請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20929
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳瑞華(Ruey-Hwa Chen) | |
dc.contributor.author | Ya-Ting Wang | en |
dc.contributor.author | 王雅葶 | zh_TW |
dc.date.accessioned | 2021-06-08T03:10:51Z | - |
dc.date.copyright | 2017-06-12 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-05-01 | |
dc.identifier.citation | 1. Vilchez, D., Saez, I. & Dillin, A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat Commun 5, 5659 (2014).
2. Wang, J. & Maldonado, M.A. The ubiquitin-proteasome system and its role in inflammatory and autoimmune diseases. Cell Mol Immunol 3, 255-261 (2006). 3. Berndsen, C.E. & Wolberger, C. New insights into ubiquitin E3 ligase mechanism. Nat Struct Mol Biol 21, 301-307 (2014). 4. Deshaies, R.J. & Joazeiro, C.A. RING domain E3 ubiquitin ligases. Annu Rev Biochem 78, 399-434 (2009). 5. Komander, D. & Rape, M. The ubiquitin code. Annu Rev Biochem 81, 203-229 (2012). 6. Kulathu, Y. & Komander, D. Atypical ubiquitylation - the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat Rev Mol Cell Biol 13, 508-523 (2012). 7. Thrower, J.S., Hoffman, L., Rechsteiner, M. & Pickart, C.M. Recognition of the polyubiquitin proteolytic signal. EMBO J 19, 94-102 (2000). 8. Spence, J., Sadis, S., Haas, A.L. & Finley, D. A ubiquitin mutant with specific defects in DNA repair and multiubiquitination. Mol Cell Biol 15, 1265-1273 (1995). 9. Sun, L. & Chen, Z.J. The novel functions of ubiquitination in signaling. Curr Opin Cell Biol 16, 119-126 (2004). 10. Mukhopadhyay, D. & Riezman, H. Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315, 201-205 (2007). 11. Ikeda, F. & Dikic, I. Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series. EMBO Rep 9, 536-542 (2008). 12. Jin, J., Li, X., Gygi, S.P. & Harper, J.W. Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Nature 447, 1135-1138 (2007). 13. Li, W. et al. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PLoS One 3, e1487 (2008). 14. Li, W. & Ye, Y. Polyubiquitin chains: functions, structures, and mechanisms. Cell Mol Life Sci 65, 2397-2406 (2008). 15. Duplan, V. & Rivas, S. E3 ubiquitin-ligases and their target proteins during the regulation of plant innate immunity. Front Plant Sci 5, 42 (2014). 16. Rotin, D. & Kumar, S. Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 10, 398-409 (2009). 17. Wang, X. & Martin, D.S. The COP9 signalosome and cullin-RING ligases in the heart. Am J Cardiovasc Dis 5, 1-18 (2015). 18. Metzger, M.B., Hristova, V.A. & Weissman, A.M. HECT and RING finger families of E3 ubiquitin ligases at a glance. J Cell Sci 125, 531-537 (2012). 19. Wenzel, D.M., Lissounov, A., Brzovic, P.S. & Klevit, R.E. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature 474, 105-108 (2011). 20. Callis, J. The ubiquitination machinery of the ubiquitin system. Arabidopsis Book 12, e0174 (2014). 21. Sarikas, A., Hartmann, T. & Pan, Z.Q. The cullin protein family. Genome Biol 12, 220 (2011). 22. Jackson, S. & Xiong, Y. CRL4s: the CUL4-RING E3 ubiquitin ligases. Trends Biochem Sci 34, 562-570 (2009). 23. Zimmerman, E.S., Schulman, B.A. & Zheng, N. Structural assembly of cullin-RING ubiquitin ligase complexes. Curr Opin Struct Biol 20, 714-721 (2010). 24. Lee, J. & Zhou, P. Pathogenic Role of the CRL4 Ubiquitin Ligase in Human Disease. Front Oncol 2, 21 (2012). 25. Yin, Y. et al. The E3 ubiquitin ligase Cullin 4A regulates meiotic progression in mouse spermatogenesis. Dev Biol 356, 51-62 (2011). 26. Cox, B.J. et al. Phenotypic annotation of the mouse X chromosome. Genome Res 20, 1154-1164 (2010). 27. Yin, Y. et al. Cell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis. J Biol Chem 291, 6923-6935 (2016). 28. Li, T., Chen, X., Garbutt, K.C., Zhou, P. & Zheng, N. Structure of DDB1 in complex with a paramyxovirus V protein: viral hijack of a propeller cluster in ubiquitin ligase. Cell 124, 105-117 (2006). 29. Angers, S. et al. Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 443, 590-593 (2006). 30. Scrima, A. et al. Structural basis of UV DNA-damage recognition by the DDB1-DDB2 complex. Cell 135, 1213-1223 (2008). 31. He, Y.J., McCall, C.M., Hu, J., Zeng, Y. & Xiong, Y. DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-ROC1 ubiquitin ligases. Genes Dev 20, 2949-2954 (2006). 32. Jin, J., Arias, E.E., Chen, J., Harper, J.W. & Walter, J.C. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell 23, 709-721 (2006). 33. Xu, C. & Min, J. Structure and function of WD40 domain proteins. Protein Cell 2, 202-214 (2011). 34. Stirnimann, C.U., Petsalaki, E., Russell, R.B. & Muller, C.W. WD40 proteins propel cellular networks. Trends Biochem Sci 35, 565-574 (2010). 35. Lee, J. & Zhou, P. DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase. Mol Cell 26, 775-780 (2007). 36. Biedermann, S. & Hellmann, H. WD40 and CUL4-based E3 ligases: lubricating all aspects of life. Trends Plant Sci 16, 38-46 (2011). 37. Letunic, I., Doerks, T. & Bork, P. SMART 6: recent updates and new developments. Nucleic Acids Res 37, D229-232 (2009). 38. Hu, J., McCall, C.M., Ohta, T. & Xiong, Y. Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol 6, 1003-1009 (2004). 39. Nishitani, H. et al. Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. EMBO J 25, 1126-1136 (2006). 40. Matsumoto, S. et al. Functional regulation of the DNA damage-recognition factor DDB2 by ubiquitination and interaction with xeroderma pigmentosum group C protein. Nucleic Acids Res 43, 1700-1713 (2015). 41. Wang, H. et al. Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol Cell 22, 383-394 (2006). 42. Guerrero-Santoro, J. et al. The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A. Cancer Res 68, 5014-5022 (2008). 43. Michaud, J. et al. Isolation and characterization of a human chromosome 21q22.3 gene (WDR4) and its mouse homologue that code for a WD-repeat protein. Genomics 68, 71-79 (2000). 44. Alexandrov, A., Martzen, M.R. & Phizicky, E.M. Two proteins that form a complex are required for 7-methylguanosine modification of yeast tRNA. RNA 8, 1253-1266 (2002). 45. Alexandrov, A., Grayhack, E.J. & Phizicky, E.M. tRNA m7G methyltransferase Trm8p/Trm82p: evidence linking activity to a growth phenotype and implicating Trm82p in maintaining levels of active Trm8p. RNA 11, 821-830 (2005). 46. Leulliot, N. et al. Structure of the yeast tRNA m7G methylation complex. Structure 16, 52-61 (2008). 47. Shaheen, R. et al. Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism. Genome Biol 16, 210 (2015). 48. Wu, J., Hou, J.H. & Hsieh, T.S. A new Drosophila gene wh (wuho) with WD40 repeats is essential for spermatogenesis and has maximal expression in hub cells. Dev Biol 296, 219-230 (2006). 49. Cheng, I.C. et al. Wuho Is a New Member in Maintaining Genome Stability through its Interaction with Flap Endonuclease 1. PLoS Biol 14, e1002349 (2016). 50. de The, H., Chomienne, C., Lanotte, M., Degos, L. & Dejean, A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 347, 558-561 (1990). 51. Goddard, A.D., Borrow, J., Freemont, P.S. & Solomon, E. Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science 254, 1371-1374 (1991). 52. Kakizuka, A. et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 66, 663-674 (1991). 53. Pandolfi, P.P. et al. Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene 6, 1285-1292 (1991). 54. Bernardi, R. & Pandolfi, P.P. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol 8, 1006-1016 (2007). 55. Jin, G., Wang, Y.J. & Lin, H.K. Emerging Cellular Functions of Cytoplasmic PML. Front Oncol 3, 147 (2013). 56. Bischof, O. et al. Deconstructing PML-induced premature senescence. EMBO J 21, 3358-3369 (2002). 57. Nguyen, L.A. et al. Physical and functional link of the leukemia-associated factors AML1 and PML. Blood 105, 292-300 (2005). 58. Xu, Z.X., Zou, W.X., Lin, P. & Chang, K.S. A role for PML3 in centrosome duplication and genome stability. Mol Cell 17, 721-732 (2005). 59. Lin, H.K., Bergmann, S. & Pandolfi, P.P. Cytoplasmic PML function in TGF-beta signalling. Nature 431, 205-211 (2004). 60. Giorgi, C. et al. PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330, 1247-1251 (2010). 61. Shimada, N., Shinagawa, T. & Ishii, S. Modulation of M2-type pyruvate kinase activity by the cytoplasmic PML tumor suppressor protein. Genes Cells 13, 245-254 (2008). 62. Shen, T.H., Lin, H.K., Scaglioni, P.P., Yung, T.M. & Pandolfi, P.P. The mechanisms of PML-nuclear body formation. Mol Cell 24, 331-339 (2006). 63. Dellaire, G. & Bazett-Jones, D.P. PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. Bioessays 26, 963-977 (2004). 64. Carracedo, A., Ito, K. & Pandolfi, P.P. The nuclear bodies inside out: PML conquers the cytoplasm. Curr Opin Cell Biol 23, 360-366 (2011). 65. Gurrieri, C. et al. Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J Natl Cancer Inst 96, 269-279 (2004). 66. Wang, Z.G. et al. Role of PML in cell growth and the retinoic acid pathway. Science 279, 1547-1551 (1998). 67. Bernardi, R. et al. Pml represses tumour progression through inhibition of mTOR. EMBO Mol Med 3, 249-257 (2011). 68. Trotman, L.C. et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523-527 (2006). 69. Scaglioni, P.P. et al. A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 126, 269-283 (2006). 70. Carracedo, A. et al. A metabolic prosurvival role for PML in breast cancer. J Clin Invest 122, 3088-3100 (2012). 71. Ito, K. et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453, 1072-1078 (2008). 72. Ito, K. et al. A PML-PPAR-delta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med 18, 1350-1358 (2012). 73. Pearson, M. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207-210 (2000). 74. Ferbeyre, G. et al. PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 14, 2015-2027 (2000). 75. Ivanschitz, L. et al. PML IV/ARF interaction enhances p53 SUMO-1 conjugation, activation, and senescence. Proc Natl Acad Sci U S A 112, 14278-14283 (2015). 76. Mallette, F.A., Goumard, S., Gaumont-Leclerc, M.F., Moiseeva, O. & Ferbeyre, G. Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence. Oncogene 23, 91-99 (2004). 77. Vernier, M. et al. Regulation of E2Fs and senescence by PML nuclear bodies. Genes Dev 25, 41-50 (2011). 78. Martin, N. et al. Physical and functional interaction between PML and TBX2 in the establishment of cellular senescence. EMBO J 31, 95-109 (2012). 79. Wang, Z.G. et al. PML is essential for multiple apoptotic pathways. Nat Genet 20, 266-272 (1998). 80. Moller, A. et al. PML is required for homeodomain-interacting protein kinase 2 (HIPK2)-mediated p53 phosphorylation and cell cycle arrest but is dispensable for the formation of HIPK domains. Cancer Res 63, 4310-4314 (2003). 81. Li, M. et al. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416, 648-653 (2002). 82. Kurki, S., Latonen, L. & Laiho, M. Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization. J Cell Sci 116, 3917-3925 (2003). 83. Bernardi, R. et al. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol 6, 665-672 (2004). 84. Salomoni, P. et al. The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage. Blood 105, 3686-3690 (2005). 85. Croxton, R. et al. Daxx represses expression of a subset of antiapoptotic genes regulated by nuclear factor-kappaB. Cancer Res 66, 9026-9035 (2006). 86. Bernardi, R. et al. PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 442, 779-785 (2006). 87. Cheng, X., Liu, Y., Chu, H. & Kao, H.Y. Promyelocytic leukemia protein (PML) regulates endothelial cell network formation and migration in response to tumor necrosis factor alpha (TNFalpha) and interferon alpha (IFNalpha). J Biol Chem 287, 23356-23367 (2012). 88. Reineke, E.L., Liu, Y. & Kao, H.Y. Promyelocytic leukemia protein controls cell migration in response to hydrogen peroxide and insulin-like growth factor-1. J Biol Chem 285, 9485-9492 (2010). 89. Kuo, H.Y. et al. PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation of MMP2. Cell Cycle 13, 3132-3142 (2014). 90. Gambacorta, M. et al. Heterogeneous nuclear expression of the promyelocytic leukemia (PML) protein in normal and neoplastic human tissues. Am J Pathol 149, 2023-2035 (1996). 91. Lallemand-Breitenbach, V. et al. Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor alpha degradation. J Exp Med 193, 1361-1371 (2001). 92. Lallemand-Breitenbach, V. et al. Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol 10, 547-555 (2008). 93. Tatham, M.H. et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol 10, 538-546 (2008). 94. Sun, H., Leverson, J.D. & Hunter, T. Conserved function of RNF4 family proteins in eukaryotes: targeting a ubiquitin ligase to SUMOylated proteins. EMBO J 26, 4102-4112 (2007). 95. Geoffroy, M.C., Jaffray, E.G., Walker, K.J. & Hay, R.T. Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies. Mol Biol Cell 21, 4227-4239 (2010). 96. Talis, A.L., Huibregtse, J.M. & Howley, P.M. The role of E6AP in the regulation of p53 protein levels in human papillomavirus (HPV)-positive and HPV-negative cells. J Biol Chem 273, 6439-6445 (1998). 97. Louria-Hayon, I. et al. E6AP promotes the degradation of the PML tumor suppressor. Cell Death Differ 16, 1156-1166 (2009). 98. Wolyniec, K. et al. E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis. Blood 120, 822-832 (2012). 99. Yuan, W.C. et al. A Cullin3-KLHL20 Ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression. Cancer Cell 20, 214-228 (2011). 100. Lin, Y.C. et al. SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling. Cancer Res 74, 6935-6946 (2014). 101. Landesman-Bollag, E. et al. Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 20, 3247-3257 (2001). 102. Seldin, D.C. & Leder, P. Casein kinase II alpha transgene-induced murine lymphoma: relation to theileriosis in cattle. Science 267, 894-897 (1995). 103. Scaglioni, P.P. et al. CK2 mediates phosphorylation and ubiquitin-mediated degradation of the PML tumor suppressor. Mol Cell Biochem 316, 149-154 (2008). 104. Rabellino, A. et al. The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. Cancer Res 72, 2275-2284 (2012). 105. Lim, J.H., Liu, Y., Reineke, E. & Kao, H.Y. Mitogen-activated protein kinase extracellular signal-regulated kinase 2 phosphorylates and promotes Pin1 protein-dependent promyelocytic leukemia protein turnover. J Biol Chem 286, 44403-44411 (2011). 106. Fanelli, M. et al. The coiled-coil domain is the structural determinant for mammalian homologues of Drosophila Sina-mediated degradation of promyelocytic leukemia protein and other tripartite motif proteins by the proteasome. J Biol Chem 279, 5374-5379 (2004). 107. Guan, D., Factor, D., Liu, Y., Wang, Z. & Kao, H.Y. The epigenetic regulator UHRF1 promotes ubiquitination-mediated degradation of the tumor-suppressor protein promyelocytic leukemia protein. Oncogene 32, 3819-3828 (2013). 108. Wu, H.C. et al. USP11 regulates PML stability to control Notch-induced malignancy in brain tumours. Nat Commun 5, 3214 (2014). 109. Geoffroy, M.C. & Chelbi-Alix, M.K. Role of promyelocytic leukemia protein in host antiviral defense. J Interferon Cytokine Res 31, 145-158 (2011). 110. Tavalai, N. & Stamminger, T. Interplay between Herpesvirus Infection and Host Defense by PML Nuclear Bodies. Viruses 1, 1240-1264 (2009). 111. Reichelt, M. et al. Entrapment of viral capsids in nuclear PML cages is an intrinsic antiviral host defense against varicella-zoster virus. PLoS Pathog 7, e1001266 (2011). 112. Chelbi-Alix, M.K. et al. Induction of the PML protein by interferons in normal and APL cells. Leukemia 9, 2027-2033 (1995). 113. Chen, Y., Wright, J., Meng, X. & Leppard, K.N. Promyelocytic Leukemia Protein Isoform II Promotes Transcription Factor Recruitment To Activate Interferon Beta and Interferon-Responsive Gene Expression. Mol Cell Biol 35, 1660-1672 (2015). 114. Ulbricht, T. et al. PML promotes MHC class II gene expression by stabilizing the class II transactivator. J Cell Biol 199, 49-63 (2012). 115. Lunardi, A. et al. A Role for PML in Innate Immunity. Genes Cancer 2, 10-19 (2011). 116. Palibrk, V. et al. PML regulates neuroprotective innate immunity and neuroblast commitment in a hypoxic-ischemic encephalopathy model. Cell Death Dis 7, e2320 (2016). 117. Grivennikov, S.I., Greten, F.R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883-899 (2010). 118. Quail, D.F. & Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat Med 19, 1423-1437 (2013). 119. Balkwill, F.R., Capasso, M. & Hagemann, T. The tumor microenvironment at a glance. J Cell Sci 125, 5591-5596 (2012). 120. Levental, K.R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891-906 (2009). 121. Wilgus, M.L. et al. Lysyl oxidase: a lung adenocarcinoma biomarker of invasion and survival. Cancer 117, 2186-2191 (2011). 122. Joyce, J.A. & Pollard, J.W. Microenvironmental regulation of metastasis. Nat Rev Cancer 9, 239-252 (2009). 123. Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539-545 (2001). 124. Sangiovanni, A. et al. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology 126, 1005-1014 (2004). 125. Stewart, T., Tsai, S.C., Grayson, H., Henderson, R. & Opelz, G. Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet 346, 796-798 (1995). 126. Gallagher, B., Wang, Z., Schymura, M.J., Kahn, A. & Fordyce, E.J. Cancer incidence in New York State acquired immunodeficiency syndrome patients. Am J Epidemiol 154, 544-556 (2001). 127. Whiteside, T.L. Regulatory T cell subsets in human cancer: are they regulating for or against tumor progression? Cancer Immunol Immunother 63, 67-72 (2014). 128. von Boehmer, H. & Daniel, C. Therapeutic opportunities for manipulating T(Reg) cells in autoimmunity and cancer. Nat Rev Drug Discov 12, 51-63 (2013). 129. Mougiakakos, D., Choudhury, A., Lladser, A., Kiessling, R. & Johansson, C.C. Regulatory T cells in cancer. Adv Cancer Res 107, 57-117 (2010). 130. Curiel, T.J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10, 942-949 (2004). 131. Jiang, Y. et al. FOXP3+ lymphocyte density in pancreatic cancer correlates with lymph node metastasis. PLoS One 9, e106741 (2014). 132. Leffers, N. et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 58, 449-459 (2009). 133. Shang, B., Liu, Y., Jiang, S.J. & Liu, Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep 5, 15179 (2015). 134. Sayour, E.J. et al. Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma. Cancer Immunol Immunother 64, 419-427 (2015). 135. Tang, Y. et al. An increased abundance of tumor-infiltrating regulatory T cells is correlated with the progression and prognosis of pancreatic ductal adenocarcinoma. PLoS One 9, e91551 (2014). 136. Tao, H. et al. Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer 75, 95-101 (2012). 137. Haas, M. et al. Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia. BMC Gastroenterol 9, 65 (2009). 138. Salama, P. et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27, 186-192 (2009). 139. Chaudhary, B. & Elkord, E. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting. Vaccines (Basel) 4 (2016). 140. Schmidt, A., Oberle, N. & Krammer, P.H. Molecular mechanisms of treg-mediated T cell suppression. Front Immunol 3, 51 (2012). 141. Shevach, E.M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636-645 (2009). 142. Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D.I. The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends Immunol 37, 208-220 (2016). 143. Ostrand-Rosenberg, S. Immune surveillance: a balance between protumor and antitumor immunity. Curr Opin Genet Dev 18, 11-18 (2008). 144. Marvel, D. & Gabrilovich, D.I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest 125, 3356-3364 (2015). 145. Chanmee, T., Ontong, P., Konno, K. & Itano, N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 6, 1670-1690 (2014). 146. Murdoch, C., Giannoudis, A. & Lewis, C.E. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104, 2224-2234 (2004). 147. Noy, R. & Pollard, J.W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49-61 (2014). 148. Qian, B. et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One 4, e6562 (2009). 149. Bonde, A.K., Tischler, V., Kumar, S., Soltermann, A. & Schwendener, R.A. Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer 12, 35 (2012). 150. Condeelis, J. & Pollard, J.W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263-266 (2006). 151. Gocheva, V. et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24, 241-255 (2010). 152. Condeelis, J. & Segall, J.E. Intravital imaging of cell movement in tumours. Nat Rev Cancer 3, 921-930 (2003). 153. Wyckoff, J.B. et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67, 2649-2656 (2007). 154. Almholt, K. et al. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice. Int J Cancer 113, 525-532 (2005). 155. Condeelis, J. & Weissleder, R. In vivo imaging in cancer. Cold Spring Harb Perspect Biol 2, a003848 (2010). 156. Sidani, M., Wyckoff, J., Xue, C., Segall, J.E. & Condeelis, J. Probing the microenvironment of mammary tumors using multiphoton microscopy. J Mammary Gland Biol Neoplasia 11, 151-163 (2006). 157. Gil-Bernabe, A.M. et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164-3175 (2012). 158. Cortez-Retamozo, V. et al. Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci U S A 109, 2491-2496 (2012). 159. Qian, B.Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222-225 (2011). 160. Coffelt, S.B., Wellenstein, M.D. & de Visser, K.E. Neutrophils in cancer: neutral no more. Nat Rev Cancer 16, 431-446 (2016). 161. Bekes, E.M. et al. Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am J Pathol 179, 1455-1470 (2011). 162. Rotondo, R. et al. IL-8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer. Int J Cancer 125, 887-893 (2009). 163. Fridlender, Z.G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: 'N1' versus 'N2' TAN. Cancer Cell 16, 183-194 (2009). 164. Mantovani, A., Cassatella, M.A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11, 519-531 (2011). 165. Sionov, R.V., Fridlender, Z.G. & Granot, Z. The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment. Cancer Microenviron 8, 125-158 (2015). 166. Powell, D.R. & Huttenlocher, A. Neutrophils in the Tumor Microenvironment. Trends Immunol 37, 41-52 (2016). 167. Gardner, A. & Ruffell, B. Dendritic Cells and Cancer Immunity. Trends Immunol 37, 855-865 (2016). 168. Lotze, M.T. Getting to the source: dendritic cells as therapeutic reagents for the treatment of patients with cancer. Ann Surg 226, 1-5 (1997). 169. Lijun, Z. et al. Tumor-infiltrating dendritic cells may be used as clinicopathologic prognostic factors in endometrial carcinoma. Int J Gynecol Cancer 22, 836-841 (2012). 170. Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu Rev Immunol 21, 685-711 (2003). 171. Gabrilovich, D.I., Nadaf, S., Corak, J., Berzofsky, J.A. & Carbone, D.P. Dendritic cells in antitumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors. Cell Immunol 170, 111-119 (1996). 172. Chaux, P., Moutet, M., Faivre, J., Martin, F. & Martin, M. Inflammatory cells infiltrating human colorectal carcinomas express HLA class II but not B7-1 and B7-2 costimulatory molecules of the T-cell activation. Lab Invest 74, 975-983 (1996). 173. Tourkova, I.L., Shurin, G.V., Wei, S. & Shurin, M.R. Small rho GTPases mediate tumor-induced inhibition of endocytic activity of dendritic cells. J Immunol 178, 7787-7793 (2007). 174. Shurin, M.R. et al. Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies? Cancer Metastasis Rev 25, 333-356 (2006). 175. Morvan, M.G. & Lanier, L.L. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer 16, 7-19 (2016). 176. Lanier, L.L. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9, 495-502 (2008). 177. Bix, M. et al. Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Nature 349, 329-331 (1991). 178. Diefenbach, A., Jensen, E.R., Jamieson, A.M. & Raulet, D.H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413, 165-171 (2001). 179. Roder, J.C. et al. A new immunodeficiency disorder in humans involving NK cells. Nature 284, 553-555 (1980). 180. Sullivan, J.L., Byron, K.S., Brewster, F.E. & Purtilo, D.T. Deficient natural killer cell activity in x-linked lymphoproliferative syndrome. Science 210, 543-545 (1980). 181. Gorelik, E., Wiltrout, R.H., Okumura, K., Habu, S. & Herberman, R.B. Role of NK cells in the control of metastatic spread and growth of tumor cells in mice. Int J Cancer 30, 107-112 (1982). 182. Nakajima, T., Mizushima, N., Nakamura, J. & Kanai, K. Surface markers of NK cells in peripheral blood of patients with cirrhosis and hepatocellular carcinoma. Immunol Lett 13, 7-10 (1986). 183. Schantz, S.P., Shillitoe, E.J., Brown, B. & Campbell, B. Natural killer cell activity and head and neck cancer: a clinical assessment. J Natl Cancer Inst 77, 869-875 (1986). 184. Spinner, M.A. et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123, 809-821 (2014). 185. Gineau, L. et al. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest 122, 821-832 (2012). 186. Groh, V., Wu, J., Yee, C. & Spies, T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419, 734-738 (2002). 187. Kaiser, B.K. et al. Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands. Nature 447, 482-486 (2007). 188. Salih, H.R., Rammensee, H.G. & Steinle, A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol 169, 4098-4102 (2002). 189. Wu, J.D. et al. Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Invest 114, 560-568 (2004). 190. Crane, C.A. et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc Natl Acad Sci U S A 111, 12823-12828 (2014). 191. Champsaur, M. & Lanier, L.L. Effect of NKG2D ligand expression on host immune responses. Immunol Rev 235, 267-285 (2010). 192. Oppenheim, D.E. et al. Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nat Immunol 6, 928-937 (2005). 193. Wilson, E.B. et al. Human tumour immune evasion via TGF-beta blocks NK cell activation but not survival allowing therapeutic restoration of anti-tumour activity. PLoS One 6, e22842 (2011). 194. Holt, D., Ma, X., Kundu, N. & Fulton, A. Prostaglandin E(2) (PGE (2)) suppresses natural killer cell function primarily through the PGE(2) receptor EP4. Cancer Immunol Immunother 60, 1577-1586 (2011). 195. Pietra, G. et al. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res 72, 1407-1415 (2012). 196. Hoskin, D.W., Mader, J.S., Furlong, S.J., Conrad, D.M. & Blay, J. Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells (Review). Int J Oncol 32, 527-535 (2008). 197. Kopp, H.G., Placke, T. & Salih, H.R. Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Res 69, 7775-7783 (2009). 198. Placke, T., Salih, H.R. & Kopp, H.G. GITR ligand provided by thrombopoietic cells inhibits NK cell antitumor activity. J Immunol 189, 154-160 (2012). 199. Placke, T., Kopp, H.G. & Salih, H.R. The wolf in sheep's clothing: Platelet-derived 'pseudo self' impairs cancer cell 'missing self' recognition by NK ce | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20929 | - |
dc.description.abstract | 腫瘤微環境對於腫瘤生長與轉移,扮演著相當重要之角色。然而,癌細胞如何調控微環境中細胞與非細胞物質之機制,至今仍未完全明瞭。 PML為一腫瘤抑制蛋白,許多研究指出PML具有多方面抑制腫瘤生長及特性的相關能力,並且在許多不同種類的腫瘤中,其表現量有降低的情形;但是目前PML對於腫瘤微環境調控之探討,仍然相當不足。在本篇論文中,我們發現WDR4可作為受質辨識器(substrate adaptor),並與Cullin4、Roc1和DDB1蛋白形成連接酶(E3 ligase),將PML進行多次泛素化 (polyubiquitination),並且降解PML。臨床上的證據也顯示出在肺癌中,WDR4/PML的作用路徑有高度活化之現象,並且此路徑的高度活化與病人不良的預後有相關性。接著我們想研究WDR4/PML路徑在肺癌進程中的生物意義,因此我們利用基因微陣列分析發現,WDR4/PML可誘導一群細胞表面蛋白或是分泌蛋白之表現,它們分別是CD73、uPAR及SAA2。藉由在生物體外(in vitro)及動物實驗,我們發現WDR4/PML可透過這些誘導出的下游基因,促進肺癌細胞移動、侵襲和轉移之能力。此外,我們利用異體移植動物實驗和基因轉殖小鼠模式,觀察到WDR4/PML會增加入侵腫瘤內的調控性T細胞 (Tregs)與腫瘤相關巨噬細胞 (M2-like macrophages)之數目,但降低細胞毒殺性T細胞(CD8+ cytotoxic T lymphocytes)之數目;因此WDR4/PML作用路徑,可以創造出一個免疫抑制的腫瘤微環境;然而,此一現象卻可以被CD73抑制劑所抑制。整體來說,我們發現WDR4是一個新興致癌蛋白,可以透過多次泛素化以降解PML,此調控會創造出免疫抑制及促進癌細胞轉移之腫瘤微環境;此研究也顯示未來在治療PML不正常降解之肺癌時,也許可以使用免疫調控之方式,以達到治療效果。 | zh_TW |
dc.description.abstract | The tumor microenvironment plays an important role in tumor growth and metastasis. However, the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood. PML is a pleiotropic tumor suppressor but its role in tumor microenvironment regulation is poorly characterized. PML protein is frequently downregulated in many cancer types, including lung cancer. Here, we identify a novel PML ubiquitination/destruction pathway mediated by ubiquitin ligase CRL4WDR4. Clinically, this PML destruction pathway is hyperactivated in lung cancer and correlates with poor prognosis. The WDR4/PML axis induces a set of cell surface or secreted factors, including CD73, uPAR, and SAA2, which elicit paracrine effects to stimulate migration, invasion, and metastasis in multiple lung cancer models. Furthermore, in both xenograft and genetically engineered mouse models, the WDR4/PML axis elevates intratumoral Tregs and M2-like macrophages and reduces CD8+ T cells to promote lung tumor growth and these immunosuppressive effects are all reversed by CD73 blockade. Our study identifies WDR4 as a novel oncoprotein which negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and pro-metastatic tumor microenvironment and suggests a potential of immune-modulatory approaches for treating lung cancer with aberrant PML degradation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T03:10:51Z (GMT). No. of bitstreams: 1 ntu-106-D99b46005-1.pdf: 7360459 bytes, checksum: fe227dcf28d2060f7999e7a25353015e (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 中文摘要 i
Abstract ii Introduction 1 1. Ubiquitin-proteasome system 1 1.1 E3 ubiquitin ligase 2 1.2 Cullin-RING E3 ligase 3 1.3 DCAFs 4 2. WDR4 6 3. Promyelocytic leukemia protein (PML) 7 3.1 Roles of PML in tumor suppression and beyond 8 3.2 Functions of PML in tumor suppression 9 3.2.1 Regulation of cellular senescence 9 3.2.2 Regulation of apoptosis 10 3.2.3 Regulation of neoangiogenesis 11 3.2.4 Regulation of cell migration, invasion and metastasis 12 3.3 Regulation of PML expression in human cancers 12 3.3.1 RNF4-mediated PML ubiquitination 13 3.3.2 E6AP-mediated PML ubiquitination 13 3.3.3 Pin1/KLHL20-mediated PML ubiquitination 14 3.3.4 PIAS1/CK2-dependent PML ubiquitination 15 3.3.5 ERK2/Pin1-dependent PML degradation 15 3.3.6 Other ubiquitin E3 ligase for PML degradation 16 3.3.7 USP11-dependent PML deubiquitination 16 3.4 Roles of PML in viral infection, innate and adaptive immunity, and cytokine production 17 4. Tumor microenvironment and metastasis 18 4.1 Chronic inflammation, immunity, and cancer 19 4.2 Roles of immune cells in microenvironmental regulation of tumor progression 20 4.2.1 Regulatory T cells (Tregs) 20 4.2.2 Myeloid-derived suppressor cells (MDSCs) 22 4.2.3 Tumor-associated Macrophages (TAMs) 23 4.2.4 Tumor-associated Neutrophils (TANs) 25 4.2.5 Dendritic cells (DCs) 26 4.2.6 Nature killer (NK) cells 26 4.3 Roles of downstream targets of WDR4/PML axis in tumor progression and metastasis 28 4.3.1 CD73 28 4.3.1.1 Role of CD73 in regulation of cancer immunity 29 4.3.1.2 Role of CD73 in tumor metastasis 29 4.3.2 Urokinase-type plasminogen activator receptor (uPAR) 30 4.3.2.1 Proteolytic function of uPAR in cancer 31 4.3.2.2 Non-proteolytic function of uPAR in cancer 31 4.3.3 Serum amyloid A (SAA) 32 Background and significance 34 Material and methods 36 Cell culture 36 Plasmids 36 Antibodies and reagents 36 RT/qPCR 37 RNA interference and lentivirus transduction 37 Western blotting, immunoprecipitation, and GST pull down 37 Ubiquitination assays 38 Microarray 38 CM preparation 38 MMP activity assay 38 Migration and invasion assays 39 Proliferation assay 39 Animal experiments 40 Histology and IHC analyses 40 Human specimens 41 Flow cytometry 41 Bioinformatics 42 Statistical analysis 42 Study approval 43 Results 44 Identification of CRL4WDR4 as a PML ubiquitin ligase 44 WDR4 promotes PML proteasomal degradation 45 WDR4/PML axis is hypeactivated in lung cancer and correlates with poor prognosis 46 WDR4/PML axis induces a set of tumor-promoting factors 47 WDR4/PML axis promotes lung cancer migration and invasion 49 WDR4/PML axis promotes lung cancer metastasis 50 WDR4/PML axis induces an immunosuppressive tumor microenvironment 51 WDR4 acts through CD73 to suppress anti-tumor immunity 52 Discussion 55 Reference 61 Figures 80 Figure 1. CRL4 is involved in PML ubiquitination. 80 Figure 2. WDR4 regulates PML ubiquitination. 81 Figure 3. WDR4 functions as a CRL4 substrate adaptor which promotes PML ubiquitination. 82 Figure 4. WDR4 can promote the ubiquitination of PML S565A mutant. 83 Figure 5. WDR4 bridges PML and Cul4 E3 ligase complexes. 84 Figure 6. WDR4 directly interacts with PML, and CRL4WDR4 functions as a novel ubiquitin ligase for PML. 85 Figure 7. WDR4 promotes PML degradation. 86 Figure 8. WDR4 knockdown increases PML level in multiple cell types. 87 Figure 9. WDR4 promotes PML proteasomal degradation. 88 Figure 10. WDR4 upregulation correlates with poor prognosis in lung cancer. 89 Figure 11. The expression of WDR4 is inverse correlated with that of PML and patient survival in lung cancer. 90 Figure 12. WDR4/PML axis induces a set of tumor-promoting factors. 92 Figure 13. CD73, uPAR and SAA2 are upregulated by WDR4 overexpression and PML knockdown in lung cancer cell lines. 93 Figure 14. CD73, uPAR and SAA2 are downstream effectors for the WDR4/PML axis. 94 Figure 15. The clinical relevance of CD73, uPAR and SAA2 in lung cancer. 95 Figure 16. WDR4 promotes lung cancer migration and invasion in vitro, which is reversed by PML knockdown. 97 Figure 17. WDR4/PML axis facilitates lung cancer migration and invasion in vitro. 98 Figure 18. The migration/invasion-promoting functions of WDR4 are also attenuated by overexpression of PML-I. 99 Figure 19. The contribution of CD73/uPAR/SAA2 induction to WDR4/PML axis-promoted lung cell migration and invasion. 100 Figure 20. CM derived from cells coexpressed PML-I with WDR4 suppress WDR4-promoted migration and invasion of parental lung cancer cells. 101 Figure 21. Depletion of CD73, uPAR or SAA2 each attenuated the paracrine effect of WDR4 on stimulating migration and invasion. 102 Figure 22. Coexpressed PML-IV or PML-I with WDR4 suppress WDR4-promoted lung cancer metastasis in vivo. 103 Figure 23. WDR4 knockdown in A549 cells and patient-derived primary lung cancer cells (CL152) suppresses lung metastasis, which is completely reversed by PML knockdown. 105 Figure 24. WDR4/PML axis does not regulate cell proliferation of mouse LLC1 cells in vitro. 107 Figure 25. WDR4/PML axis promotes lung cancer metastasis and also induces downstream effectors in a syngeneic mouse model. 108 Figure 26. WDR4/PML axis regulates cell proliferation and tumor growth in vivo. 110 Figure 27. The roles of WDR4/PML axis in regulating intratumoral immune cells in a syngeneic mouse model. 111 Figure 28. WDR4/PML axis induces an immunosuppressive tumor microenvironment in a syngeneic mouse model. 112 Figure 29. A role of WDR4/PML axis in fostering an immunosuppressive tumor microenvironment. 113 Figure 30. WDR4/PML axis also induces downstream effectors in GEMM for human lung adenocarcinoma. 115 Figure 31. WDR4 ablation suppresses p53-deficiency/K-Ras-driven lung tumorigenesis. 116 Figure 32. WDR4 deficiency impairs lung tumor formation and progression. 117 Figure 33. WDR4 deficiency prolongs survival rate of mice. 118 Figure 34. WDR4 ablation creates anti-tumor microenvironment. 119 Figure 35. WDR4 deficiency enhances the population of tumor-infiltrating CD8+ CTLs, whereas reduces that of Tregs in lung tumors. 120 Figure 36. WDR4 ablation reduces the population of tumor-infiltrating M2-like macrophages in lung tumors. 122 Figure 37. PD-1 expression on Tregs and CD8+ T cells is decreased in WDR4-deficient lung tumors of GEMM. 123 Figure 38. Blockade of CD73 suppresses cell proliferation and reduces tumor burden in lung tumor of GEMM. 124 Figure 39. WDR4 ablation suppresses p53-deficiency/K-Ras-driven lung tumorigenesis by inhibiting CD73-dependent immunosuppressive functions. 125 Figure 40. Model for WDR4-mediated PML degradation and its impacts on tumor microenvironment. 126 Appendixes 127 Appendix 1. Screen for Cul4 substrate adaptors that regulate PML-I ubiquitination. 127 Appendix 2. WDR4 regulates PML ubiquitination. 128 Appendix 3. R219A mutant of WDR4 is defect in the ability for autoubiquitination and PML ubiquitination 129 Appendix 4. Identification of the region in WDR4 responsible for PML binding. 130 Appendix 5. dTL1, the PML-binding mutant of WDR4, cannot promote PML ubiquitination. 132 Appendix 6. R219A and dTL1 mutants of WDR4 cannot promote PML degradation. 133 Appendix 7. WDR4 reduces PML half-life. 134 Appendix 8. WDR4 R219A and dTL1 mutants do not significantly elevate the expression of CD73, uPAR and SAA2. 135 Appendix 9. CD73, uPAR and SAA2 are downstream effectors for the WDR4/PML axis. 136 Appendix 10. Hypoxia induces SAA2 expression in a HIF-1 dependent manner. 137 Appendix 11. WDR4/PML axis regulates CD73, uPAR and SAA2 through HIF-1. 138 Appendix 12. The activities of MMP2 and MMP9 are consistently upregulated by WDR4 overexpression and PML knockdown. 139 Appendix 13. WDR4 promotes lung cancer migration and invasion in vitro, which is reversed by PML knockdown. 140 Appendix 14. WDR4/PML axis facilitates lung cancer migration and invasion in vitro. 141 Appendix 15. The contribution of CD73/uPAR/SAA2 induction to WDR4/PML axis-promoted lung cell migration and invasion. 142 Appendix 16. WDR4/PML axis confers an environment beneficial for migration and invasion of lung cancer cells. 143 Appendix 17. CM derived from cells coexpressed PML-IV with WDR4 suppress WDR4-promoted migration and invasion of parental lung cancer cells. 144 Table 1: Summary of the IHC data of WDR4 expression in various malignant and benign tumors 145 Table 2: Information for antibodies used in this study 146 Table 3: Primers for quantitative PCR and mouse genotyping 148 Table 4: Targeting sequences for siRNAs and shRNAs 150 Table 5: Clinical pathological characteristics of lung cancer patients 151 | |
dc.language.iso | en | |
dc.title | WDR4驅動PML降解以形成免疫抑制及促進細胞轉移的肺腫瘤微環境之機制研究 | zh_TW |
dc.title | WDR4-driven PML destruction fosters immunosuppressive and pro-metastatic lung tumor microenvironment | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 周玉山(Yuh-Shan Jou),賴明宗(Ming-Zong Lai),施修明(Hsiu-Ming Shih),徐立中(Li-Chung Hsu) | |
dc.subject.keyword | PML,泛素化,細胞轉移,腫瘤免疫,肺癌, | zh_TW |
dc.subject.keyword | PML,ubiquitination,metastasis,tumor immunity,lung cancer, | en |
dc.relation.page | 151 | |
dc.identifier.doi | 10.6342/NTU201700779 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2017-05-01 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-106-1.pdf 目前未授權公開取用 | 7.19 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。