進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-1905201715175400
論文名稱(中文) 探討在慢性骨髓性白血病(CML)中核醣體蛋白S6激酶1(S6K1)對於順鉑抗藥性(cisplatin resistance)所扮演的角色
論文名稱(英文) The role of ribosomal protein S6 kinase 1(S6K1) on cisplatin resistance in chronic myeloid leukemia (CML)
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 105
學期 2
出版年 106
研究生(中文) 蕭綾儀
研究生(英文) Ling-Yi Xiao
學號 S58981476
學位類別 博士
語文別 英文
論文頁數 138頁
口試委員 指導教授-簡偉明
口試委員-呂增宏
口試委員-黃金鼎
口試委員-賴明德
口試委員-馬明琪
中文關鍵字 慢性骨髓性白血病  環磷酸腺苷  核糖體蛋白S6激酶1  p53蛋白 
英文關鍵字 CML  cAMP  S6K1  p53  cisplatin 
學科別分類
中文摘要 95%慢性骨髓性白血病 (chronic myeloid leukemia, CML)病人皆帶有BCR-ABL融合基因。BCR-ABL融合基因酪氨酸激酶抑制劑 (tyrosine kinase inhibitors, TKIs)成為治療慢性骨髓性白血病標靶藥物,但復發的或在急性轉化期 (blast crisis phase, BC phase)的病人對於此抑制劑並無反應或產生抗藥性。因而尋找不同的治療方法對於治療慢性骨髓性白血病還是重要的。環磷酸腺苷(cyclic AMP, cAMP)可藉由調控核糖體蛋白S6激酶1 ( ribosomal protein S6 Kinase 1, S6K1)影響細胞增生。另外,抑癌基因p53的表現除了與慢性骨髓性白血病的病程相關和抗藥性也有間接關係。所以此篇研究的目的在於探討環磷酸腺苷、核糖體蛋白S6激酶1和p53三者的關係是否影響化療藥物對於慢性骨髓性白血病細胞的毒性。我們利用環磷酸腺苷促效劑(cAMP agonists)增加環磷酸腺苷濃度後,發現慢性骨髓性白血病細胞產生對化療藥物cisplatin的抗藥性。接著,我們分別利用蛋白激酶A(protein kinase A, PKA)和環磷酸腺苷激活蛋白( exchange protein directly activated by cAMP, EPAC)活化劑得知環磷酸腺苷是藉由蛋白激酶A調控cisplatin抗藥性。我們也看到增加環磷酸腺苷後造成磷酸化核糖體蛋白S6激酶1和核醣體蛋白S6(ribosomal protein S6, RPS6)程度下降。同時,藉由磷酸化核糖體蛋白S6激酶1抑制劑以及基因減量(knockdown)證實當磷酸化核糖體蛋白S6激酶1受到抑制時會造成cisplatin抗藥性。而S6K1則是藉由調控DNA-dependent protein kinase, catalytic subunit (DNA-PKcs), H2A histone family member X (H2AX)和Poly ADP-ribose polymerase (PARP) 而造成cisplatin 抗藥性。除此之外,p53在慢性骨髓性白血病細胞的表現量則會影響核糖體蛋白S6激酶1所調控的cisplatin抗藥性現象。綜合以上,當慢性骨髓性白血病人在使用化療藥物進行治療時必須考慮環磷酸腺苷的濃度。更重要的是我們發現p53的表現對於是否欲選擇核糖體蛋白S6激酶1抑制劑作為化療藥物的佐劑(adjuvant agent)是很重要的。
英文摘要 More than 95% chronic myeloid leukemia (CML) patients carry the constitutively activated tyrosine kinase, BCR-ABL fusion protein. Therefore, tyrosine kinase inhibitors (TKIs) are designed for CML treatment. However, some patients have no response to TKIs especially for those patients with relapsed or diagnosed at blast crisis (BC) phase. Thus, it is needed for developing alternative approaches for CML treatment. Cyclic AMP (cAMP) regulates cell proliferation via ribosomal protein S6 kinase 1 (S6K1). The expression of tumor suppressor gene, p53, is involved in the disease progression and affects drug resistance in CML. The purpose of our study is to investigate whether the relationship between cAMP, S6K1 and p53 in drug resistance in CML cells. We observed that increased level of cAMP conferred cisplatin resistance in CML cells. From the experiments of the activators of protein kinase A (PKA) and exchange protein directly by cAMP (EPAC), we observed that PKA is the effector on cAMP-induced cisplatin resistance. We also found that increased level in cAMP reduced the formation of pS6K1 and pRPS6. Furthermore, inhibition and knockdown of S6K1 lead to cisplatin resistance in CML cells. Next, we observed that S6K1 acts via DNA-PKcs, H2AX and PARP regulating cisplatin resistance. Last but not the least, p53 expression attenuates the effect of S6K1 on cisplatin resistance in CML cells. In conclusion, the level of cAMP should be considered when choosing chemotherapeutic drug such as cisplatin for CML treatment. More importantly, we suggest that p53 expression is crucial for choosing the inhibitor of S6K1 signaling pathway as the adjuvant agent with chemotherapeutic drug in CML treatment.
論文目次 摘要 i
Abstract ii
致謝 iii
Contents iv
List of Figures v
Abbreviations x
Introduction 1
Experimental Designs 11
Specific Aims 12
Materials and Method 16
Results 21
Conclusion 36
Discussion 37
References 45
Figures 54
Publications 125
參考文獻 1. Handbook of Chronic Myeloid Leukemia. (2014).
2. M. W. Deininger, J. M. Goldman, J. V. Melo, The molecular biology of chronic myeloid leukemia. Blood 96, 3343-3356 (2000).
3. M. Baccarani, F. Castagnetti, G. Gugliotta, F. Palandri, G. Rosti, Treatment recommendations for chronic myeloid leukemia. Mediterr J Hematol Infect Dis 6, e2014005 (2014).
4. J. Kuroda, Y. Shimura, M. Yamamoto-Sugitani, N. Sasaki, M. Taniwaki, Multifaceted mechanisms for cell survival and drug targeting in chronic myelogenous leukemia. Current cancer drug targets 13, 69-79 (2013).
5. CANCER REGISTRY ANNUAL REPORT, 2013 TAIWAN. 衛生福利部, (2016).
6. C. S. Chang, Y. H. Yang, C. N. Hsu, M. T. Lin, Trends in the treatment changes and medication persistence of chronic myeloid leukemia in Taiwan from 1997 to 2007: a longitudinal population database analysis. BMC health services research 12, 359 (2012).
7. C. Fava, A. Morotti, I. Dogliotti, G. Saglio, G. Rege-Cambrin, Update on emerging treatments for chronic myeloid leukemia. Expert opinion on emerging drugs 20, 183-196 (2015).
8. I. Skorta et al., Imatinib mesylate induces cisplatin hypersensitivity in Bcr-Abl+ cells by differential modulation of p53 transcriptional and proapoptotic activity. Cancer research 69, 9337-9345 (2009).
9. A. J. Tipping et al., Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 16, 2349-2357 (2002).
10. H. S. Coskun, S. S. Goksu, M. Sahin, G. Alanoglu, Bleomycin, etoposide and cisplatin (BEP) combination with concurrent imatinib mesylate (GLEEVEC) in chronic myeloid leukemia (CML) patient with mesenchymal tumor. Medical oncology 25, 110-112 (2008).
11. Y. Wei, K. K. To, S. C. Au-Yeung, Synergistic cytotoxicity from combination of imatinib and platinum-based anticancer drugs specifically in Bcr-Abl positive leukemia cells. Journal of pharmacological sciences 129, 210-215 (2015).
12. Lobaplatin: D 19466. Drugs in R&D 4, 369-372 (2003).
13. E. Paietta, K. Mittermayer, J. Schwarzmeier, Proliferation kinetics and cyclic AMP as prognostic factors in adult acute leukemia. Cancer 46, 102-108 (1980).
14. G. Tortora et al., Site-selective cAMP analogs at micromolar concentrations induce growth arrest and differentiation of acute promyelocytic, chronic myelocytic, and acute lymphocytic human leukemia cell lines. Blood 71, 230-233 (1988).
15. M. N. Weitzmann, N. Savage, Cyclic adenosine 3',5'-monophosphate, a second messenger in interleukin-1 mediated K562 cytostasis. Biochemical and biophysical research communications 190, 564-570 (1993).
16. E. M. Weissinger et al., Activation of protein kinase A (PKA) by 8-Cl-cAMP as a novel approach for antileukaemic therapy. British journal of cancer 91, 186-192 (2004).
17. H. O. Pae et al., Increased intracellular cAMP renders HL-60 cells resistant to cytotoxicity of taxol. Immunopharmacology and immunotoxicology 21, 233-245 (1999).
18. B. M. Choi et al., Cyclic adenosine monophosphate inhibits ursolic acid-induced apoptosis via activation of protein kinase A in human leukaemic HL-60 cells. Pharmacol Toxicol 86, 53-58 (2000).
19. G. Gausdal et al., Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis. Cell death & disease 4, e516 (2013).
20. C. Chin et al., Radiosensitization by targeting radioresistance-related genes with protein kinase A inhibitor in radioresistant cancer cells. Experimental & molecular medicine 37, 608-618 (2005).
21. M. Safa et al., Inhibitory role of cAMP on doxorubicin-induced apoptosis in pre-B ALL cells through dephosphorylation of p53 serine residues. Apoptosis : an international journal on programmed cell death 15, 196-203 (2010).
22. A. Fatemi, A. Kazemi, M. Kashiri, M. Safa, Elevation of cAMP Levels Inhibits Doxorubicin-Induced Apoptosis in Pre- B ALL NALM- 6 Cells Through Induction of BAD Phosphorylation and Inhibition of P53 Accumulation. Int J Mol Cell Med 4, 94-102 (2015).
23. B. F. Bahrami, P. Ataie-Kachoie, M. H. Pourgholami, D. L. Morris, p70 Ribosomal protein S6 kinase (Rps6kb1): an update. Journal of clinical pathology 67, 1019-1025 (2014).
24. Y. Zhang et al., Signal transduction pathways involved in phosphorylation and activation of p70S6K following exposure to UVA irradiation. The Journal of biological chemistry 276, 20913-20923 (2001).
25. R. L. Yamnik et al., S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. The Journal of biological chemistry 284, 6361-6369 (2009).
26. E. K. Kim et al., Phosphorylated S6K1 is a possible marker for endocrine therapy resistance in hormone receptor-positive breast cancer. Breast cancer research and treatment 126, 93-99 (2011).
27. L. Zhou, Y. Huang, J. Li, Z. Wang, The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Medical oncology 27, 255-261 (2010).
28. H. M. Ismail, Overexpression of s6 kinase 1 in brain tumours is associated with induction of hypoxia-responsive genes and predicts patients' survival. Journal of oncology 2012, 416927 (2012).
29. U. Akar et al., Targeting p70S6K prevented lung metastasis in a breast cancer xenograft model. Molecular cancer therapeutics 9, 1180-1187 (2010).
30. C. X. Bian et al., P70S6K 1 regulation of angiogenesis through VEGF and HIF-1alpha expression. Biochemical and biophysical research communications 398, 395-399 (2010).
31. W. H. Lee et al., Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1alpha activity through p70 ribosomal S6 kinase-1 inhibition and H2O2-scavenging effect. Molecular cancer therapeutics 8, 2791-2802 (2009).
32. K. R. Park et al., beta-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer letters 312, 178-188 (2011).
33. C. W. Song et al., Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep 2, 362 (2012).
34. H. Kim, J. Park, K. H. Tak, S. Y. Bu, E. Kim, Chemopreventive effects of curcumin on chemically induced mouse skin carcinogenesis in BK5.insulin-like growth factor-1 transgenic mice. In vitro cellular & developmental biology. Animal 50, 883-892 (2014).
35. B. Bilanges, B. Vanhaesebroeck, A new tool to dissect the function of p70 S6 kinase. The Biochemical journal 431, e1-3 (2010).
36. S. E. Hong et al., S6K1 inhibition enhances tamoxifen-induced cell death in MCF-7 cells through translational inhibition of Mcl-1 and survivin. Cell biology and toxicology 29, 273-282 (2013).
37. H. N. Choi et al., Inhibition of S6K1 enhances glucose deprivation-induced cell death via downregulation of anti-apoptotic proteins in MCF-7 breast cancer cells. Biochemical and biophysical research communications 432, 123-128 (2013).
38. Y. B. Khotskaya et al., S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer. American journal of translational research 6, 361-376 (2014).
39. X. Song, A. K. Dilly, S. Y. Kim, H. A. Choudry, Y. J. Lee, Rapamycin-enhanced mitomycin C-induced apoptotic death is mediated through the S6K1-Bad-Bak pathway in peritoneal carcinomatosis. Cell death & disease 5, e1281 (2014).
40. C. Ly, A. F. Arechiga, J. V. Melo, C. M. Walsh, S. T. Ong, Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer research 63, 5716-5722 (2003).
41. J. Li et al., Rapamycin provides a therapeutic option through inhibition of mTOR signaling in chronic myelogenous leukemia. Oncology reports 27, 461-466 (2012).
42. S. Parmar et al., Differential regulation of the p70 S6 kinase pathway by interferon alpha (IFNalpha) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells. Blood 106, 2436-2443 (2005).
43. A. Burchert et al., Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 19, 1774-1782 (2005).
44. P. Yoon et al., Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL-expressing cells. Molecular cancer therapeutics 5, 2815-2823 (2006).
45. H. Honda et al., Acquired loss of p53 induces blastic transformation in p210(bcr/abl)-expressing hematopoietic cells: a transgenic study for blast crisis of human CML. Blood 95, 1144-1150 (2000).
46. H. Ahuja et al., The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia. The Journal of clinical investigation 87, 2042-2047 (1991).
47. A. Rovira et al., P53 tumor suppressor gene in chronic myelogenous leukemia: a sequential study. Annals of hematology 70, 129-133 (1995).
48. L. Stuppia et al., p53 loss and point mutations are associated with suppression of apoptosis and progression of CML into myeloid blastic crisis. Cancer genetics and cytogenetics 98, 28-35 (1997).
49. T. Velasco-Hernandez, C. Vicente-Duenas, I. Sanchez-Garcia, D. Martin-Zanca, p53 restoration kills primitive leukemia cells in vivo and increases survival of leukemic mice. Cell cycle 12, 122-132 (2013).
50. H. G. Wendel et al., Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. Proceedings of the National Academy of Sciences of the United States of America 103, 7444-7449 (2006).
51. Z. Goldberg, Y. Levav, S. Krichevsky, E. Fibach, Y. Haupt, Treatment of chronic myeloid leukemia cells with imatinib (STI571) impairs p53 accumulation in response to DNA damage. Cell cycle 3, 1188-1195 (2004).
52. Z. Ji, F. C. Mei, A. L. Miller, E. B. Thompson, X. Cheng, Protein kinase A (PKA) isoform RIIbeta mediates the synergistic killing effect of cAMP and glucocorticoid in acute lymphoblastic leukemia cells. The Journal of biological chemistry 283, 21920-21925 (2008).
53. E. H. Naderi et al., Bone marrow stroma-derived PGE2 protects BCP-ALL cells from DNA damage-induced p53 accumulation and cell death. Molecular cancer 14, 14 (2015).
54. Z. Ji, F. C. Mei, B. H. Johnson, E. B. Thompson, X. Cheng, Protein kinase A, not Epac, suppresses hedgehog activity and regulates glucocorticoid sensitivity in acute lymphoblastic leukemia cells. The Journal of biological chemistry 282, 37370-37377 (2007).
55. M. Grandoch et al., Epac inhibits apoptosis of human leukocytes. Journal of leukocyte biology 86, 847-849 (2009).
56. A. E. Christensen et al., cAMP analog mapping of Epac1 and cAMP kinase. Discriminating analogs demonstrate that Epac and cAMP kinase act synergistically to promote PC-12 cell neurite extension. The Journal of biological chemistry 278, 35394-35402 (2003).
57. R. C. Hewer, G. B. Sala-Newby, Y. J. Wu, A. C. Newby, M. Bond, PKA and Epac synergistically inhibit smooth muscle cell proliferation. Journal of molecular and cellular cardiology 50, 87-98 (2011).
58. J. M. Enserink et al., A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nature cell biology 4, 901-906 (2002).
59. J. M. Suh et al., Regulation of the Phosphatidylinositol 3-Kinase, Akt/Protein Kinase B, FRAP/Mammalian Target of Rapamycin, and Ribosomal S6 Kinase 1 Signaling Pathways by Thyroid-stimulating Hormone (TSH) and Stimulating type TSH Receptor Antibodies in the Thyroid Gland. Journal of Biological Chemistry 278, 21960-21971 (2003).
60. S. Blancquaert et al., cAMP-Dependent Activation of Mammalian Target of Rapamycin (mTOR) in Thyroid Cells. Implication in Mitogenesis and Activation of CDK4. Molecular endocrinology 24, 1453-1468 (2010).
61. M. Palaniappan, K. M. J. Menon, Human Chorionic Gonadotropin Stimulates Theca-Interstitial Cell Proliferation and Cell Cycle Regulatory Proteins by a cAMP-Dependent Activation of AKT/mTORC1 Signaling Pathway. Molecular endocrinology 24, 1782-1793 (2010).
62. V. Cepeda et al., Biochemical mechanisms of cisplatin cytotoxicity. Anti-cancer agents in medicinal chemistry 7, 3-18 (2007).
63. H. D. Halicka, H. Zhao, M. Podhorecka, F. Traganos, Z. Darzynkiewicz, Cytometric detection of chromatin relaxation, an early reporter of DNA damage response. Cell cycle 8, 2233-2237 (2009).
64. G. R. Aravindan, J. Bjordahl, L. K. Jost, D. P. Evenson, Susceptibility of human sperm to in situ DNA denaturation is strongly correlated with DNA strand breaks identified by single-cell electrophoresis. Experimental cell research 236, 231-237 (1997).
65. L. R. Pearce et al., Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). The Biochemical journal 431, 245-255 (2010).
66. K. P. Lai et al., S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response. The EMBO journal 29, 2994-3006 (2010).
67. L. Chen, L. Liu, Y. Luo, S. Huang, MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. Journal of neurochemistry 105, 251-261 (2008).
68. T. J. Gaymes, G. J. Mufti, F. V. Rassool, Myeloid leukemias have increased activity of the nonhomologous end-joining pathway and concomitant DNA misrepair that is dependent on the Ku70/86 heterodimer. Cancer research 62, 2791-2797 (2002).
69. L. A. Casciola-Rosen, G. J. Anhalt, A. Rosen, DNA-dependent protein kinase is one of a subset of autoantigens specifically cleaved early during apoptosis. The Journal of experimental medicine 182, 1625-1634 (1995).
70. Q. Song et al., DNA-dependent protein kinase catalytic subunit: a target for an ICE-like protease in apoptosis. The EMBO journal 15, 3238-3246 (1996).
71. C. E. Redon et al., Histone gammaH2AX and poly(ADP-ribose) as clinical pharmacodynamic biomarkers. Clinical cancer research : an official journal of the American Association for Cancer Research 16, 4532-4542 (2010).
72. P. L. Olive, J. P. Banath, Kinetics of H2AX phosphorylation after exposure to cisplatin. Cytometry. Part B, Clinical cytometry 76, 79-90 (2009).
73. T. Nikolova et al., The gammaH2AX assay for genotoxic and nongenotoxic agents: comparison of H2AX phosphorylation with cell death response. Toxicological sciences : an official journal of the Society of Toxicology 140, 103-117 (2014).
74. A. Sallmyr, A. E. Tomkinson, F. V. Rassool, Up-regulation of WRN and DNA ligase IIIalpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks. Blood 112, 1413-1423 (2008).
75. L. A. Tobin et al., Targeting abnormal DNA double-strand break repair in tyrosine kinase inhibitor-resistant chronic myeloid leukemias. Oncogene 32, 1784-1793 (2013).
76. K. Do, A. P. Chen, Molecular pathways: targeting PARP in cancer treatment. Clinical cancer research : an official journal of the American Association for Cancer Research 19, 977-984 (2013).
77. N. Gambi, F. Tramontano, P. Quesada, Poly(ADPR)polymerase inhibition and apoptosis induction in cDDP-treated human carcinoma cell lines. Biochemical pharmacology 75, 2356-2363 (2008).
78. J. Sand-Dejmek et al., Concordant and opposite roles of DNA-PK and the "facilitator of chromatin transcription" (FACT) in DNA repair, apoptosis and necrosis after cisplatin. Molecular cancer 10, 74 (2011).
79. A. S. Calkins, J. D. Iglehart, J. B. Lazaro, DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1. Nucleic acids research 41, 7378-7386 (2013).
80. B. Magnuson, B. Ekim, D. C. Fingar, Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. The Biochemical journal 441, 1-21 (2012).
81. M. Rosner, K. Schipany, M. Hengstschlager, p70 S6K1 nuclear localization depends on its mTOR-mediated phosphorylation at T389, but not on its kinase activity towards S6. Amino acids 42, 2251-2256 (2012).
82. D. R. Alessi, M. T. Kozlowski, Q. P. Weng, N. Morrice, J. Avruch, 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. Current biology : CB 8, 69-81 (1998).
83. N. Pullen, Phosphorylation and Activation of p70s6k by PDK1. Science 279, 707-710 (1998).
84. E. H. Naderi, H. W. Findley, E. Ruud, H. K. Blomhoff, S. Naderi, Activation of cAMP signaling inhibits DNA damage-induced apoptosis in BCP-ALL cells through abrogation of p53 accumulation. Blood 114, 608-618 (2009).
85. J. C. Law, M. K. Ritke, J. C. Yalowich, G. H. Leder, R. E. Ferrell, Mutational inactivation of the p53 gene in the human erythroid leukemic K562 cell line. Leukemia research 17, 1045-1050 (1993).
86. L. Collavin, A. Lunardi, G. Del Sal, p53-family proteins and their regulators: hubs and spokes in tumor suppression. Cell death and differentiation 17, 901-911 (2010).
87. J. G. Gong et al., The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399, 806-809 (1999).
88. J. Ren et al., p73beta is regulated by protein kinase Cdelta catalytic fragment generated in the apoptotic response to DNA damage. The Journal of biological chemistry 277, 33758-33765 (2002).
89. A. Meshkini, R. Yazdanparast, Regulation of p38, PKC/Foxo3a/p73 signaling network by GTP during erythroid differentiation in chronic myelogenous leukemia. Cell biochemistry and biophysics 67, 675-687 (2013).
90. D. H. Russell, Type I cyclic AMP-dependent protein kinase as a positive effector of growth. Adv Cyclic Nucleotide Res 9, 493-506 (1978).
91. Y. S. Cho-Chung, Hypothesis. Cyclic AMP and its receptor protein in tumor growth regulation in vivo. Journal of cyclic nucleotide research 6, 163-177 (1980).
92. Q. Liu, E. Nguyen, S. Doskeland, E. Segal-Bendirdjian, cAMP-Dependent Protein Kinase A (PKA)-Mediated c-Myc Degradation Is Dependent on the Relative Proportion of PKA-I and PKA-II Isozymes. Molecular pharmacology 88, 469-476 (2015).
93. B. S. Erikstein et al., Protein kinase A activators and the pan-PPAR agonist tetradecylthioacetic acid elicit synergistic anti-leukaemic effects in AML through CREB. Leukemia research 34, 77-84 (2010).
94. B. S. Skalhegg et al., Isozymes of cyclic AMP-dependent protein kinases (PKA) in human lymphoid cell lines: levels of endogenous cAMP influence levels of PKA subunits and growth in lymphoid cell lines. Journal of cellular physiology 177, 85-93 (1998).
95. R. Ilouz et al., Localization and quaternary structure of the PKA RIbeta holoenzyme. Proceedings of the National Academy of Sciences of the United States of America 109, 12443-12448 (2012).
96. C. de Joussineau et al., mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD). Human molecular genetics 23, 5418-5428 (2014).
97. M. M. Kloster, E. H. Naderi, H. Carlsen, H. K. Blomhoff, S. Naderi, Hyperactivation of NF-kappaB via the MEK signaling is indispensable for the inhibitory effect of cAMP on DNA damage-induced cell death. Molecular cancer 10, 45 (2011).
98. E. Weisberg et al., Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells. Blood 111, 3723-3734 (2008).
99. R. Ciarcia et al., Combined effects of PI3K and SRC kinase inhibitors with imatinib on intracellular calcium levels, autophagy, and apoptosis in CML-PBL cells. Cell cycle 12, 2839-2848 (2013).
100. M. G. Mohi et al., Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proceedings of the National Academy of Sciences of the United States of America 101, 3130-3135 (2004).
101. C. Sillaber et al., Evaluation of antileukaemic effects of rapamycin in patients with imatinib-resistant chronic myeloid leukaemia. European journal of clinical investigation 38, 43-52 (2008).
102. A. Gonzalez-Rodriguez, J. Alba, V. Zimmerman, S. C. Kozma, A. M. Valverde, S6K1 deficiency protects against apoptosis in hepatocytes. Hepatology 50, 216-229 (2009).
103. S. Sridharan, A. Basu, S6 kinase 2 promotes breast cancer cell survival via Akt. Cancer research 71, 2590-2599 (2011).
104. E. M. Matthew et al., The p53 target Plk2 interacts with TSC proteins impacting mTOR signaling, tumor growth and chemosensitivity under hypoxic conditions. Cell cycle 8, 4168-4175 (2009).
105. P. Hasty, Z. D. Sharp, T. J. Curiel, J. Campisi, mTORC1 and p53: clash of the gods? Cell cycle 12, 20-25 (2013).
106. M. Rosner, M. Hengstschlager, Nucleocytoplasmic localization of p70 S6K1, but not of its isoforms p85 and p31, is regulated by TSC2/mTOR. Oncogene 30, 4509-4522 (2011).
107. H. J. Boeckman, K. S. Trego, J. J. Turchi, Cisplatin sensitizes cancer cells to ionizing radiation via inhibition of nonhomologous end joining. Molecular cancer research : MCR 3, 277-285 (2005).
108. X. Tian et al., The relationship between the down-regulation of DNA-PKcs or Ku70 and the chemosensitization in human cervical carcinoma cell line HeLa. Oncology reports 18, 927-932 (2007).
109. F. Andrade et al., Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis. Immunity 8, 451-460 (1998).
110. A. J. Davis, K. J. Lee, D. J. Chen, The N-terminal region of the DNA-dependent protein kinase catalytic subunit is required for its DNA double-stranded break-mediated activation. The Journal of biological chemistry 288, 7037-7046 (2013).
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2022-06-01起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2022-06-01起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw