請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37229
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 徐立中(Li-Chung Hsu) | |
dc.contributor.author | I-Lin Ho | en |
dc.contributor.author | 何宜霖 | zh_TW |
dc.date.accessioned | 2021-06-13T15:21:57Z | - |
dc.date.available | 2016-10-05 | |
dc.date.copyright | 2011-10-05 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-08-11 | |
dc.identifier.citation | Azuma, Y., S. H. Tan, et al. (2001). 'Expression and regulation of the mammalian SUMO-1 E1 enzyme.' FASEB J 15(10): 1825-1827.
Balkwill, F. and A. Mantovani (2001). 'Inflammation and cancer: back to Virchow?' Lancet 357(9255): 539-545. Bonizzi, G. and M. Karin (2004). 'The two NF-kappaB activation pathways and their role in innate and adaptive immunity.' Trends Immunol 25(6): 280-288. Cao, Y., G. Bonizzi, et al. (2001). 'IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development.' Cell 107(6): 763-775. Chaffer, C. L. and R. A. Weinberg (2011). 'A perspective on cancer cell metastasis.' Science 331(6024): 1559-1564. Colotta, F., P. Allavena, et al. (2009). 'Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.' Carcinogenesis 30(7): 1073-1081. Condeelis, J. and J. W. Pollard (2006). 'Macrophages: obligate partners for tumor cell migration, invasion, and metastasis.' Cell 124(2): 263-266. Coussens, L. M. and Z. Werb (2002). 'Inflammation and cancer.' Nature 420(6917): 860-867. De Santa, F., M. G. Totaro, et al. (2007). 'The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing.' Cell 130(6): 1083-1094. Fried, H. and U. Kutay (2003). 'Nucleocytoplasmic transport: taking an inventory.' Cell Mol Life Sci 60(8): 1659-1688. Gill, G. (2004). 'SUMO and ubiquitin in the nucleus: different functions, similar mechanisms?' Genes Dev 18(17): 2046-2059. Grivennikov, S. I., F. R. Greten, et al. (2010). 'Immunity, inflammation, and cancer.' Cell 140(6): 883-899. Grivennikov, S. I. and M. Karin (2010). 'Inflammation and oncogenesis: a vicious connection.' Curr Opin Genet Dev 20(1): 65-71. Haglund, K. and I. Dikic (2005). 'Ubiquitylation and cell signaling.' EMBO J 24(19): 3353-3359. Hayden, M. S. and S. Ghosh (2004). 'Signaling to NF-kappaB.' Genes Dev 18(18): 2195-2224. Huang, W. C., W. S. Chen, et al. (2011). 'Hepatitis B Virus X protein induces IKKalpha nuclear translocation via Akt-dependent phosphorylation to promote the motility of hepatocarcinoma cells.' J Cell Physiol. Huber, M. A., N. Azoitei, et al. (2004). 'NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression.' J Clin Invest 114(4): 569-581. Ishov, A. M., A. G. Sotnikov, et al. (1999). 'PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1.' J Cell Biol 147(2): 221-234. Jemal, A., F. Bray, et al. (2011). 'Global cancer statistics.' CA Cancer J Clin 61(2): 69-90. Kang, J. S., E. F. Saunier, et al. (2008). 'The type I TGF-beta receptor is covalently modified and regulated by sumoylation.' Nat Cell Biol 10(6): 654-664. Khasawneh, J., M. D. Schulz, et al. (2009). 'Inflammation and mitochondrial fatty acid beta-oxidation link obesity to early tumor promotion.' Proc Natl Acad Sci U S A 106(9): 3354-3359. Kim, K. I. and S. H. Baek (2009). 'Small ubiquitin-like modifiers in cellular malignancy and metastasis.' Int Rev Cell Mol Biol 273: 265-311. Kirsh, O., J. S. Seeler, et al. (2002). 'The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase.' EMBO J 21(11): 2682-2691. Lin, X., B. Sun, et al. (2003). 'Opposed regulation of corepressor CtBP by SUMOylation and PDZ binding.' Mol Cell 11(5): 1389-1396. Luo, J. L., W. Tan, et al. (2007). 'Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin.' Nature 446(7136): 690-694. Mantovani, A., P. Allavena, et al. (2008). 'Cancer-related inflammation.' Nature 454(7203): 436-444. Meira, L. B., J. M. Bugni, et al. (2008). 'DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice.' J Clin Invest 118(7): 2516-2525. Melchior, F., M. Schergaut, et al. (2003). 'SUMO: ligases, isopeptidases and nuclear pores.' Trends Biochem Sci 28(11): 612-618. Meluh, P. B. and D. Koshland (1995). 'Evidence that the MIF2 gene of Saccharomyces cerevisiae encodes a centromere protein with homology to the mammalian centromere protein CENP-C.' Mol Biol Cell 6(7): 793-807. Naugler, W. E., T. Sakurai, et al. (2007). 'Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.' Science 317(5834): 121-124. Nguyen, D. X., P. D. Bos, et al. (2009). 'Metastasis: from dissemination to organ-specific colonization.' Nat Rev Cancer 9(4): 274-284. Okayasu, I., T. Ohkusa, et al. (1996). 'Promotion of colorectal neoplasia in experimental murine ulcerative colitis.' Gut 39(1): 87-92. Park, E. J., J. H. Lee, et al. (2010). 'Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.' Cell 140(2): 197-208. Perkins, N. D. (2007). 'Integrating cell-signalling pathways with NF-kappaB and IKK function.' Nat Rev Mol Cell Biol 8(1): 49-62. Pichler, A. and F. Melchior (2002). 'Ubiquitin-related modifier SUMO1 and nucleocytoplasmic transport.' Traffic 3(6): 381-387. Renner, F., R. Moreno, et al. (2010). 'SUMOylation-dependent localization of IKKepsilon in PML nuclear bodies is essential for protection against DNA-damage-triggered cell death.' Mol Cell 37(4): 503-515. Rius, J., M. Guma, et al. (2008). 'NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha.' Nature 453(7196): 807-811. Rodriguez, M. S., C. Dargemont, et al. (2001). 'SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting.' J Biol Chem 276(16): 12654-12659. Sachdev, S., L. Bruhn, et al. (2001). 'PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies.' Genes Dev 15(23): 3088-3103. Seeler, J. S., O. Bischof, et al. (2007). 'SUMO, the three Rs and cancer.' Curr Top Microbiol Immunol 313: 49-71. Seeler, J. S., A. Marchio, et al. (2001). 'Common properties of nuclear body protein SP100 and TIF1alpha chromatin factor: role of SUMO modification.' Mol Cell Biol 21(10): 3314-3324. Sil, A. K., S. Maeda, et al. (2004). 'IkappaB kinase-alpha acts in the epidermis to control skeletal and craniofacial morphogenesis.' Nature 428(6983): 660-664. Takahashi, H., H. Ogata, et al. (2010). 'Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation.' Cancer Cell 17(1): 89-97. Tan, W., W. Zhang, et al. (2011). 'Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling.' Nature 470(7335): 548-553. Walther, T. C., H. S. Pickersgill, et al. (2002). 'The cytoplasmic filaments of the nuclear pore complex are dispensable for selective nuclear protein import.' J Cell Biol 158(1): 63-77. Wilkinson, K. A. and J. M. Henley (2010). 'Mechanisms, regulation and consequences of protein SUMOylation.' Biochem J 428(2): 133-145. Wong, B. R., R. Josien, et al. (1998). 'The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor.' J Biol Chem 273(43): 28355-28359. Wong, V. W., J. Yu, et al. (2009). 'High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B.' Int J Cancer 124(12): 2766-2770. Yan, S. R., R. R. Joseph, et al. (2005). 'Activation of NF-kappaB following detachment delays apoptosis in intestinal epithelial cells.' Oncogene 24(43): 6482-6491. Yang, J. and R. A. Weinberg (2008). 'Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis.' Dev Cell 14(6): 818-829. Yu, H., M. Kortylewski, et al. (2007). 'Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment.' Nat Rev Immunol 7(1): 41-51. Zhang, H., H. Saitoh, et al. (2002). 'Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex.' Mol Cell Biol 22(18): 6498-6508. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37229 | - |
dc.description.abstract | 癌症雄踞各大死因之首已有十數年之久,而癌症轉移更是造成百分之九十以上癌症死亡的主要因素。轉錄因子NF-κB 對於調控許多細胞反應佔有極重要的角色,然而,NF-κB也被證明參與於癌症的發生中。由IKKα,IKKβ與IKKγ共同組成的IKK複合體是調控NF-κB訊息傳遞路徑的主要調控者。近年來,有研究指出在前列腺癌與乳癌中, RANKL會刺激IKKα進入細胞核中並抑制一轉移抑制蛋白質Maspin,進而促使癌症轉移發生。儘管IKKα的細胞核定位訊號(Nuclear localization signal)已經被發現, IKKα入核的詳細分子機制仍舊不清楚。
在此份研究中,我們在人類乳癌細胞MCF-7中發現了一個調控IKKα入核的新分子機制。小泛素化(SUMOylation)是一種普遍的轉譯後化學性修飾,並參與在許多重要的細胞反應中,包含調控細胞質與細胞核之間的物質運輸。當乳癌細胞處於細胞脫離(cell detachment)或RANKL的刺激下時,我們觀察到IKKα進入細胞核並伴隨著小泛素化的發生。除此之外,我們也發現在RANKL的刺激下,IKKα會與一SUMO E3 ligase RanBP2交互作用,顯示RanBP2可能參與於IKKα的小泛素化。在IKKα小泛素化去除之後,IKKα進入細胞核的量減少,同時也抑制了乳癌細胞的遷移能力。總而言之,我們發現了IKKα入核需要小泛素化的修飾,並且去除掉小泛素化可以降低乳癌細胞的遷移能力。這樣的研究結果可望對乳癌發生提供一些新的觀點,並希望能應用於乳癌治療上。 | zh_TW |
dc.description.abstract | Cancer is the major cause of death worldwide, and cancer metastasis is the critical factor with a poor prognosis resulting in a mortality rate of more than 90%. Transcription factor NF-κB is pivotal for many cellular responses, however, NF-κB has also been demonstrated to be involved in cancer development and progression. IKK complex, which is composed of IKKα, IKKβ and IKKγ, is the key regulator in NF-κB signaling pathway. Recently, IKKα has been reported to promote prostate cancer and breast cancer metastasis by activating its nuclear translocation leading to repress metastatic inhibitor, Maspin after RANKL engagement. Although the nuclear localization signal of IKKα has been already identified, the molecular mechanism of IKKα nuclear translocation still remains to be investigated.
In this study, we unraveled a novel mechanism of IKKα nuclear translocation in human breast cancer cell MCF-7. Post-translational modifications confer many important cellular responses, including cytoplasmic-nuclear transport. Upon the stimulation of cell detachment and RANKL engagement, we observed IKKα nuclear translocation, which is accompanied with a post-translational modification. The abolishment of the post-translational modification can inhibit IKKα nuclear translocation and decreased cancer cell migration. Taken together, we demonstrated that the post-translational modification is required for IKKα nuclear translocation, and the abolishment of the post-translational modification can decrease breast cancer cell migration. This study should provide new insights into the regulation of breast cancer progression and contribute to therapy of breast cancer. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T15:21:57Z (GMT). No. of bitstreams: 1 ntu-100-R98448003-1.pdf: 2067250 bytes, checksum: 7fe70d4107bfee380ba6e8af559c50a3 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | 摘要.......................................................1
Abstract...................................................2 Contents...................................................4 Introduction...............................................6 NF-κB signaling.........................................6 NF-κB and tumor progression.............................8 Tumor initiation.........................................8 Tumor promotion.........................................10 Tumor metastasis........................................11 SUMOylation machinery...................................15 Specific aim............................................17 Materials and Methods.....................................19 Reagents..................................................19 Plasmids..................................................19 Cell culture and transfection.............................21 Generation of IKKα-silenced and expressed MCF-7 cells....22 Preparation of whole cell lysate.........................23 Preparation of nuclear and cytosolic extracts............23 Immunoblotting...........................................24 Immnoprecipitation.......................................25 GST protein purification.................................25 Immnofluorescence staining...............................27 Migration assay..........................................27 statistic analysis.......................................28 Results..................................................29 1. Detachment induced IKKa phosphorylation and nuclear translocation in human breast cancer cell line MCF 7........................................................29 2. MCF-7 cells detachment leaded to IKKα SUMOylaiton...30 3. MCF-7 cells detachment induced association of IKKα with RanBP2..............................................31 4 RANKL induced IKKα nuclear translocation and SUMOylation in MCF-7 Cells...............................32 5. SUMOylation is required for IKKα nuclear translocation............................................34 6. Inhibition of IKKα nuclear translocationdecreased cancer cell migration....................................35 Discussion...............................................37 Figures..................................................44 Figure 1..............................................44 Figure 2..............................................45 Figure 3..............................................47 Figure 4..............................................49 Figure 5..............................................50 Figure 6..............................................52 Figure 7..............................................54 Figure 8..............................................56 Figure 9............................................58 Figure 10..............................................60 Reference.................................................61 | |
dc.language.iso | en | |
dc.title | IKKα 小泛素化在乳癌細胞遷移中扮演的角色 | zh_TW |
dc.title | The role of IKKα SUMOylation in breast cancer cell migration | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 楊性芳(Hsin-Fang Yang-Yen),陳俊任(Chun Jen Chen) | |
dc.subject.keyword | IKKa,小泛素化,乳癌, | zh_TW |
dc.subject.keyword | SUMOylation,IKKa,breast cancer, | en |
dc.relation.page | 65 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-08-11 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-100-1.pdf 目前未授權公開取用 | 2.02 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。