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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳進庭 | |
| dc.contributor.author | Mu-Ching Huang | en |
| dc.contributor.author | 黃睦晴 | zh_TW |
| dc.date.accessioned | 2021-07-11T15:49:16Z | - |
| dc.date.available | 2023-08-17 | |
| dc.date.copyright | 2018-08-17 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-07-31 | |
| dc.identifier.citation | 1. Edwards, J.C., A novel p64-related Cl- channel: subcellular distribution and nephron segment-specific expression. Am J Physiol, 1999. 276(3 Pt 2): p. F398-408.
2. Chuang, J.Z., et al., A 29 kDa intracellular chloride channel p64H1 is associated with large dense-core vesicles in rat hippocampal neurons. J Neurosci, 1999. 19(8): p. 2919-28. 3. Howell, S., R.R. Duncan, and R.H. Ashley, Identification and characterisation of a homologue of p64 in rat tissues. FEBS Lett, 1996. 390(2): p. 207-10. 4. Littler, D.R., et al., The enigma of the CLIC proteins: Ion channels, redox proteins, enzymes, scaffolding proteins? FEBS Lett, 2010. 584(10): p. 2093-101. 5. Berryman, M.A. and J.R. Goldenring, CLIC4 is enriched at cell-cell junctions and colocalizes with AKAP350 at the centrosome and midbody of cultured mammalian cells. Cell Motil Cytoskeleton, 2003. 56(3): p. 159-72. 6. Suh, K.S., et al., CLIC4, skin homeostasis and cutaneous cancer: surprising connections. Mol Carcinog, 2007. 46(8): p. 599-604. 7. Suh, K.S., et al., The organellular chloride channel protein CLIC4/mtCLIC translocates to the nucleus in response to cellular stress and accelerates apoptosis. J Biol Chem, 2004. 279(6): p. 4632-41. 8. Malik, M., et al., Inducible NOS-induced chloride intracellular channel 4 (CLIC4) nuclear translocation regulates macrophage deactivation. Proc Natl Acad Sci U S A, 2012. 109(16): p. 6130-5. 9. Zhang, H.H., et al., Estradiol-17beta stimulates specific receptor and endogenous nitric oxide-dependent dynamic endothelial protein S-nitrosylation: analysis of endothelial nitrosyl-proteome. Endocrinology, 2010. 151(8): p. 3874-87. 10. Suh, K.S., et al., CLIC4 mediates and is required for Ca2+-induced keratinocyte differentiation. J Cell Sci, 2007. 120(Pt 15): p. 2631-40. 11. Shukla, A., et al., TGF-beta signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3. Nat Cell Biol, 2009. 11(6): p. 777-84. 12. Wojciak-Stothard, B., et al., Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction in pulmonary arterial hypertension. Circulation, 2014. 129(17): p. 1770-80. 13. Shukla, A., et al., CLIC4 regulates TGF-beta-dependent myofibroblast differentiation to produce a cancer stroma. Oncogene, 2014. 33(7): p. 842-50. 14. Suh, K.S., et al., Reciprocal modifications of CLIC4 in tumor epithelium and stroma mark malignant progression of multiple human cancers. Clin Cancer Res, 2007. 13(1): p. 121-31. 15. Suh, K.S., et al., CLIC4 is a tumor suppressor for cutaneous squamous cell cancer. Carcinogenesis, 2012. 33(5): p. 986-95. 16. Ronnov-Jessen, L., et al., Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-beta1-mediated conversion of fibroblasts to myofibroblasts. Am J Pathol, 2002. 161(2): p. 471-80. 17. Yao, Q., et al., CLIC4 mediates TGF-beta1-induced fibroblast-to-myofibroblast transdifferentiation in ovarian cancer. Oncol Rep, 2009. 22(3): p. 541-8. 18. Boyer, L.A., et al., Core transcriptional regulatory circuitry in human embryonic stem cells. Cell, 2005. 122(6): p. 947-56. 19. Fernandez-Salas, E., et al., p53 and tumor necrosis factor alpha regulate the expression of a mitochondrial chloride channel protein. J Biol Chem, 1999. 274(51): p. 36488-97. 20. Fernandez-Salas, E., et al., mtCLIC/CLIC4, an organellular chloride channel protein, is increased by DNA damage and participates in the apoptotic response to p53. Mol Cell Biol, 2002. 22(11): p. 3610-20. 21. Shiio, Y., et al., Quantitative proteomic analysis of myc-induced apoptosis: a direct role for Myc induction of the mitochondrial chloride ion channel, mtCLIC/CLIC4. J Biol Chem, 2006. 281(5): p. 2750-6. 22. Gellert, M., M.N. Lipsett, and D.R. Davies, HELIX FORMATION BY GUANYLIC ACID. Proceedings of the National Academy of Sciences, 1962. 48(12): p. 2013-2018. 23. Qin, Y. and L.H. Hurley, Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regions. Biochimie, 2008. 90(8): p. 1149-71. 24. Keniry, M.A., Quadruplex structures in nucleic acids. Biopolymers, 2000. 56(3): p. 123-46. 25. Todd, A.K., M. Johnston, and S. Neidle, Highly prevalent putative quadruplex sequence motifs in human DNA. Nucleic Acids Res, 2005. 33(9): p. 2901-7. 26. Sundquist, W.I. and A. Klug, Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops. Nature, 1989. 342(6251): p. 825-9. 27. Paeschke, K., et al., Telomere end-binding proteins control the formation of G-quadruplex DNA structures in vivo. Nat Struct Mol Biol, 2005. 12(10): p. 847-54. 28. Zahler, A.M., et al., Inhibition of telomerase by G-quartet DNA structures. Nature, 1991. 350(6320): p. 718-20. 29. Huppert, J.L. and S. Balasubramanian, G-quadruplexes in promoters throughout the human genome. Nucleic Acids Res, 2007. 35(2): p. 406-13. 30. Eddy, J. and N. Maizels, Gene function correlates with potential for G4 DNA formation in the human genome. Nucleic Acids Res, 2006. 34(14): p. 3887-96. 31. Lim, K.W., et al., Coexistence of two distinct G-quadruplex conformations in the hTERT promoter. J Am Chem Soc, 2010. 132(35): p. 12331-42. 32. Palumbo, S.L., S.W. Ebbinghaus, and L.H. Hurley, Formation of a unique end-to-end stacked pair of G-quadruplexes in the hTERT core promoter with implications for inhibition of telomerase by G-quadruplex-interactive ligands. J Am Chem Soc, 2009. 131(31): p. 10878-91. 33. Bidzinska, J., et al., G-Quadruplex Structures in the Human Genome as Novel Therapeutic Targets. Molecules, 2013. 18(10): p. 12368-12395. 34. Sun, H.X., et al., A newly identified G-quadruplex as a potential target regulating Bcl-2 expression. Biochimica Et Biophysica Acta-General Subjects, 2014. 1840(10): p. 3052-3057. 35. Du, Z., Y. Zhao, and N. Li, Genome-wide analysis reveals regulatory role of G4 DNA in gene transcription. Genome Res, 2008. 18(2): p. 233-41. 36. Bochman, M.L., K. Paeschke, and V.A. Zakian, DNA secondary structures: stability and function of G-quadruplex structures. Nature Reviews Genetics, 2012. 13(11): p. 770-780. 37. Kulis, M. and M. Esteller, DNA Methylation and Cancer. Epigenetics and Cancer, Pt A, 2010. 70: p. 27-56. 38. Lin, J., et al., Stabilization of G-quadruplex DNA by C-5-methyl-cytosine in bcl-2 promoter: Implications for epigenetic regulation. Biochemical and Biophysical Research Communications, 2013. 433(4): p. 368-373. 39. Stevens, A.J., et al., G-Quadruplex Structures and CpG Methylation Cause Drop-Out of the Maternal Allele in Polymerase Chain Reaction Amplification of the Imprinted MEST Gene Promoter. Plos One, 2014. 9(12). 40. Li, P.T., et al., Expression of the human telomerase reverse transcriptase gene is modulated by quadruplex formation in its first exon due to DNA methylation. J Biol Chem, 2017. 292(51): p. 20859-20870. 41. Renaud, S., et al., Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene. Nucleic Acids Res, 2007. 35(4): p. 1245-56. 42. Cirri, P. and P. Chiarugi, Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev, 2012. 31(1-2): p. 195-208. 43. Warburg, O., On the origin of cancer cells. Science, 1956. 123(3191): p. 309-14. 44. Pavlides, S., et al., The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle, 2009. 8(23): p. 3984-4001. 45. Fiaschi, T., et al., Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay. Cancer Research, 2012. 72(19): p. 5130-5140. 46. Orimo, A., et al., Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 2005. 121(3): p. 335-348. 47. Giannoni, E., et al., Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res, 2010. 70(17): p. 6945-56. 48. Giannoni, E., et al., Cancer Associated Fibroblasts Exploit Reactive Oxygen Species Through a Proinflammatory Signature Leading to Epithelial Mesenchymal Transition and Stemness. Antioxidants & Redox Signaling, 2011. 14(12): p. 2361-2371. 49. Duda, D.G., et al., Malignant cells facilitate lung metastasis by bringing their own soil. Proceedings of the National Academy of Sciences of the United States of America, 2010. 107(50): p. 21677-21682. 50. Massague, J., TGFbeta signalling in context. Nat Rev Mol Cell Biol, 2012. 13(10): p. 616-30. 51. Roberts, A.B., et al., Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci U S A, 1985. 82(1): p. 119-23. 52. Derynck, R. and Y.E. Zhang, Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003. 425(6958): p. 577-84. 53. Zhang, Y.E., Non-Smad pathways in TGF-beta signaling. Cell Res, 2009. 19(1): p. 128-39. 54. Calon, A., et al., Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell, 2012. 22(5): p. 571-84. 55. Evans, R.A., et al., TGF-beta1-mediated fibroblast-myofibroblast terminal differentiation-the role of Smad proteins. Exp Cell Res, 2003. 282(2): p. 90-100. 56. Shangguan, L., et al., Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects. Stem Cells, 2012. 30(12): p. 2810-9. 57. Oft, M., R.J. Akhurst, and A. Balmain, Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol, 2002. 4(7): p. 487-94. 58. Stuelten, C.H., et al., Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-alpha and TGF-beta. J Cell Sci, 2005. 118(Pt 10): p. 2143-53. 59. Yu, Q. and I. Stamenkovic, Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev, 2000. 14(2): p. 163-76. 60. Guido, C., et al., Metabolic reprogramming of cancer-associated fibroblasts by TGF-beta drives tumor growth: connecting TGF-beta signaling with 'Warburg-like' cancer metabolism and L-lactate production. Cell Cycle, 2012. 11(16): p. 3019-35. 61. Capparelli, C., et al., CTGF drives autophagy, glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth. Cell Cycle, 2012. 11(12): p. 2272-84. 62. 江珮琪, 探討CLIC4於光動力致氧化壓力下之調控機制及其對細胞生物效應之影響, in 生化科技學系. 2013, 國立臺灣大學: 台北市. p. 209. 63. Serini, G. and G. Gabbiani, Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res, 1999. 250(2): p. 273-83. 64. Tomasek, J.J., et al., Myofibroblasts and mechano-regulation of connective tissue remodelling. Nature Reviews Molecular Cell Biology, 2002. 3: p. 349. 65. Rasanen, K. and A. Vaheri, TGF-beta1 causes epithelial-mesenchymal transition in HaCaT derivatives, but induces expression of COX-2 and migration only in benign, not in malignant keratinocytes. J Dermatol Sci, 2010. 58(2): p. 97-104. 66. 賴亭薇, 探討氯離子通道蛋白CLIC4 對於基質金屬蛋白MMP9 之調控機制, in 生化科技學系. 2014, 國立臺灣大學: 台北市. p. 82. 67. Sen, D. and W. Gilbert, A sodium-potassium switch in the formation of four-stranded G4-DNA. Nature, 1990. 344(6265): p. 410-4. 68. Okudela, K., et al., Proteome analysis for downstream targets of oncogenic KRAS--the potential participation of CLIC4 in carcinogenesis in the lung. PLoS One, 2014. 9(2): p. e87193. 69. Cogoi, S., A.E. Shchekotikhin, and L.E. Xodo, HRAS is silenced by two neighboring G-quadruplexes and activated by MAZ, a zinc-finger transcription factor with DNA unfolding property. Nucleic Acids Res, 2014. 42(13): p. 8379-88. 70. Raiber, E.A., et al., A non-canonical DNA structure is a binding motif for the transcription factor SP1 in vitro. Nucleic Acids Research, 2012. 40(4): p. 1499-1508. 71. Sun, D., K. Guo, and Y.J. Shin, Evidence of the formation of G-quadruplex structures in the promoter region of the human vascular endothelial growth factor gene. Nucleic Acids Res, 2011. 39(4): p. 1256-65. 72. Gonzalez, V., et al., Identification and characterization of nucleolin as a c-myc G-quadruplex-binding protein. J Biol Chem, 2009. 284(35): p. 23622-35. 73. Uribe, D.J., et al., Heterogeneous nuclear ribonucleoprotein K and nucleolin as transcriptional activators of the vascular endothelial growth factor promoter through interaction with secondary DNA structures. Biochemistry, 2011. 50(18): p. 3796-806. 74. Brazda, V., et al., DNA and RNA quadruplex-binding proteins. Int J Mol Sci, 2014. 15(10): p. 17493-517. 75. Tang, W., et al., The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription. Hum Mol Genet, 2016. 25(10): p. 2060-2069. 76. Mendoza, O., et al., G-quadruplexes and helicases. Nucleic Acids Res, 2016. 44(5): p. 1989-2006. 77. Chen, M.C., et al., Insights into the mechanism of a G-quadruplex-unwinding DEAH-box helicase. Nucleic Acids Res, 2015. 43(4): p. 2223-31. 78. Kruger, A.C., et al., Interaction of hnRNP A1 with telomere DNA G-quadruplex structures studied at the single molecule level. Eur Biophys J, 2010. 39(9): p. 1343-50. 79. Paramasivam, M., et al., Protein hnRNP A1 and its derivative Up1 unfold quadruplex DNA in the human KRAS promoter: implications for transcription. Nucleic Acids Res, 2009. 37(9): p. 2841-53. 80. Khateb, S., et al., Destabilization of tetraplex structures of the fragile X repeat sequence (CGG)n is mediated by homolog-conserved domains in three members of the hnRNP family. Nucleic Acids Res, 2004. 32(14): p. 4145-54. 81. Khateb, S., et al., The tetraplex (CGG)n destabilizing proteins hnRNP A2 and CBF-A enhance the in vivo translation of fragile X premutation mRNA. Nucleic Acids Res, 2007. 35(17): p. 5775-88. 82. Enokizono, Y., et al., Destruction of quadruplex by proteins, and its biological implications in replication and telomere maintenance. Nucleic Acids Res Suppl, 2003(3): p. 231-2. 83. Santibanez, J.F., et al., Transforming growth factor-beta1 modulates matrix metalloproteinase-9 production through the Ras/MAPK signaling pathway in transformed keratinocytes. Biochem Biophys Res Commun, 2002. 296(2): p. 267-73. 84. Kim, E.S., M.S. Kim, and A. Moon, TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol, 2004. 25(5): p. 1375-82. 85. Tobar, N., V. Villar, and J.F. Santibanez, ROS-NFkappaB mediates TGF-beta1-induced expression of urokinase-type plasminogen activator, matrix metalloproteinase-9 and cell invasion. Mol Cell Biochem, 2010. 340(1-2): p. 195-202. 86. Safina, A., E. Vandette, and A.V. Bakin, ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene, 2007. 26(17): p. 2407-22. 87. Safina, A., et al., TAK1 is required for TGF-beta 1-mediated regulation of matrix metalloproteinase-9 and metastasis. Oncogene, 2008. 27(9): p. 1198-207. 88. Lasfar, A. and K.A. Cohen-Solal, Resistance to transforming growth factor beta-mediated tumor suppression in melanoma: are multiple mechanisms in place? Carcinogenesis, 2010. 31(10): p. 1710-7. 89. Kasai, H., et al., TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res, 2005. 6: p. 56. 90. Tirino, V., et al., TGF-beta1 exposure induces epithelial to mesenchymal transition both in CSCs and non-CSCs of the A549 cell line, leading to an increase of migration ability in the CD133+ A549 cell fraction. Cell Death Dis, 2013. 4: p. e620. 91. Wang, X., et al., 5-Aminolaevulinic Acid-Based Photodynamic Therapy Restrains Pathological Hyperplasia of Fibroblasts. Med Sci Monit, 2017. 23: p. 46-56. 92. Han, Y. and B.A. Garcia, Combining genomic and proteomic approaches for epigenetics research. Epigenomics, 2013. 5(4): p. 439-52. 93. Dejardin, J. and R.E. Kingston, Purification of proteins associated with specific genomic Loci. Cell, 2009. 136(1): p. 175-86. 94. Mittler, G., F. Butter, and M. Mann, A SILAC-based DNA protein interaction screen that identifies candidate binding proteins to functional DNA elements. Genome Res, 2009. 19(2): p. 284-93. 95. Kennedy-Darling, J., et al., Discovery of Chromatin-Associated Proteins via Sequence-Specific Capture and Mass Spectrometric Protein Identification in Saccharomyces cerevisiae. J Proteome Res, 2014. 96. Guillen-Ahlers, H., et al., HyCCAPP as a tool to characterize promoter DNA-protein interactions in Saccharomyces cerevisiae. Genomics, 2016. 107(6): p. 267-73. 97. Romera, C., et al., Improvement of porphyrins for G-quadruplex DNA targeting. Biochimie, 2011. 93(8): p. 1310-7. 98. Izbicka, E., et al., Effects of cationic porphyrins as G-quadruplex interactive agents in human tumor cells. Cancer Res, 1999. 59(3): p. 639-44. 99. Grand, C.L., et al., The cationic porphyrin TMPyP4 down-regulates c-MYC and human telomerase reverse transcriptase expression and inhibits tumor growth in vivo. Mol Cancer Ther, 2002. 1(8): p. 565-73. 100. Huppert, J.L., et al., G-quadruplexes: the beginning and end of UTRs. Nucleic Acids Res, 2008. 36(19): p. 6260-8. 101. Hansel-Hertsch, R., et al., G-quadruplex structures mark human regulatory chromatin. Nat Genet, 2016. 48(10): p. 1267-72. 102. Mladenova, V., E. Mladenov, and G. Russev, Organization of Plasmid DNA into Nucleosome-Like Structures after Transfection in Eukaryotic Cells. Biotechnology & Biotechnological Equipment, 2009. 23(1): p. 1044-1047. 103. Fukuhara, M., et al., A G-quadruplex structure at the 5' end of the H19 coding region regulates H19 transcription. Sci Rep, 2017. 8: p. 45815. 104. Sun, D. and L.H. Hurley, Biochemical techniques for the characterization of G-quadruplex structures: EMSA, DMS footprinting, and DNA polymerase stop assay. Methods Mol Biol, 2010. 608: p. 65-79. 105. Sun, D., K. Guo, and Y.-J. Shin, Evidence of the formation of G-quadruplex structures in the promoter region of the human vascular endothelial growth factor gene. Nucleic Acids Research, 2011. 39(4): p. 1256-1265. 106. Fleming, A.M., et al., A Role for the Fifth G-Track in G-Quadruplex Forming Oncogene Promoter Sequences during Oxidative Stress: Do These 'Spare Tires' Have an Evolved Function? ACS Cent Sci, 2015. 1(5): p. 226-233. 107. Fleming, A.M., Y. Ding, and C.J. Burrows, Oxidative DNA damage is epigenetic by regulating gene transcription via base excision repair. Proc Natl Acad Sci U S A, 2017. 114(10): p. 2604-2609. 108. Todd, A.K. and S. Neidle, The relationship of potential G-quadruplex sequences in cis-upstream regions of the human genome to SP1-binding elements. Nucleic Acids Res, 2008. 36(8): p. 2700-4. 109. Kumar, P., et al., Zinc-finger transcription factors are associated with guanine quadruplex motifs in human, chimpanzee, mouse and rat promoters genome-wide. Nucleic Acids Res, 2011. 39(18): p. 8005-16. 110. Lew, A., W.J. Rutter, and G.C. Kennedy, Unusual DNA structure of the diabetes susceptibility locus IDDM2 and its effect on transcription by the insulin promoter factor Pur-1/MAZ. Proc Natl Acad Sci U S A, 2000. 97(23): p. 12508-12. 111. Palumbo, S.L., et al., A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activity. Nucleic Acids Res, 2008. 36(6): p. 1755-69. 112. Membrino, A., et al., G4-DNA formation in the HRAS promoter and rational design of decoy oligonucleotides for cancer therapy. PLoS One, 2011. 6(9): p. e24421. 113. Zeraati, M., et al., I-motif DNA structures are formed in the nuclei of human cells. Nat Chem, 2018. 114. Unnikrishnan, A., et al., A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network. Nucleic Acids Res, 2016. 44(22): p. 10644-10661. 115. Dawson, P.J., et al., MCF10AT: a model for the evolution of cancer from proliferative breast disease. Am J Pathol, 1996. 148(1): p. 313-9. 116. Santner, S.J., et al., Malignant MCF10CA1 cell lines derived from premalignant human breast epithelial MCF10AT cells. Breast Cancer Res Treat, 2001. 65(2): p. 101-10. 117. Balani, S., L.V. Nguyen, and C.J. Eaves, Modeling the process of human tumorigenesis. Nature Communications, 2017. 8: p. 15422. 118. Korah, J., et al., A transcriptionally active pRb-E2F1-P/CAF signaling pathway is central to TGFbeta-mediated apoptosis. Cell Death Dis, 2012. 3: p. e407. 119. Jang, Y.S., et al., TGF-beta1 stimulates mouse macrophages to express APRIL through Smad and p38MAPK/CREB pathways. Mol Cells, 2011. 32(3): p. 251-5. 120. Docagne, F., et al., Sp1 and Smad transcription factors co-operate to mediate TGF-beta-dependent activation of amyloid-beta precursor protein gene transcription. Biochem J, 2004. 383(Pt 2): p. 393-9. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/79163 | - |
| dc.description.abstract | 在腫瘤發展的過程中，CLIC4基因在腫瘤細胞中的表現逐漸減少，而在腫瘤微環境中的基質細胞表現卻逐漸增加，在腫瘤細胞及基質間對於CLIC4表現的差異性，和腫瘤的發展歷程有一定的關連性，且對於腫瘤發展皆有正向的影響。然而目前關於此基因的表現是如何被調控，所知卻相當有限，因此本研究主要的目的為探討CLIC4基因相關的調控機制。已知腫瘤微環境中所富含的fibroblast，主要受到癌細胞分泌之TGF-β誘導而轉變為myofibroblast。藉由MRC5細胞的研究結果顯示，CLIC4的轉錄在此過程中會受到TGF-β所誘導而上升，同時，CLIC4也能進一步調控下游分子MMP9的表現。分析CLIC4啟動子(promoter)，發現當中有轉錄因子、潛在的二級結構以及甲基化修飾共同存在的區域。透過SEAP reporter assay分析找出潛在的轉錄因子結合的區域;之後藉由軟體預測CLIC4啟動子中含有形成G-quadruplex (G4)二級結構的序列，並利用NMR分析幾段具有較高潛力形成G4的片段(Potential G4s，PG4s)，證實這些序列確實能夠形成G4結構。reporter assay分析結果顯示，當中的PG4-3結構對於CLIC4轉錄可能是重要的，進一步以CRISPR/Cas9直接編輯genome中CLIC4 啟動子序列，透過pop-in / pop-out策略挑選破壞genome中PG4-3序列的cell clone，在in vivo中證實此G4結構對於CLIC4表現的重要性，目前推測PG4-3可能作為阻礙repressor結合的角色;最後，我們觀察到甲基化修飾的現象確實存在於腫瘤細胞中，且與CLIC4表現量有相關性，說明甲基化修飾可能是腫瘤細胞調控CLIC4表現的方式。綜合以上的研究，我們證實CLIC4 啟動子中的二級結構-G4，以及甲基化修飾，對於CLIC4基因表現調控扮演著重要的角色。 | zh_TW |
| dc.description.abstract | During tumor progression, chloride intracellular channel protein 4 (CLIC4) has been found to be downregulated in tumor cells but upregulated in stroma cells in tumor microenvironment. The reciprocal expression of CLIC4 in each site could contribute to cancer malignancy. However, little is known about how this gene is regulated. In this study, we investigated the regulatory mechanisms involved in CLIC4 gene transcription. It has been shown that fibroblast, one of the major components of stromal cells is activated by TGF-β and become myofibroblast. During this process, the transcription of CLIC4 is also induced by TGF-β; meanwhile, the expression of MMP9 is mediated by CLIC4. Upon dissecting CLIC4 promoter, putative transcription factor binding sites, the possible secondary structure and DNA methylation were found in common region. Reporter assay was conducted to defined critical region. G-quadruplex (G4) forming sequences were predicted and could actually form G4 structure in vitro with NMR. The reporter assay showed that G4 structure might have their significance in CLIC4 expression. Using CRISPR/Cas9 system to edit CLIC4 promoter sequence in cell genome mediated by pop-in/pop-out strategy, we also confirmed the significance of G4 structure for CLIC4 expression in vivo. Moreover, DNA methylation of CLIC4 promoter was found to be correlated with its mRNA expression level, implying DNA methylation might be one of the regulatory mechanisms of cancer cell to downregulate CLIC4 expression. In conclusion, we’ve found the secondary structure-G4 and methylation in CLIC4 promoter play a role in transcriptional regulation. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:49:16Z (GMT). No. of bitstreams: 1 ntu-107-D02b22005-1.pdf: 16511497 bytes, checksum: 30ccd6f476b29eb579f99cbe38a769ba (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 謝誌 I
摘要 II Abstract III 目錄 V 圖目錄 X 第一章 緒論 1 1.1胞內氯離子通道蛋白(Chloride intracellular channel 4, CLIC4) 1 1.1.1 CLIC4基本介紹 1 1.1.2 CLIC4在腫瘤中的角色 2 1.1.3 CLIC4基因調控機制 3 1.2 G-quadruplex, G4 5 1.2.1 G4基本介紹 5 1.2.2 G4在轉錄中的角色 6 1.2.3 G4與甲基化間的關聯性 7 1.3腫瘤相關纖維母細胞(Cancer-associated-fibroblast, CAF) 9 1.3.1 CAF的起源 9 1.3.2 CAF對腫瘤的影響 9 1.4 TGF-β 訊息傳遞路徑 12 1.4.1 TGF-β訊息路徑作用機制 12 1.4.2 癌症中的TGF-β訊息路徑 13 1.4.3 TGF-β於CAF的影響 13 1.4.4 針對TGF-β訊息路徑的治療方法 14 1.5研究動機與目的 15 1.6 研究架構 17 第二章 材料與方法 18 2.1藥品與儀器 18 2.1.1 藥品 18 2.1.2細胞培養耗材 19 2.1.3儀器 20 2.2 細胞培養 21 2.2.1 細胞株 (Cell line) 21 2.2.2 細胞培養與繼代 22 2.2.3細胞解凍與冷凍 22 2.2.4 細胞計數 23 2.3 mRNA定量分析 23 2.3.1 RNA 萃取 (RNA extraction) 23 2.3.2 反轉錄 (Reverse Transcription, RT) 24 2.3.3 聚合酶鏈鎖反應 (Polymerase Chain Reaction, PCR) 24 2.3.4 洋菜膠體電泳分析 25 2.3.5 即時定量聚合酶連鎖反應(Real-time Polymerase Chain Reaction, real-time PCR) 26 2.4西方墨點法 (Western blot) 27 2.4.1 蛋白質萃取 (Protein extraction) 27 2.4.2 烷基硫酸鈉聚丙醯胺凝膠電泳 (SDS-PAGE) 27 2.4.3 化學冷光免疫分析(Chemiluminescence Immunoassay, CLIA) 28 2.5 報導基因(reporter assay)質體建構 29 2.5.1目標基因序列的PCR放大 29 2.5.2 TA cloning 31 2.5.3 質體建構 31 2.5.4 定點突變 (site-directed mutagenesis) 32 2.6以SEAP assay測定promoter片段活性 34 2.6.1 轉染預測定之SEAP reporter plasmid 34 2.6.2 SEAP活性測定 35 2.6.3 細胞存活率分析：粒線體去氫酶活性分析 (MTT assay) 36 2.6.4 Promoter活性計算 36 2.7 G4 穩定劑處理 37 2.7.1 G4穩定劑配置 37 2.7.2 G4穩定劑處理條件 37 2.8 轉錄因子預測 37 2.9 RNAi gene knockdown 38 2.10 CRISPR/Cas9編輯genome序列 38 2.10.1 設計及製作sgRNA 38 2.10.2 細胞核轉染Nucleofection 40 2.10.3 T7 Endonuclease Assay (T7EI assay) 41 2.10.4 Gibson assembly 42 2.10.5 Round-the-horn PCR 44 2.10.6 In vitro Cas9 digestion 45 2.11 電泳遷移率實驗 (Electrophoretic mobility shift assay, EMSA) 45 2.12 DNA親和性沉澱分析 (DNA affinity purification assay, DAPA) 46 2.13 染色質免疫沈澱 (Chromatin immunoprecipitation, ChIP) 47 2.14統計分析 48 第三章 研究結果 49 3.1調控CLIC4表現 49 3.1.1以TGF-β調控CLIC4表現 49 3.1.2 以ALA-PDT光動力調控經TGF-β所誘導之CLIC4表現 51 3.2 CLIC4與MMP9間的關聯性 53 3.2.1調控CLIC4表現對於MMP9表現的影響 53 3.3 分析CLIC4 promoter 54 3.4 找尋可能調控CLIC4表現的轉錄因子 55 3.4.1 找尋TGF-β誘導CLIC4表現之轉錄因子 55 3.4.2 調控CLIC4已知的轉錄因子 56 3.4.3 調控CLIC4 (-362, -125)中可能的轉錄因子 57 3.5 G-quadruplex對於CLIC4表現之影響 58 3.5.1 分析CLIC4 promoter中是否存在G-quadruplex 58 3.5.2 比較三段PG4s對於CLIC4表現之重要性 59 3.5.3 以G4穩定劑穩定PG4-3結構對CLIC4表現的影響 59 3.5.4 破壞或穩定PG4-3之G4結構對CLIC4表現的影響 60 3.5.5於較長的promoter中觀察PG4-3對CLIC4轉錄的影響 61 3.6 以CRISPR編輯genome中CLIC4 PG4-3序列 62 3.6.1 挑選出triple-positive cell clone 62 3.6.2 挑選出triple negative cell clone 65 3.7 CLIC4表現量與其甲基化之相關性 67 3.7.1 分析不同癌細胞株中CLIC4表現量 67 3.7.2 分析不同細胞株中CLIC4 promoter甲基化程度 67 3.8不同調控機制間是否互相影響? 69 3.8.1 甲基化是否影響G4穩定性？ 69 3.8.2 G4是否影響轉錄因子結合？ 69 第四章 討論 73 4.1 TGF-β於不同細胞的影響 73 4.2 CLIC4之可能的轉錄因子 76 4.3 G4對於CLIC4表現的影響 79 4.3.1 CLIC4 promoter中可能還有其他G4存在 79 4.3.2 G4穩定劑可能的影響 80 4.3.3 PG4-3有利於CLIC4表現 81 4.4 CLIC4 promoter甲基化修飾的重要性 83 4.5 甲基化修飾與G4結構的關係 84 4.6 PG4-3影響CLIC4表現可能的機制 86 第五章 結論 88 第六章 未來研究方向 90 附圖 93 圖表 104 參考文獻 191 | |
| dc.language.iso | zh-TW | |
| dc.subject | CRISPR/Cas9 | zh_TW |
| dc.subject | TGF-β | zh_TW |
| dc.subject | myofibroblast | zh_TW |
| dc.subject | 啟動子 | zh_TW |
| dc.subject | 轉錄因子 | zh_TW |
| dc.subject | G-quadruplex | zh_TW |
| dc.subject | 甲基化 | zh_TW |
| dc.subject | CRISPR/Cas9 | en |
| dc.subject | myofibroblast | en |
| dc.subject | TGF-β | en |
| dc.subject | promoter | en |
| dc.subject | transcription factor | en |
| dc.subject | G-quadruplex | en |
| dc.subject | DNA methylation | en |
| dc.title | 氯離子通道蛋白CLIC4基因之調控機轉探討 | zh_TW |
| dc.title | The Regulatory Mechanisms Involved in CLIC4 Gene Expression | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 楊維中,蔡翠敏,李銘仁,吳?承 | |
| dc.subject.keyword | myofibroblast,TGF-β,啟動子,轉錄因子,G-quadruplex,甲基化,CRISPR/Cas9, | zh_TW |
| dc.subject.keyword | myofibroblast,TGF-β,promoter,transcription factor,G-quadruplex,DNA methylation,CRISPR/Cas9, | en |
| dc.relation.page | 200 | |
| dc.identifier.doi | 10.6342/NTU201802204 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-07-31 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| dc.date.embargo-lift | 2023-08-17 | - |
| 顯示於系所單位： | 生化科技學系 | |
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