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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 | Chih-Chun Chan | en |
dc.contributor.author | 詹智鈞 | zh_TW |
dc.date.accessioned | 2021-06-16T10:14:57Z | - |
dc.date.available | 2018-09-06 | |
dc.date.copyright | 2013-09-06 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-19 | |
dc.identifier.citation | Adams, J. M. and S. Cory (2007). 'The Bcl-2 apoptotic switch in cancer development and therapy.' Oncogene 26(9): 1324-1337.
Adhikari, A. and Z. J. Chen (2009). 'Diversity of polyubiquitin chains.' Dev Cell 16(4): 485-486. Agrawal, S. G., F. T. Liu, C. Wiseman, S. Shirali, H. Liu, D. Lillington, M. Q. Du, D. Syndercombe-Court, A. C. Newland, J. G. Gribben and L. Jia (2008). 'Increased proteasomal degradation of Bax is a common feature of poor prognosis chronic lymphocytic leukemia.' Blood 111(5): 2790-2796. Aichberger, K. J., K. V. Gleixner, I. Mirkina, S. Cerny-Reiterer, B. Peter, V. Ferenc, M. Kneidinger, C. Baumgartner, M. Mayerhofer, A. Gruze, W. F. Pickl, C. Sillaber and P. Valent (2009). 'Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs.' Blood 114(26): 5342-5351. Akiyama, T., P. Bouillet, T. Miyazaki, Y. Kadono, H. Chikuda, U. I. Chung, A. Fukuda, A. Hikita, H. Seto, T. Okada, T. Inaba, A. Sanjay, R. Baron, H. Kawaguchi, H. Oda, K. Nakamura, A. Strasser and S. Tanaka (2003). 'Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim.' EMBO J 22(24): 6653-6664. Arena, V., M. Martini, M. Luongo, A. Capelli and L. M. Larocca (2003). 'Mutations of the BIK gene in human peripheral B-cell lymphomas.' Genes Chromosomes Cancer 38(1): 91-96. Bell, D. A., Y. Liu and G. A. Cortopassi (1995). 'Occurrence of bcl-2 oncogene translocation with increased frequency in the peripheral blood of heavy smokers.' J Natl Cancer Inst 87(3): 223-224. Benard, G., A. Neutzner, G. Peng, C. Wang, F. Livak, R. J. Youle and M. Karbowski (2010). 'IBRDC2, an IBR-type E3 ubiquitin ligase, is a regulatory factor for Bax and apoptosis activation.' EMBO J 29(8): 1458-1471. Boyd, J. M., G. J. Gallo, B. Elangovan, A. B. Houghton, S. Malstrom, B. J. Avery, R. G. Ebb, T. Subramanian, T. Chittenden, R. J. Lutz and et al. (1995). 'Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins.' Oncogene 11(9): 1921-1928. Bredel, M., C. Bredel, D. Juric, G. R. Harsh, H. Vogel, L. D. Recht and B. I. Sikic (2005). 'High-resolution genome-wide mapping of genetic alterations in human glial brain tumors.' Cancer Res 65(10): 4088-4096. 34 Broemer, M. and P. Meier (2009). 'Ubiquitin-mediated regulation of apoptosis.' Trends Cell Biol 19(3): 130-140. Bullock, A. N., J. E. Debreczeni, A. M. Edwards, M. Sundstrom and S. Knapp (2006). 'Crystal structure of the SOCS2-elongin C-elongin B complex defines a prototypical SOCS box ubiquitin ligase.' Proc Natl Acad Sci U S A 103(20): 7637-7642. Castells, A., Y. Ino, D. N. Louis, V. Ramesh, J. F. Gusella and A. K. Rustgi (1999). 'Mapping of a target region of allelic loss to a 0.5-cM interval on chromosome 22q13 in human colorectal cancer.' Gastroenterology 117(4): 831-837. Chao, D. T. and S. J. Korsmeyer (1998). 'BCL-2 family: regulators of cell death.' Annu Rev Immunol 16: 395-419. Chen, B., M. Retzlaff, T. Roos and J. Frydman (2011). 'Cellular strategies of protein quality control.' Cold Spring Harb Perspect Biol 3(8): a004374. Cheng, E. H., D. G. Kirsch, R. J. Clem, R. Ravi, M. B. Kastan, A. Bedi, K. Ueno and J. M. Hardwick (1997). 'Conversion of Bcl-2 to a Bax-like death effector by caspases.' Science 278(5345): 1966-1968. Cheng, E. H., M. C. Wei, S. Weiler, R. A. Flavell, T. W. Mak, T. Lindsten and S. J. Korsmeyer (2001). 'BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis.' Mol Cell 8(3): 705-711. Ciechanover, A., H. Heller, S. Elias, A. L. Haas and A. Hershko (1980). 'ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation.' Proc Natl Acad Sci U S A 77(3): 1365-1368. Ciechanover, A. and A. L. Schwartz (1998). 'The ubiquitin-proteasome pathway: the complexity and myriad functions of proteins death.' Proc Natl Acad Sci U S A 95(6): 2727-2730. Cohen, G. M. (1997). 'Caspases: the executioners of apoptosis.' Biochem J 326 ( Pt 1): 1-16. Cory, S. and J. M. Adams (2002). 'The Bcl2 family: regulators of the cellular life-or-death switch.' Nat Rev Cancer 2(9): 647-656. Cory, S., D. C. Huang and J. M. Adams (2003). 'The Bcl-2 family: roles in cell survival and oncogenesis.' Oncogene 22(53): 8590-8607. Cyr, D. M., J. Hohfeld and C. Patterson (2002). 'Protein quality control: U-box-containing E3 ubiquitin ligases join the fold.' Trends Biochem Sci 27(7): 368-375. Danial, N. N., C. F. Gramm, L. Scorrano, C. Y. Zhang, S. Krauss, A. M. Ranger, S. R. Datta, M. E. Greenberg, L. J. Licklider, B. B. Lowell, S. P. Gygi and S. J. Korsmeyer (2003). 'BAD and glucokinase reside in a mitochondrial complex 35 that integrates glycolysis and apoptosis.' Nature 424(6951): 952-956. Deshaies, R. J. (1999). 'SCF and Cullin/Ring H2-based ubiquitin ligases.' Annu Rev Cell Dev Biol 15: 435-467. Elangovan, B. and G. Chinnadurai (1997). 'Functional dissection of the pro-apoptotic protein Bik. Heterodimerization with anti-apoptosis proteins is insufficient for induction of cell death.' J Biol Chem 272(39): 24494-24498. Endo, T. A., M. Masuhara, M. Yokouchi, R. Suzuki, H. Sakamoto, K. Mitsui, A. Matsumoto, S. Tanimura, M. Ohtsubo, H. Misawa, T. Miyazaki, N. Leonor, T. Taniguchi, T. Fujita, Y. Kanakura, S. Komiya and A. Yoshimura (1997). 'A new protein containing an SH2 domain that inhibits JAK kinases.' Nature 387(6636): 921-924. Frenzel, A., F. Grespi, W. Chmelewskij and A. Villunger (2009). 'Bcl2 family proteins in carcinogenesis and the treatment of cancer.' Apoptosis 14(4): 584-596. Germain, M., J. P. Mathai and G. C. Shore (2002). 'BH-3-only BIK functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria.' J Biol Chem 277(20): 18053-18060. Gillissen, B., F. Essmann, V. Graupner, L. Starck, S. Radetzki, B. Dorken, K. Schulze-Osthoff and P. T. Daniel (2003). 'Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway.' EMBO J 22(14): 3580-3590. Gross, A., J. M. McDonnell and S. J. Korsmeyer (1999). 'BCL-2 family members and the mitochondria in apoptosis.' Genes Dev 13(15): 1899-1911. Hanada, M., C. Aime-Sempe, T. Sato and J. C. Reed (1995). 'Structure-function analysis of Bcl-2 protein. Identification of conserved domains important for homodimerization with Bcl-2 and heterodimerization with Bax.' J Biol Chem 270(20): 11962-11969. Hershko, A. and A. Ciechanover (1998). 'The ubiquitin system.' Annu Rev Biochem 67: 425-479. Hershko, A., A. Ciechanover, H. Heller, A. L. Haas and I. A. Rose (1980). 'Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis.' Proc Natl Acad Sci U S A 77(4): 1783-1786. Higa, L. A., M. Wu, T. Ye, R. Kobayashi, H. Sun and H. Zhang (2006). 'CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation.' Nat Cell Biol 8(11): 1277-1283. Hilton, D. J., R. T. Richardson, W. S. Alexander, E. M. Viney, T. A. Willson, N. S. Sprigg, R. Starr, S. E. Nicholson, D. Metcalf and N. A. Nicola (1998). 'Twenty proteins containing a C-terminal SOCS box form five structural classes.' Proc 36 Natl Acad Sci U S A 95(1): 114-119. Hinds, M. G., M. Lackmann, G. L. Skea, P. J. Harrison, D. C. Huang and C. L. Day (2003). 'The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity.' EMBO J 22(7): 1497-1507. Huibregtse, J. M., M. Scheffner, S. Beaudenon and P. M. Howley (1995). 'A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase.' Proc Natl Acad Sci U S A 92(7): 2563-2567. Inobe, T., S. Fishbain, S. Prakash and A. Matouschek (2011). 'Defining the geometry of the two-component proteasome degron.' Nat Chem Biol 7(3): 161-167. Inuzuka, H., S. Shaik, I. Onoyama, D. Gao, A. Tseng, R. S. Maser, B. Zhai, L. Wan, A. Gutierrez, A. W. Lau, Y. Xiao, A. L. Christie, J. Aster, J. Settleman, S. P. Gygi, A. L. Kung, T. Look, K. I. Nakayama, R. A. DePinho and W. Wei (2011). 'SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction.' Nature 471(7336): 104-109. Joazeiro, C. A. and A. M. Weissman (2000). 'RING finger proteins: mediators of ubiquitin ligase activity.' Cell 102(5): 549-552. Kaelin, W. G., Jr. (2002). 'Molecular basis of the VHL hereditary cancer syndrome.' Nat Rev Cancer 2(9): 673-682. Kamura, T., K. Maenaka, S. Kotoshiba, M. Matsumoto, D. Kohda, R. C. Conaway, J. W. Conaway and K. I. Nakayama (2004). 'VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases.' Genes Dev 18(24): 3055-3065. Kamura, T., S. Sato, D. Haque, L. Liu, W. G. Kaelin, Jr., R. C. Conaway and J. W. Conaway (1998). 'The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families.' Genes Dev 12(24): 3872-3881. Kipreos, E. T. and M. Pagano (2000). 'The F-box protein family.' Genome Biol 1(5): REVIEWS3002. Lecker, S. H., A. L. Goldberg and W. E. Mitch (2006). 'Protein degradation by the ubiquitin-proteasome pathway in normal and disease states.' J Am Soc Nephrol 17(7): 1807-1819. Lee, J. W., Y. H. Soung, S. Y. Kim, S. W. Nam, C. J. Kim, Y. G. Cho, J. H. Lee, H. S. Kim, W. S. Park, S. H. Kim, J. Y. Lee, N. J. Yoo and S. H. Lee (2004). 'Inactivating mutations of proapoptotic Bad gene in human colon cancers.' Carcinogenesis 25(8): 1371-1376. Letai, A., M. D. Sorcinelli, C. Beard and S. J. Korsmeyer (2004). 'Antiapoptotic BCL-2 is required for maintenance of a model leukemia.' Cancer Cell 6(3): 241-249. Ley, R., K. Balmanno, K. Hadfield, C. Weston and S. J. Cook (2003). 'Activation of the 37 ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim.' J Biol Chem 278(21): 18811-18816. Li, B. and Q. P. Dou (2000). 'Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression.' Proc Natl Acad Sci U S A 97(8): 3850-3855. Li, C., R. Li, J. R. Grandis and D. E. Johnson (2008). 'Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells.' Mol Cancer Ther 7(6): 1647-1655. Li, Y. M., Y. Wen, B. P. Zhou, H. P. Kuo, Q. Ding and M. C. Hung (2003). 'Enhancement of Bik antitumor effect by Bik mutants.' Cancer Res 63(22): 7630-7633. Liu, J. and R. Nussinov (2011). 'Flexible cullins in cullin-RING E3 ligases allosterically regulate ubiquitination.' J Biol Chem 286(47): 40934-40942. Lorick, K. L., J. P. Jensen, S. Fang, A. M. Ong, S. Hatakeyama and A. M. Weissman (1999). 'RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination.' Proc Natl Acad Sci U S A 96(20): 11364-11369. Lotan, R., A. Rotem, H. Gonen, J. P. Finberg, S. Kemeny, H. Steller, A. Ciechanover and S. Larisch (2005). 'Regulation of the proapoptotic ARTS protein by ubiquitin-mediated degradation.' J Biol Chem 280(27): 25802-25810. Mahrour, N., W. B. Redwine, L. Florens, S. K. Swanson, S. Martin-Brown, W. D. Bradford, K. Staehling-Hampton, M. P. Washburn, R. C. Conaway and J. W. Conaway (2008). 'Characterization of Cullin-box sequences that direct recruitment of Cul2-Rbx1 and Cul5-Rbx2 modules to Elongin BC-based ubiquitin ligases.' J Biol Chem 283(12): 8005-8013. Marshansky, V., X. Wang, R. Bertrand, H. Luo, W. Duguid, G. Chinnadurai, N. Kanaan, M. D. Vu and J. Wu (2001). 'Proteasomes modulate balance among proapoptotic and antiapoptotic Bcl-2 family members and compromise functioning of the electron transport chain in leukemic cells.' J Immunol 166(5): 3130-3142. Mathai, J. P., M. Germain and G. C. Shore (2005). 'BH3-only BIK regulates BAX,BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death.' J Biol Chem 280(25): 23829-23836. McDonnell, T. J. and S. J. Korsmeyer (1991). 'Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18).' Nature 349(6306): 254-256. 38 McLaughlin-Drubin, M. E. and K. Munger (2009). 'Oncogenic activities of human papillomaviruses.' Virus Res 143(2): 195-208. Mebratu, Y. A., B. F. Dickey, C. Evans and Y. Tesfaigzi (2008). 'The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFNgamma-induced cell death.' J Cell Biol 183(3): 429-439. Naka, T., M. Narazaki, M. Hirata, T. Matsumoto, S. Minamoto, A. Aono, N. Nishimoto, T. Kajita, T. Taga, K. Yoshizaki, S. Akira and T. Kishimoto (1997). 'Structure and function of a new STAT-induced STAT inhibitor.' Nature 387(6636): 924-929. Naujokat, C. and T. Saric (2007). 'Concise review: role and function of the ubiquitin-proteasome system in mammalian stem and progenitor cells.' Stem Cells 25(10): 2408-2418. Nguyen, M., D. G. Millar, V. W. Yong, S. J. Korsmeyer and G. C. Shore (1993). 'Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence.' J Biol Chem 268(34): 25265-25268. Nijhawan, D., M. Fang, E. Traer, Q. Zhong, W. Gao, F. Du and X. Wang (2003). 'Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation.' Genes Dev 17(12): 1475-1486. Nikrad, M., T. Johnson, H. Puthalalath, L. Coultas, J. Adams and A. S. Kraft (2005). 'The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim.' Mol Cancer Ther 4(3): 443-449. Niture, S. K. and A. K. Jaiswal (2011). 'INrf2 (Keap1) targets Bcl-2 degradation and controls cellular apoptosis.' Cell Death Differ 18(3): 439-451. Okumura, F., M. Matsuzaki, K. Nakatsukasa and T. Kamura (2012). 'The Role of Elongin BC-Containing Ubiquitin Ligases.' Front Oncol 2: 10. Petros, A. M., A. Medek, D. G. Nettesheim, D. H. Kim, H. S. Yoon, K. Swift, E. D. Matayoshi, T. Oltersdorf and S. W. Fesik (2001). 'Solution structure of the antiapoptotic protein bcl-2.' Proc Natl Acad Sci U S A 98(6): 3012-3017. Petros, A. M., D. G. Nettesheim, Y. Wang, E. T. Olejniczak, R. P. Meadows, J. Mack, K. Swift, E. D. Matayoshi, H. Zhang, C. B. Thompson and S. W. Fesik (2000). 'Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies.' Protein Sci 9(12): 2528-2534. Petroski, M. D. and R. J. Deshaies (2005). 'Function and regulation of cullin-RING ubiquitin ligases.' Nat Rev Mol Cell Biol 6(1): 9-20. Pintard, L., A. Willems and M. Peter (2004). 'Cullin-based ubiquitin ligases: Cul3-BTB complexes join the family.' EMBO J 23(8): 1681-1687. Reed, J. C. (2000). 'Mechanisms of apoptosis.' Am J Pathol 157(5): 1415-1430. 39 Reed, J. C., T. Miyashita, S. Takayama, H. G. Wang, T. Sato, S. Krajewski, C. Aime-Sempe, S. Bodrug, S. Kitada and M. Hanada (1996). 'BCL-2 family proteins: regulators of cell death involved in the pathogenesis of cancer and resistance to therapy.' J Cell Biochem 60(1): 23-32. Sarikas, A., T. Hartmann and Z. Q. Pan (2011). 'The cullin protein family.' Genome Biol 12(4): 220. Scheffner, M., U. Nuber and J. M. Huibregtse (1995). 'Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade.' Nature 373(6509): 81-83. Schrader, E. K., K. G. Harstad and A. Matouschek (2009). 'Targeting proteins for degradation.' Nat Chem Biol 5(11): 815-822. Schwickart, M., X. Huang, J. R. Lill, J. Liu, R. Ferrando, D. M. French, H. Maecker, K. O'Rourke, F. Bazan, J. Eastham-Anderson, P. Yue, D. Dornan, D. C. Huang and V. M. Dixit (2010). 'Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival.' Nature 463(7277): 103-107. Simmonds, M. and A. Storey (2008). 'Identification of the regions of the HPV 5 E6 protein involved in Bak degradation and inhibition of apoptosis.' Int J Cancer 123(10): 2260-2266. Skowyra, D., K. L. Craig, M. Tyers, S. J. Elledge and J. W. Harper (1997). 'F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex.' Cell 91(2): 209-219. Starr, R., T. A. Willson, E. M. Viney, L. J. Murray, J. R. Rayner, B. J. Jenkins, T. J. Gonda, W. S. Alexander, D. Metcalf, N. A. Nicola and D. J. Hilton (1997). 'A family of cytokine-inducible inhibitors of signalling.' Nature 387(6636): 917-921. Stebbins, C. E., W. G. Kaelin, Jr. and N. P. Pavletich (1999). 'Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.' Science 284(5413): 455-461. Sturm, I., C. Stephan, B. Gillissen, R. Siebert, M. Janz, S. Radetzki, K. Jung, S. Loening, B. Dorken and P. T. Daniel (2006). 'Loss of the tissue-specific proapoptotic BH3-only protein Nbk/Bik is a unifying feature of renal cell carcinoma.' Cell Death Differ 13(4): 619-627. Thompson, S., A. N. Pearson, M. D. Ashley, V. Jessick, B. M. Murphy, P. Gafken, D. C. Henshall, K. T. Morris, R. P. Simon and R. Meller (2011). 'Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection.' J Biol Chem 286(22): 19331-19339. Tong, Y., Q. Yang, C. Vater, L. K. Venkatesh, D. Custeau, T. Chittenden, G. Chinnadurai and H. Gourdeau (2001). 'The pro-apoptotic protein, Bik, exhibits potent 40 antitumor activity that is dependent on its BH3 domain.' Mol Cancer Ther 1(2): 95-102. Tsujimoto, Y. (1998). 'Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria?' Genes Cells 3(11): 697-707. Underbrink, M. P., H. L. Howie, K. M. Bedard, J. I. Koop and D. A. Galloway (2008). 'E6 proteins from multiple human betapapillomavirus types degrade Bak and protect keratinocytes from apoptosis after UVB irradiation.' J Virol 82(21): 10408-10417. Verma, S., M. L. Budarf, B. S. Emanuel and G. Chinnadurai (2000). 'Structural analysis of the human pro-apoptotic gene Bik: chromosomal localization, genomic organization and localization of promoter sequences.' Gene 254(1-2): 157-162. Wang, K., X. M. Yin, D. T. Chao, C. L. Milliman and S. J. Korsmeyer (1996). 'BID: a novel BH3 domain-only death agonist.' Genes Dev 10(22): 2859-2869. Wang, Y., R. Cao, D. Liu, A. Chervin, J. Yuan, J. An and Z. Huang (2007). 'Oligomerization of BH4-truncated Bcl-x(L) in solution.' Biochem Biophys Res Commun 361(4): 1006-1011. Wei, M. C., W. X. Zong, E. H. Cheng, T. Lindsten, V. Panoutsakopoulou, A. J. Ross, K. A. Roth, G. R. MacGregor, C. B. Thompson and S. J. Korsmeyer (2001). 'Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.' Science 292(5517): 727-730. Westphal, D., G. Dewson, P. E. Czabotar and R. M. Kluck (2011). 'Molecular biology of Bax and Bak activation and action.' Biochim Biophys Acta 1813(4): 521-531. Zhang, J. G., A. Farley, S. E. Nicholson, T. A. Willson, L. M. Zugaro, R. J. Simpson, R. L. Moritz, D. Cary, R. Richardson, G. Hausmann, B. J. Kile, S. B. Kent, W. S. Alexander, D. Metcalf, D. J. Hilton, N. A. Nicola and M. Baca (1999). 'The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation.' Proc Natl Acad Sci U S A 96(5): 2071-2076. Zhong, Q., W. Gao, F. Du and X. Wang (2005). 'Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis.' Cell 121(7): 1085-1095. Zhu, H., L. Zhang, F. Dong, W. Guo, S. Wu, F. Teraishi, J. J. Davis, P. J. Chiao and B. Fang (2005). 'Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors.' Oncogene 24(31): 4993-4999. Zimmerman, E. S., B. A. Schulman and N. Zheng (2010). 'Structural assembly of cullin-RING ubiquitin ligase complexes.' Curr Opin Struct Biol 20(6): 41 714-721. Zinkel, S. S., K. E. Hurov, C. Ong, F. M. Abtahi, A. Gross and S. J. Korsmeyer (2005). 'A role for proapoptotic BID in the DNA-damage response.' Cell 122(4): 579-591. Zong, W. X., T. Lindsten, A. J. Ross, G. R. MacGregor and C. B. Thompson (2001). 'BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak.' Genes Dev 15(12): 1481-1486. Zou, Y., H. Peng, B. Zhou, Y. Wen, S. C. Wang, E. M. Tsai and M. C. Hung (2002). 'Systemic tumor suppression by the proapoptotic gene bik.' Cancer Res 62(1): 8-12. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60292 | - |
dc.description.abstract | BIK (Bcl-2-interacting killer) 為促進凋亡之BH3-only家族中的一員,在癌症中扮演了腫瘤抑制者的角色。最近發現,BIK可作為抗癌藥物之有效標的。抗癌藥物Bortezomib處理下會導致BIK的堆積,暗示著BIK的降解可能參與了腫瘤的生成。為了找出蛋白酶體降解BIK之機制,我們想找出負責降解BIK的E3接合酶。目前已知Cullin-RING接合酶為最普遍的E3接合酶。透過表現各種不同Cullin的顯性失活突變體在293T細胞中,我們發現Cul2和Cul5可能影響BIK表現。已知Cul2和Cul5必須透過受質辨識單元 (substrate recognition subunit; SRS) 來辨認受質,為了找出可辨識BIK、並與Cul2或Cul5以及Elongin BC結合之受質辨識單元,我們建構了51個受質辨識單元,並將其個別表現在293T細胞中。由GST pull-down實驗發現有6個受質辨識單元可與BIK結合,當中KLHDC3、ASB1及ASB7在後續實驗證明能抑制BIK蛋白表現。然而,這三個蛋白質中,只有剔除ASB7的表現會增加BIK的蛋白質量,以及延長BIK降解之半衰期。細胞中若同時表現Cul5接合酶複合體及ASB7時,會大幅促進BIK泛素化修飾程度。總而言之,我們發現Cul5-ROC2-Elongin BC與ASB7形成之泛素接合酶複合體,能促進BIK之泛素化進而降解。生物資訊學的分析發現,不論是ASB7蛋白質及其mRNA,在某些癌症有較高的表現,後續我們會去確認在這些癌症中ASB7是否會抑制BIK的表現。 | zh_TW |
dc.description.abstract | BIK (Bcl-2-interacting killer), a BH3-only pro-apoptotic protein, functions as a tumor suppressor in human cancer. Recently, BIK has emerged as a prominent target of anti-cancer drugs. Treatment of certain cancer cells with the proteasome inhibitor-Bortezomib leads to BIK accumulation, implying the importance of BIK proteasomal degradation pathway in cancer biology. To demonstrate the underlying mechanisms of BIK degradation, we intend to identify the ubiquitin E3 ligase of BIK. Cullin-RING ligases represent the largest ubiquitin ligase family. By overexpressing various dominant-negative forms of cullins in 293T cells, we identified Cullin2 (Cul2)- and Cullin5 (Cul5)- ligases as candidate regulators of BIK protein level. Both Cul2 and Cul5 are Elongin BC-based E3 ligases and require a substrate recognition subunit (SRS) for substrate recruitment. To identify the SRS that links Cul/Elongin BC to BIK, we cloned and overexpressed 51 SRSs in 293T cells. Among them, we identified six SRSs that could interact with BIK by GST pull-down assay. By overexpressing these SRSs individually into 293T cells, we showed that KLHDC3, ASB1 and ASB7 could downregulate BIK expression. However, only knockdown of ASB7 increased BIK protein level and prolonged BIK half-life. Cotransfection of Cul5-based complex and ASB7 together led to a great induction of BIK polyubiquitination. Together, our study identified an ubiquitin E3 ligase complex containing ROC2, Cul5, Elongin BC, and ASB7, which is responsible for BIK ubiquitination and degradation. Bioinformatics analysis revealed that ASB7 mRNA and protein are upregulated in certain types of cancers. Future study will aim to determine whether ASB7 contributes to BIK downregulation in these tumors. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T10:14:57Z (GMT). No. of bitstreams: 1 ntu-102-R00B46012-1.pdf: 1855640 bytes, checksum: 1d443f9a36b6eb3f0880187e1a727068 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 中文摘要 ....i
Abstract .... ii I. Introduction ..... 1 1. The ubiquitin-proteasome system .... 2 1.1 The E3 ubiquitin ligases .... 3 1.2 The Cullin-RING E3 ligases..... 4 1.3 The SOCS box protein family .... 6 2. Bcl-2 family proteins .... 7 2.1 An overview .... 7 2.2 The BIK protein .... 11 3. Ubiquitination of Bcl-2 family proteins in regulation of apoptosis.... 13 II. Materials and methods .... 17 Plasmids .... 18 Cell culture and transient transfection .... 18 Antibodies and reagents.... 19 Western blotting .... 19 GST pull-down assay .... 20 Establishment of KLHDC3, ASB1 and ASB7 knockdown lines by lentivirus system .... 20 RT/real-time PCR .... 21 In vivo ubiquitination assay .... 21 In vivo degradation assay .... 22 III. Results .... 23 BIK undergoes proteasomal degradation .... 24 BIK is modified by ubiquitination .... 24 BIK protein expression is upregulated by dominant negative mutants of Cullin2 (Cul2) and Cullin5 (Cul5).... 25 Identification of the substrate recognition subunits (SRSs) that interact with BIK ....25 ASB7 overexpression decreases BIK steady-state level and ASB7 depletion increases BIK protein expression .... 26 The SOCS box of ASB7 is critical for downregulating BIK protein expression .... 27 ASB7-associated Cul5 E3 ligase complex promotes the ubiquitination of BIK in vivo .... 28 IV. Discussion .... 29 V. Reference .... 33 VI. Figures and Tables .... 42 | |
dc.language.iso | zh-TW | |
dc.title | 探討BIK之泛素化降解機制 | zh_TW |
dc.title | The mechanism of BIK proteasomal degradation | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 張久瑗(Jeou-Yuan Chen),陳宏文(Hung-Wen Chen) | |
dc.subject.keyword | BIK,蛋白酶,體,泛素化,E3接合酶,Cul5,受質辨識單元,ASB7, | zh_TW |
dc.subject.keyword | BIK,proteasome,ubiquitination,E3 ligase,Cul5,SRS,ASB7, | en |
dc.relation.page | 62 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-08-19 | |
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 |
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