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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李文森(Wen-Sen Lee) | |
| dc.contributor.author | Hsu-Chen Lin | en |
| dc.contributor.author | 林栩禎 | zh_TW |
| dc.date.accessioned | 2021-06-14T17:17:33Z | - |
| dc.date.available | 2016-10-05 | |
| dc.date.copyright | 2011-10-05 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-08-11 | |
| dc.identifier.citation | 1. Council, N.R., Recommended Dietary Allowances. 10th ed. 1989, Washington, D.C.: National Academy Press. 150-8.
2. Camilo, E., et al., Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology, 1996. 110(4): p. 991-8. 3. Litwack, G.e.a., Folic acid and folates. Vitam Horm, 2008. 79. 4. Sauberlich, H.E., Bioavailability of vitamins. Prog Food Nutr Sci, 1985. 9(1-2): p. 1-33. 5. Bottiglieri T, C.R., Reynolds EH, Folate and neuropsychiatry. In: Bailey LB, ed. Folate in health and disease. 1995, New York: : Marcel Dekker. 6. Verhaar, M.C., et al., Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial. Circulation, 1999. 100(4): p. 335-8. 7. Reynolds, E.H., Benefits and risks of folic acid to the nervous system. J Neurol Neurosurg Psychiatry, 2002. 72(5): p. 567-71. 8. Lonn, E., et al., Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med, 2006. 354(15): p. 1567-77. 9. Kim, Y.I., Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem, 1999. 10(2): p. 66-88. 10. Choi, S.W. and J.B. Mason, Folate status: effects on pathways of colorectal carcinogenesis. J Nutr, 2002. 132(8 Suppl): p. 2413S-2418S. 11. Lashner, B.A., Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol, 1993. 119(9): p. 549-54. 12. Novakovic, P., et al., Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis, 2006. 27(5): p. 916-24. 13. Crott, J.W., et al., Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines. J Nutr Biochem, 2008. 19(5): p. 328-35. 14. Pellis, L., et al., High folic acid increases cell turnover and lowers differentiation and iron content in human HT29 colon cancer cells. Br J Nutr, 2008. 99(4): p. 703-8. 15. Attias, Z., H. Werner, and N. Vaisman, Folic acid and its metabolites modulate IGF-I receptor gene expression in colon cancer cells in a p53-dependent manner. Endocr Relat Cancer, 2006. 13(2): p. 571-81. 16. Duthie, S.J., Folic-acid-mediated inhibition of human colon-cancer cell growth. Nutrition, 2001. 17(9): p. 736-7. 17. Nagothu, K.K., et al., Folic acid-mediated inhibition of serum-induced activation of EGFR promoter in colon cancer cells. Am J Physiol Gastrointest Liver Physiol, 2004. 287(3): p. G541-6. 18. Kim, Y.I., Folate and colorectal cancer: An evidence-based critical review. Mol Nutr Food Res, 2007. 51(3): p. 267-92. 19. Risau, W., Mechanisms of angiogenesis. Nature, 1997. 386(6626): p. 671-4. 20. Folkman, J., Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med, 1995. 1(1): p. 27-31. 21. Bussolati, B., et al., Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide. Am J Pathol, 2001. 159(3): p. 993-1008. 22. Papetti, M. and I.M. Herman, Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol, 2002. 282(5): p. C947-70. 23. Hendrix, M.J., et al., Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer, 2003. 3(6): p. 411-21. 24. Folberg, R. and A.J. Maniotis, Vasculogenic mimicry. APMIS, 2004. 112(7-8): p. 508-25. 25. Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med, 1971. 285(21): p. 1182-6. 26. Harris, A.L., Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer, 2002. 2(1): p. 38-47. 27. Hartwell, L.H., J. Culotti, and B. Reid, Genetic control of the cell-division cycle in yeast. I. Detection of mutants. Proc Natl Acad Sci U S A, 1970. 66(2): p. 352-9. 28. Alberts, B., et al., Molecular Biology of the Cell 4th ed. 2002, New York: Garland Science. 29. Xiong, Y., et al., p21 is a universal inhibitor of cyclin kinases. Nature, 1993. 366(6456): p. 701-4. 30. Toyoshima, H. and T. Hunter, p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell, 1994. 78(1): p. 67-74. 31. Fischer, P.M. and D.P. Lane, Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. Curr Med Chem, 2000. 7(12): p. 1213-45. 32. Sandhu, C. and J. Slingerland, Deregulation of the cell cycle in cancer. Cancer Detect Prev, 2000. 24(2): p. 107-18. 33. Bloom, J. and M. Pagano, Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin Cancer Biol, 2003. 13(1): p. 41-7. 34. Pages, G., et al., Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci U S A, 1993. 90(18): p. 8319-23. 35. Lopez-Ilasaca, M., Signaling from G-protein-coupled receptors to mitogen-activated protein (MAP)-kinase cascades. Biochem Pharmacol, 1998. 56(3): p. 269-77. 36. Seger, R. and E.G. Krebs, The MAPK signaling cascade. FASEB J, 1995. 9(9): p. 726-35. 37. Whalen, A.M., et al., Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase. Mol Cell Biol, 1997. 17(4): p. 1947-58. 38. Jung, G.A., et al., Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras-ERK-p21Cip/WAF1 pathway. BMC Cell Biol, 2008. 9: p. 66. 39. Kim, D.I., et al., Requirement for Ras/Raf/ERK pathway in naringin-induced G1-cell-cycle arrest via p21WAF1 expression. Carcinogenesis, 2008. 29(9): p. 1701-9. 40. Lee, E.J., et al., Naringin-induced p21WAF1-mediated G(1)-phase cell cycle arrest via activation of the Ras/Raf/ERK signaling pathway in vascular smooth muscle cells. Food Chem Toxicol, 2008. 46(12): p. 3800-7. 41. Moshal, K.S., et al., Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway. Am J Physiol Cell Physiol, 2006. 290(3): p. C883-91. 42. Stroes, E.S., et al., Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res, 2000. 86(11): p. 1129-34. 43. Doshi, S.N., et al., Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation, 2002. 105(1): p. 22-6. 44. 蘇怡帆, BJ-FA 對於人類血管內皮細胞的生長抑制作用及分子機轉. 2004, 台北醫學大學: Taipei. 45. Ho, P.Y., et al., Inhibition of human vascular endothelial cells proliferation by terbinafine. Int J Cancer, 2004. 111(1): p. 51-9. 46. Hsu, S.P., et al., Progesterone inhibits human endothelial cell proliferation through a p53-dependent pathway. Cell Mol Life Sci, 2008. 65(23): p. 3839-50. 47. el-Deiry, W.S., et al., WAF1, a potential mediator of p53 tumor suppression. Cell, 1993. 75(4): p. 817-25. 48. Lodish, H., et al., Molecular Cell Biology. 6 ed. 2008, New York, USA: Sara Tenney. 49. Duncia, J.V., et al., MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett, 1998. 8(20): p. 2839-44. 50. Gysin, S., et al., Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res, 2005. 65(11): p. 4870-80. 51. Migliaccio, A., et al., Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J, 1998. 17(7): p. 2008-18. 52. Evans, J., et al., Prokineticin 1 signaling and gene regulation in early human pregnancy. Endocrinology, 2008. 149(6): p. 2877-87. 53. van der Molen, E.F., et al., The effect of folic acid on the homocysteine metabolism in human umbilical vein endothelial cells (HUVECs). Eur J Clin Invest, 1996. 26(4): p. 304-9. 54. Verhaar, M.C., et al., 5-methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation, 1998. 97(3): p. 237-41. 55. Leamon, C.P. and A.L. Jackman, Exploitation of the folate receptor in the management of cancer and inflammatory disease. Vitam Horm, 2008. 79: p. 203-33. 1. Council, N.R., Recommended Dietary Allowances. 10th ed. 1989, Washington, D.C.: National Academy Press. 150-8. 2. Camilo, E., et al., Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology, 1996. 110(4): p. 991-8. 3. Litwack, G.e.a., Folic acid and folates. Vitam Horm, 2008. 79. 4. Sauberlich, H.E., Bioavailability of vitamins. Prog Food Nutr Sci, 1985. 9(1-2): p. 1-33. 5. Bottiglieri T, C.R., Reynolds EH, Folate and neuropsychiatry. In: Bailey LB, ed. Folate in health and disease. 1995, New York: : Marcel Dekker. 6. Verhaar, M.C., et al., Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial. Circulation, 1999. 100(4): p. 335-8. 7. Reynolds, E.H., Benefits and risks of folic acid to the nervous system. J Neurol Neurosurg Psychiatry, 2002. 72(5): p. 567-71. 8. Lonn, E., et al., Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med, 2006. 354(15): p. 1567-77. 9. Kim, Y.I., Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem, 1999. 10(2): p. 66-88. 10. Choi, S.W. and J.B. Mason, Folate status: effects on pathways of colorectal carcinogenesis. J Nutr, 2002. 132(8 Suppl): p. 2413S-2418S. 11. Lashner, B.A., Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol, 1993. 119(9): p. 549-54. 12. Novakovic, P., et al., Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis, 2006. 27(5): p. 916-24. 13. Crott, J.W., et al., Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines. J Nutr Biochem, 2008. 19(5): p. 328-35. 14. Pellis, L., et al., High folic acid increases cell turnover and lowers differentiation and iron content in human HT29 colon cancer cells. Br J Nutr, 2008. 99(4): p. 703-8. 15. Attias, Z., H. Werner, and N. Vaisman, Folic acid and its metabolites modulate IGF-I receptor gene expression in colon cancer cells in a p53-dependent manner. Endocr Relat Cancer, 2006. 13(2): p. 571-81. 16. Duthie, S.J., Folic-acid-mediated inhibition of human colon-cancer cell growth. Nutrition, 2001. 17(9): p. 736-7. 17. Nagothu, K.K., et al., Folic acid-mediated inhibition of serum-induced activation of EGFR promoter in colon cancer cells. Am J Physiol Gastrointest Liver Physiol, 2004. 287(3): p. G541-6. 18. Kim, Y.I., Folate and colorectal cancer: An evidence-based critical review. Mol Nutr Food Res, 2007. 51(3): p. 267-92. 19. Risau, W., Mechanisms of angiogenesis. Nature, 1997. 386(6626): p. 671-4. 20. Folkman, J., Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med, 1995. 1(1): p. 27-31. 21. Bussolati, B., et al., Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide. Am J Pathol, 2001. 159(3): p. 993-1008. 22. Papetti, M. and I.M. Herman, Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol, 2002. 282(5): p. C947-70. 23. Hendrix, M.J., et al., Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer, 2003. 3(6): p. 411-21. 24. Folberg, R. and A.J. Maniotis, Vasculogenic mimicry. APMIS, 2004. 112(7-8): p. 508-25. 25. Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med, 1971. 285(21): p. 1182-6. 26. Harris, A.L., Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer, 2002. 2(1): p. 38-47. 27. Hartwell, L.H., J. Culotti, and B. Reid, Genetic control of the cell-division cycle in yeast. I. Detection of mutants. Proc Natl Acad Sci U S A, 1970. 66(2): p. 352-9. 28. Alberts, B., et al., Molecular Biology of the Cell 4th ed. 2002, New York: Garland Science. 29. Xiong, Y., et al., p21 is a universal inhibitor of cyclin kinases. Nature, 1993. 366(6456): p. 701-4. 30. Toyoshima, H. and T. Hunter, p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell, 1994. 78(1): p. 67-74. 31. Fischer, P.M. and D.P. Lane, Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. Curr Med Chem, 2000. 7(12): p. 1213-45. 32. Sandhu, C. and J. Slingerland, Deregulation of the cell cycle in cancer. Cancer Detect Prev, 2000. 24(2): p. 107-18. 33. Bloom, J. and M. Pagano, Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin Cancer Biol, 2003. 13(1): p. 41-7. 34. Pages, G., et al., Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci U S A, 1993. 90(18): p. 8319-23. 35. Lopez-Ilasaca, M., Signaling from G-protein-coupled receptors to mitogen-activated protein (MAP)-kinase cascades. Biochem Pharmacol, 1998. 56(3): p. 269-77. 36. Seger, R. and E.G. Krebs, The MAPK signaling cascade. FASEB J, 1995. 9(9): p. 726-35. 37. Whalen, A.M., et al., Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase. Mol Cell Biol, 1997. 17(4): p. 1947-58. 38. Jung, G.A., et al., Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras-ERK-p21Cip/WAF1 pathway. BMC Cell Biol, 2008. 9: p. 66. 39. Kim, D.I., et al., Requirement for Ras/Raf/ERK pathway in naringin-induced G1-cell-cycle arrest via p21WAF1 expression. Carcinogenesis, 2008. 29(9): p. 1701-9. 40. Lee, E.J., et al., Naringin-induced p21WAF1-mediated G(1)-phase cell cycle arrest via activation of the Ras/Raf/ERK signaling pathway in vascular smooth muscle cells. Food Chem Toxicol, 2008. 46(12): p. 3800-7. 41. Moshal, K.S., et al., Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway. Am J Physiol Cell Physiol, 2006. 290(3): p. C883-91. 42. Stroes, E.S., et al., Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res, 2000. 86(11): p. 1129-34. 43. Doshi, S.N., et al., Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation, 2002. 105(1): p. 22-6. 44. 蘇怡帆, BJ-FA 對於人類血管內皮細胞的生長抑制作用及分子機轉. 2004, 台北醫學大學: Taipei. 45. Ho, P.Y., et al., Inhibition of human vascular endothelial cells proliferation by terbinafine. Int J Cancer, 2004. 111(1): p. 51-9. 46. Hsu, S.P., et al., Progesterone inhibits human endothelial cell proliferation through a p53-dependent pathway. Cell Mol Life Sci, 2008. 65(23): p. 3839-50. 47. el-Deiry, W.S., et al., WAF1, a potential mediator of p53 tumor suppression. Cell, 1993. 75(4): p. 817-25. 48. Lodish, H., et al., Molecular Cell Biology. 6 ed. 2008, New York, USA: Sara Tenney. 49. Duncia, J.V., et al., MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett, 1998. 8(20): p. 2839-44. 50. Gysin, S., et al., Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res, 2005. 65(11): p. 4870-80. 51. Migliaccio, A., et al., Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J, 1998. 17(7): p. 2008-18. 52. Evans, J., et al., Prokineticin 1 signaling and gene regulation in early human pregnancy. Endocrinology, 2008. 149(6): p. 2877-87. 53. van der Molen, E.F., et al., The effect of folic acid on the homocysteine metabolism in human umbilical vein endothelial cells (HUVECs). Eur J Clin Invest, 1996. 26(4): p. 304-9. 54. Verhaar, M.C., et al., 5-methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation, 1998. 97(3): p. 237-41. 55. Leamon, C.P. and A.L. Jackman, Exploitation of the folate receptor in the management of cancer and inflammatory disease. Vitam Horm, 2008. 79: p. 203-33. 56. Salazar, M.D. and M. Ratnam, The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer Metastasis Rev, 2007. 26(1): p. 141-52. 57. Leamon, C.P., Folate-targeted drug strategies for the treatment of cancer. Curr Opin Investig Drugs, 2008. 9(12): p. 1277-86. 58. el-Deiry, W.S., et al., WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res, 1994. 54(5): p. 1169-74. 59. Chen, J., et al., Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA. Nature, 1995. 374(6520): p. 386-8. 60. Voisin, L., et al., Genetic demonstration of a redundant role of extracellular signal-regulated kinase 1 (ERK1) and ERK2 mitogen-activated protein kinases in promoting fibroblast proliferation. Mol Cell Biol, 2010. 30(12): p. 2918-32. 61. Xing, J., et al., Src regulates cell cycle protein expression and renal epithelial cell proliferation via PI3K/Akt signaling-dependent and -independent mechanisms. Am J Physiol Renal Physiol, 2008. 295(1): p. F145-52. 62. Hawthorne, V.S., et al., ErbB2-mediated Src and signal transducer and activator of transcription 3 activation leads to transcriptional up-regulation of p21Cip1 and chemoresistance in breast cancer cells. Mol Cancer Res, 2009. 7(4): p. 592-600. 63. Cayer, M.P., et al., c-Src tyrosine kinase co-associates with and phosphorylates signal transducer and activator of transcription 5b which mediates the proliferation of normal human B lymphocytes. Clin Exp Immunol, 2009. 156(3): p. 419-27. 64. Miotti, S., et al., Interaction of folate receptor with signaling molecules lyn and G(alpha)(i-3) in detergent-resistant complexes from the ovary carcinoma cell line IGROV1. J Cell Sci, 2000. 113 Pt 2: p. 349-57. 65. Ashokkumar, B., et al., Effect of folate oversupplementation on folate uptake by human intestinal and renal epithelial cells. Am J Clin Nutr, 2007. 86(1): p. 159-66. 66. Zhang, X.M., et al., Folate stimulates ERK1/2 phosphorylation and cell proliferation in fetal neural stem cells. Nutr Neurosci, 2009. 12(5): p. 226-32. 67. Hartmann, L.C., et al., Folate receptor overexpression is associated with poor outcome in breast cancer. Int J Cancer, 2007. 121(5): p. 938-42. 68. Basal, E., et al., Functional folate receptor alpha is elevated in the blood of ovarian cancer patients. PLoS One, 2009. 4(7): p. e6292. 69. Steinfeld, R., et al., Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet, 2009. 85(3): p. 354-63. 70. Bille, C., et al., Autoantibodies to folate receptor alpha during early pregnancy and risk of oral clefts in Denmark. Pediatr Res, 2010. 67(3): p. 274-9. 71. de Haan, W., A folate receptor defect that causes treatable neurological disorder in children. Clin Genet, 2010. 77(5): p. 435-6. 72. Pisano, M.M., et al., Novel folate binding protein-1 interactions in embryonic orofacial tissue. Life Sci, 2010. 86(7-8): p. 275-80. 73. Puig-Kroger, A., et al., Folate receptor beta is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-inflammatory/regulatory macrophages. Cancer Res, 2009. 69(24): p. 9395-403. 74. van der Heijden, J.W., et al., Folate receptor beta as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients. Arthritis Rheum, 2009. 60(1): p. 12-21. 75. Xia, W., et al., A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages. Blood, 2009. 113(2): p. 438-46. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/41109 | - |
| dc.description.abstract | 本篇研究計畫主要探討水溶性維生素葉酸（Folic Acid）抑制人類臍靜脈內皮細胞（Human umbilical vein endothelial cell, HUVEC）生長作用的可能分子機轉。近年來，在癌症的相關研究當中，藉由抑制血管新生（Angiogenesis）進而抑制腫瘤生長的研究相當受到重視。研究發現，許多抑制血管新生的化合物不但能有效抑制癌細胞的生長，且具有相對較低的副作用。在本實驗室先前的研究證實，葉酸對於人類臍靜脈內皮細胞生長具有抑制的作用，且此抑制作用是透過影響細胞的細胞週期而達成。葉酸能促使人類臍靜脈內皮細胞的細胞週期停滯於G0/G1期，且主要是透過增加細胞週期停滯相關蛋白P21及P27的表現。本研究延續先前實驗室的發現，進一步釐清葉酸抑制人類臍靜脈內皮細胞生長作用的分子機轉。在本研究中，利用Western Blot（WB）的實驗分析證實，葉酸能夠去刺激P21的蛋白表現，且增加的效果和葉酸的劑量呈現正相關。而利用Luciferase Activity Assay以及RT-PCR的分析也分別發現葉酸能夠去促進p21 promoter的活性和p21 mRNA的表現量。更深入觀察細胞內的訊息傳遞路徑，在給予葉酸刺激的早期便會促進ERK蛋白的磷酸化。進一步利用給予ERK抑制劑U0126和Transfect dominant negative ERK2（DN-ERK2）兩種方式阻斷ERK的訊息傳遞路徑，並利用WB和3H-Thymidine Incorporation觀察阻斷ERK的訊息傳遞路徑後p21蛋白的表現量和細胞DNA 合成量的多寡。實驗證實，經由兩種方式抑制阻斷ERK的訊息傳遞路徑都會使葉酸促進P21蛋白的表現量增加以及抑制DNA合成的作用消失。最後，我們也發現，利用Transfect DN-ERK2方式阻斷ERK的訊息傳遞路徑，會使得葉酸促進p21 promoter活性的作用消失。經由以上實驗結果可以初步的推估，葉酸對人類臍靜脈內皮細胞生長的影響是經由ERK調控的途徑去促進p21 promoter活性，進一步促進p21 mRNA和P21蛋白的表現量，而導致細胞增生的抑制作用。 | zh_TW |
| dc.description.abstract | The main purpose of this study is to investigate the underlying molecule mechanisms folic Acid–induced anti-proliferation effect on human umbilical vein endothelial cells (HUVEC). Recently, anti-angiogenesis has been considered to be an alternative strategy on cancer therapy. Seveal compounds with anti-angiogenic activity have been demonstrated to exert an anti-cancer activity with fewer side effects. In our lab, we have previously found that folic acid inhibits angiogenesis through arresting the cell cycle of human umbilical vein endothelial cell. We demonstrated that folic acid increased the levels of p21 and p27 protein, which caused a decrease of CDK2 activity, and finally arrested the cell cycle at the G0/G1 phase. Here, we reported that folic acid dose-dependently increased the levels of p21 protein. Luciferase activity assay and RT-PCR demonstrated that folic acid induced the p21 promoter activity and mRNA level. Moreover, the levels of phosphorylated ERK protein were increased at 5 min after folic acid treatment. Blockade of the ERK pathway by ERK inhibitor (U0126) or dominant ERK2 (DN-ERK2) transfection prevented the folic acid-induced increases of p21 protein and promoter activity, and inhibition of DNA synthesis. The present study demonstrated that folic acid increased the p21 transcription though an ERK-dependent pathway. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-14T17:17:33Z (GMT). No. of bitstreams: 1 ntu-100-R96441012-1.pdf: 2348848 bytes, checksum: 78de6b785cd90162e025cb78919d4bca (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 中文摘要 ...................................................................................................................... - 1 -
Abstract ......................................................................................................................... - 2 - 圖目錄 .......................................................................................................................... - 5 - 表目錄 .......................................................................................................................... - 6 - 壹、 研究背景 ............................................................................................................. - 7 - 壹-1葉酸 ................................................................................................................ - 7 - 壹-2血管新生 ........................................................................................................ - 9 - 壹-3細胞週期 ...................................................................................................... - 11 - 壹-4 erk（Extracellular signal-regulated protein kinase） .................................. - 12 - 壹-5研究動機 ...................................................................................................... - 12 - 貳、 研究材料與方法 ............................................................................................... - 14 - 貳-1常用試劑與儀器 .......................................................................................... - 14 - 貳-2細胞培養 ...................................................................................................... - 17 - 貳-3 p53 RNA interference .................................................................................. - 19 - 貳-4 Dominant Negative ERK2 Plasmid Transfection ......................................... - 20 - 貳-5西方墨點法 .................................................................................................. - 22 - 貳-6免疫沉澱法（Immunoprecipitation） ........................................................ - 26 - 貳-7 3H-thymidine incorporation ......................................................................... - 28 - 貳-8 RT-PCR（Reverse Transcription Polymerase Chain Reaction） ............... - 30 - 貳-9 Promoter activity assay (Luciferase Assay) ................................................. - 32 - 貳-10 immunoflurocant ........................................................................................ - 34 - 參、實驗結果分析. ................................................................................................... - 35 - 參-1 p21蛋白的表現量與葉酸給予的濃度呈現正相關 ................................... - 35 - 參-2葉酸透過影響p21的轉錄來改變p21蛋白的表現量 .............................. - 35 - 參-3葉酸影響p21蛋白表現的作用是一種p53-dependent的路徑 ................ - 36 - 參-4葉酸促進p21蛋白表現及抑制DNA合成的作用是經由ERK所調控 . - 37 - 參-5葉酸促進p21蛋白表現的可能途徑為：hRFC-pSrc→pERK→P21 promoter→P21 mRNA→P21 protein.............................................................................. - 39 - 肆、 討論 ................................................................................................................... - 54 - 伍、 參考文獻 ........................................................................................................... - 59 - 陸、 附錄 ................................................................................................................... - 66 - | |
| dc.language.iso | zh-TW | |
| dc.title | 葉酸調控人類臍靜脈內皮細胞p21蛋白表現之分子機轉 | zh_TW |
| dc.title | The molecular mechanism of folic acid-induced up-regulation of p21 protein in human umbilical vein endothelial cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 張國柱(Kuo-Chu Chang) | |
| dc.contributor.oralexamcommittee | 林時宜,阮淑慧 | |
| dc.subject.keyword | 葉酸,P21蛋白,ERK,人類臍靜脈內皮細胞,細胞週期, | zh_TW |
| dc.subject.keyword | Folic acid,P21,ERK,HUVEC,Cell cycle, | en |
| dc.relation.page | 70 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-08-12 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生理學研究所 | zh_TW |
| 顯示於系所單位： | 生理學科所 | |
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