(1): p. 25-33. 64. Ye, X., et al., Recognition of phosphodegron motifs in human cyclin E by the SCF(Fbw7) ubiquitin ligase. J Biol Chem, 2004. 279(48): p. 50110-9. 65. Frame, S. and P. Cohen, GSK3 takes centre stage more than 20 years after its discovery. Biochem J, 2001. 359(Pt 1): p. 1-16. 66. Luo, J., Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. Cancer Lett, 2009. 273(2): p. 194-200. 67. Woodgett, J.R., Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J, 1990. 9(8): p. 2431-8. 68. Woodgett, J.R., cDNA cloning and properties of glycogen synthase kinase-3. Methods Enzymol, 1991. 200: p. 564-77. 69. Doble, B.W. and J.R. Woodgett, GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci, 2003. 116(Pt 7): p. 1175-86. 70. Fang, X., et al., Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci U S A, 2000. 97(22): p. 11960-5. 71. Cross, D.A., et al., Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 1995. 378(6559): p. 785-9. 72. Kim, M.J., et al., The role of tamoxifen in combination with cisplatin on oral squamous cell carcinoma cell lines. Cancer Lett, 2007. 245(1-2): p. 284-92. 73. Stambolic, V. and J.R. Woodgett, Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J, 1994. 303 ( Pt 3): p. 701-4. 74. Sutherland, C., I.A. Leighton, and P. Cohen, Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J, 1993. 296 ( Pt 1): p. 15-9. 75. Ciani, L. and P.C. Salinas, WNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci, 2005. 6(5): p. 351-62. 76. Yook, J.I., et al., A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol, 2006. 8(12): p. 1398-406. 77. Gotschel, F., et al., Inhibition of GSK3 differentially modulates NF-kappaB, CREB, AP-1 and beta-catenin signaling in hepatocytes, but fails to promote TNF-alpha-induced apoptosis. Exp Cell Res, 2008. 314(6): p. 1351-66. 78. Bahram, F., et al., c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. Blood, 2000. 95(6): p. 2104-10. 79. de Castro, J., et al., beta-catenin expression pattern in primary oesophageal squamous cell carcinoma. Relationship with clinicopathologic features and clinical outcome. Virchows Arch, 2000. 437(6): p. 599-604. 80. Zheng, H., et al., Phosphorylated GSK3beta-ser9 and EGFR are good prognostic factors for lung carcinomas. Anticancer Res, 2007. 27(5B): p. 3561-9. 81. Tian, D., et al., Role of glycogen synthase kinase 3 in squamous differentiation induced by cigarette smoke in porcine tracheobronchial epithelial cells. Food Chem Toxicol, 2006. 44(9): p. 1590-6. 82. Winter, M., et al., Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nat Cell Biol, 2008. 10(7): p. 812-24. 83. Karrasch, T., et al., PI3K-dependent GSK3ss(Ser9)-phosphorylation is implicated in the intestinal epithelial cell wound-healing response. PLoS One, 2011. 6(10): p. e26340. 84. Kim, J.Y., et al., Functional regulation of Slug/Snail2 is dependent on GSK-3beta-mediated phosphorylation. FEBS J, 2012. 279(16): p. 2929-39. 85. Fiol, C.J., et al., Ordered multisite protein phosphorylation. Analysis of glycogen synthase kinase 3 action using model peptide substrates. J Biol Chem, 1990. 265(11): p. 6061-5. 86. Liu, C., et al., Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell, 2002. 108(6): p. 837-47. 87. Ciechanover, A., The ubiquitin proteolytic system: from a vague idea, through basic mechanisms, and onto human diseases and drug targeting. Neurology, 2006. 66(2 Suppl 1): p. S7-19. 88. Glickman, M.H. and A. Ciechanover, The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev, 2002. 82(2): p. 373-428. 89. Wood, L.D., et al., The genomic landscapes of human breast and colorectal cancers. Science, 2007. 318(5853): p. 1108-13. 90. Maser, R.S., et al., Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature, 2007. 447(7147): p. 966-71. 91. Esser, C., S. Alberti, and J. Hohfeld, Cooperation of molecular chaperones with the ubiquitin/proteasome system. Biochim Biophys Acta, 2004. 1695(1-3): p. 171-88. 92. Ballinger, C.A., et al., Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol, 1999. 19(6): p. 4535-45. 93. Connell, P., et al., The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol, 2001. 3(1): p. 93-6. 94. McDonough, H. and C. Patterson, CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones, 2003. 8(4): p. 303-8. 95. Aravind, L. and E.V. Koonin, The U box is a modified RING finger - a common domain in ubiquitination. Curr Biol, 2000. 10(4): p. R132-4. 96. Kajiro, M., et al., The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways. Nat Cell Biol, 2009. 11(3): p. 312-9. 97. Meacham, G.C., et al., The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol, 2001. 3(1): p. 100-5. 98. Tateishi, Y., et al., Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor. EMBO J, 2004. 23(24): p. 4813-23. 99. Xu, W., et al., Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc Natl Acad Sci U S A, 2002. 99(20): p. 12847-52. 100. Rees, I., et al., The E3 ubiquitin ligase CHIP binds the androgen receptor in a phosphorylation-dependent manner. Biochim Biophys Acta, 2006. 1764(6): p. 1073-9. 101. Shimura, H., et al., CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem, 2004. 279(6): p. 4869-76. 102. Dickey, C.A., et al., Deletion of the ubiquitin ligase CHIP leads to the accumulation, but not the aggregation, of both endogenous phospho- and caspase-3-cleaved tau species. J Neurosci, 2006. 26(26): p. 6985-96. 103. Ewing, R.M., et al., Large-scale mapping of human protein-protein interactions by mass spectrometry. Mol Syst Biol, 2007. 3: p. 89. 104. Gavin, A.C., et al., Proteome survey reveals modularity of the yeast cell machinery. Nature, 2006. 440(7084): p. 631-6. 105. Jeronimo, C., et al., Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Mol Cell, 2007. 27(2): p. 262-74. 106. Krogan, N.J., et al., Global landscape of protein complexes in the yeast Saccharomyces cerevisiae. Nature, 2006. 440(7084): p. 637-43. 107. Breitkreutz, A., et al., A global protein kinase and phosphatase interaction network in yeast. Science, 2010. 328(5981): p. 1043-6. 108. Choi, H., et al., SAINT: probabilistic scoring of affinity purification-mass spectrometry data. Nat Methods, 2011. 8(1): p. 70-3. 109. Craig, R., J.P. Cortens, and R.C. Beavis, Open source system for analyzing, validating, and storing protein identification data. J Proteome Res, 2004. 3(6): p. 1234-42. 110. Deutsch, E.W., et al., A guided tour of the Trans-Proteomic Pipeline. Proteomics, 2010. 10(6): p. 1150-9. 111. Fermin, D., et al., Abacus: a computational tool for extracting and pre-processing spectral count data for label-free quantitative proteomic analysis. Proteomics, 2011. 11(7): p. 1340-5. 112. Ahmed, S.F., et al., The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation. J Biol Chem, 2012. 287(19): p. 15996-6006. 113. Esser, C., M. Scheffner, and J. Hohfeld, The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. J Biol Chem, 2005. 280(29): p. 27443-8. 114. Wang, S., et al., CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer. Gut, 2012. 115. Ding, Q., et al., Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol, 2007. 27(11): p. 4006-17. 116. Maurer, U., et al., Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell, 2006. 21(6): p. 749-60. 117. Inuzuka, H., et al., SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature, 2011. 471(7336): p. 104-9. 118. Khanna, C. and K. Hunter, Modeling metastasis in vivo. Carcinogenesis, 2005. 26(3): p. 513-23. 119. Cooper, C.R., et al., Stromal factors involved in prostate carcinoma metastasis to bone. Cancer, 2003. 97(3 Suppl): p. 739-47. 120. De Wever, O. and M. Mareel, Role of tissue stroma in cancer cell invasion. J Pathol, 2003. 200(4): p. 429-47. 121. Schmidt-Hansen, B., et al., Functional significance of metastasis-inducing S100A4(Mts1) in tumor-stroma interplay. J Biol Chem, 2004. 279(23): p. 24498-504. 122. Bibby, M.C., Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages. Eur J Cancer, 2004. 40(6): p. 852-7. 123. Rajakishore, M., Glycogen synthase kinase 3 beta: can it be a target for oral cancer. Molecular Cancer, 2010. 9(144): p. 1-15. 124. Kang, T., et al., GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers. Cancer Cell, 2008. 13(1): p. 36-47. 125. Farago, M., et al., Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis. Cancer Res, 2005. 65(13): p. 5792-801. 126. He, X., et al., Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature, 1995. 374(6523): p. 617-22. 127. Patel, R., et al., Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression. J Clin Invest, 2013. 123(3): p. 1157-75. 128. Leis, H., et al., Expression, localization, and activity of glycogen synthase kinase 3beta during mouse skin tumorigenesis. Mol Carcinog, 2002. 35(4): p. 180-5. 129. Friedl, P. and S. Alexander, Cancer invasion and the microenvironment: plasticity and reciprocity. Cell, 2011. 147(5): p. 992-1009. 130. Al-Mulla, F., et al., Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3beta. Cancer Res, 2011. 71(4): p. 1334-43. 131. Cheng, J.C., N. Auersperg, and P.C. Leung, EGF-induced EMT and invasiveness in serous borderline ovarian tumor cells: a possible step in the transition to low-grade serous carcinoma cells? PLoS One, 2012. 7(3): p. e34071. 132. Come, C., et al., Roles of the transcription factors snail and slug during mammary morphogenesis and breast carcinoma progression. J Mammary Gland Biol Neoplasia, 2004. 9(2): p. 183-93. 133. Byles, V., et al., SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene, 2012. 31(43): p. 4619-29. 134. Katoh, Y. and M. Katoh, Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med, 2009. 9(7): p. 873-86. 135. John, J.K., et al., GSK3beta inhibition blocks melanoma cell/host interactions by downregulating N-cadherin expression and decreasing FAK phosphorylation. J Invest Dermatol, 2012. 132(12): p. 2818-27. 136. Conacci-Sorrell, M., et al., Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. J Cell Biol, 2003. 163(4): p. 847-57. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/62636 | - |
| dc.description.abstract | 轉譯後修飾在細胞生理調節上扮演很重要的角色，主要是透過對蛋白質穩定及定位，進而影響他們的功能。在本論文裡，我們會探討鋅指結構的轉錄抑制因子Slug被glycogen synthase kinase 3 beta (GSK3β)磷酸化及之後被C terminus of HSC70-Interacting Protein (CHIP)泛素化的蛋白質降解。我們利用體外磷酸化試驗與液相層析質譜儀等方式發現GSK3β磷酸的位置主要在Ser100及Ser104，其次為Ser92及Ser96。磷酸過後的Slug會使其蛋白穩定度下降。接著，我們利用蛋白質分析法找到E3泛素蛋白連接酶CHIP，並驗證了減少CHIP的表現則可以提高Slug蛋白的表現並降低Slug的泛素與降解，且不影響Slug信使核糖核酸的多寡。相反地，不被磷酸的Slug-4SA變異體，則不易被CHIP降解，也因此這些不被降解的Slug促進了E-cadherin的轉錄抑制，使得肺腺癌細胞更容易發生上皮- 間質細胞的轉換(EMT)而造成癌侵襲，另外我們也在動物活體試驗中證明不降解的Slug更促進癌轉移的發生。最後，我們檢驗了肺腺癌檢體與癌細胞株，發現GSK3β的活性高低與Slug蛋白表現有關，並且在癌細胞中也是如此。進一步在病人檢體的[GSK3β具活性，Slug蛋白低表現量]的子群中，我們發現60%病人的CHIP表現量也相對較高，意味著CHIP可能在GSK3β調控的Slug蛋白降解裡扮演著重要的角色。總括而言，我們的研究發現一條新的GSK3β-CHIP-Slug機制，透過Slug蛋白的累積或降解，調控肺腺癌的轉移。 | zh_TW |
| dc.description.abstract | Post-translational modification plays an important role in regulating the stability, localization, and the functions of many proteins. In this thesis, we report that the zinc-finger-containing transcriptional repressor, Slug, can be phosphorylated by glycogen synthase kinase 3 beta (GSK3β) and later ubiquitinated by the C terminus of HSC70-Interacting Protein (CHIP) for proteasomal degradation. We identified S100 and S104 as the major phosphorylation sites for GSK3β, and S92 and S96, the minor ones. Further analysis shows that phosphorylation of Slug facilitates its protein turnover. To characterize which E3 ligase is involved in GSK3β-mediated Slug degradation, we conducted the proteomic analysis which reveals that CHIP interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes Slug-WT protein without a change in the Slug mRNA level and reduces Slug ubiquitination and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug further leads to the repression of E-cadherin expression and enhances epithelial-mesenchymal transition (EMT), therefore promoting cancer cell migration, invasion, and metastasis. Furthermore, we show that the GSK3β-pSer9 level correlates with the expression of Slug in patients with non-small cell lung cancer (NSCLC). Within the group of [GSK3β active, Slug low], 60% of the cases have an overexpression of CHIP, implicating the significant role CHIP may play in the GSK3β-mediated Slug degradation. Collectively, our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T16:06:10Z (GMT). No. of bitstreams: 1 ntu-102-D95448006-1.pdf: 3519693 bytes, checksum: deb131ca6e071735bab37fbfcc43e8b3 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | TABLE OF CONTENTS
TABLE OF CONTENTS i LIST OF FIGURES iv LIST OF TABLES vi 中文摘要 1 ABSTRACT 2 CHAPTER 1. GENERAL BACKGROUND 3 1.1 Lung cancer 4 1.2 The microenvironment that promotes metastasis 5 1.3 Epithelial-mesenchymal transition (EMT) 6 1.4 Post-translational modification 7 1.5 Phosphorylation and Ubiquitination 9 1.6 Purposes and aims of this study 10 CHAPTER 2. GSK3β-MEDIATED SLUG PHOSPHORYLATION AFFECTS SLUG TURNOVER 12 2.1 Introduction 13 2.1.1 Slug signaling and lung cancer 13 2.1.2 Slug phosphorylation and degradation 14 2.1.3 GSK3β and cancers 16 2.2 Materials and Methods 18 2.2.1 Cell lines and selection of stable clones 18 2.2.2 Antibodies and Reagents 18 2.2.3 Plasmid constructs 19 2.2.4 Viruses and transduction 20 2.2.5 Immunoprecipitation and immunoblotting 21 2.2.6 Cycloheximide protein synthesis inhibition assay 22 2.2.7 Reverse-transcriptase polymerase chain reaction (RT-PCR) and real-time quantitative PCR. 22 2.2.8 Transwell Migration and invasion assay 23 2.2.9 In vitro kinase assay 24 2.2.10 In vivo kinase assay 25 2.2.11 LC-MS/MS Analysis for phosphopeptides 26 2.2.12 Statistical analysis 28 2.3 Results 29 2.3.1 The activity of GSK3β inversely correlates with the protein expression of Slug 29 2.3.2 GSK3β affects Slug protein turnover 30 2.3.3 Identification of GSK3β-mediated Slug phosphorylation sites 31 2.3.4 GSK3β-mediated Slug phosphorylation affects Slug protein turnover 33 2.4 Discussion 34 CHAPTER 3. The E3 LIGASE, CHIP, IS INVOLVED IN GSK3β-MEDIATED SLUG DEGRADATION 54 3.1 Introduction 55 3.1.1 The ubiquitin–proteasome system (UPS) 55 3.1.2 CHIP and cancers 56 3.1.3 Proteomic identification of E3 ligases 56 3.2 Materials and Methods 58 3.2.1 Co-immunoprecipitation 58 3.2.2 Viruses and transduction 59 3.2.3 SAINT 59 3.2.4 Antibodies and reagents 60 3.3 Results 62 3.3.1 Preparation of protein samples and analysis of SAINT 62 3.3.2 The E3 ligase CHIP is involved in GSK3β-mediated phosphorylation-dependent Slug degradation 62 3.4 Discussion 65 CHAPTER 4. THE FUNCTIONAL ANALYSIS OF GSK3β-MEDIATED PHOSPHORYLATION OF SLUG AND THEIR CLINICAL CORRELATION 73 4.1 Introduction 74 4.1.1 Comparison of in vivo metastasis models 74 4.1.2 Clinical relevance of GSK3β, CHIP, and Slug 75 4.2 Materials and Methods 77 4.2.1 Luciferase activity assays 77 4.2.2 Antibodies 77 4.2.3 Migration and invasion assay 78 4.2.4 Time-lapse microscopy 78 4.2.5 Experimental metastasis in vivo 78 4.2.6 Patient and tumor specimens 79 4.2.7 Immunohistochemistry 79 4.2.8 Statistical analysis 80 4.3 Results 82 4.3.1 Stabilized Slug promotes cell migration and invasion 82 4.3.2 Nonphosphorylatable Slug mutant (4SA) increases cancer metastasis in vivo 83 4.3.3 The GSK3β-pSer9 level is associated with the expression of Slug in NSCLC tumor specimens 84 4.4 Discussion 86 CHAPTER 5. CONCLUSION AND FUTURE WORK 101 REFERENCES 106 APPENDIX 116 | |
| dc.language.iso | en | |
| dc.subject | 上皮-間質細胞轉換過程 | zh_TW |
| dc.subject | GSK3β | zh_TW |
| dc.subject | Slug | zh_TW |
| dc.subject | CHIP | zh_TW |
| dc.subject | 磷酸化 | zh_TW |
| dc.subject | phosphorylation | en |
| dc.subject | Slug | en |
| dc.subject | CHIP | en |
| dc.subject | EMT | en |
| dc.subject | GSK3β | en |
| dc.title | Slug轉錄因子的轉譯後修飾與其在肺腺癌上癌侵襲及轉移之探討 | zh_TW |
| dc.title | Characterization of the Post-Translational Modifications of the Transcriptional Repressor Slug and Its Effects on Lung Adenocarcinoma | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 陳健尉(Jian-Wei Chen),洪澤民(Tse-Ming Hong),徐立中(Li-Chung Hsu),吳君泰(June-Tai Wu) | |
| dc.subject.keyword | GSK3β,Slug,CHIP,上皮-間質細胞轉換過程,磷酸化, | zh_TW |
| dc.subject.keyword | GSK3β,Slug,CHIP,EMT,phosphorylation, | en |
| dc.relation.page | 118 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-06-18 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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