跳到主要內容

臺灣博碩士論文加值系統

(18.205.192.201) 您好!臺灣時間:2021/08/05 10:46
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:蔡元皓
研究生(外文):Yuan-Hau Tsai
論文名稱:卡波西氏瘤疱疹病毒K15蛋白之功能性研究
論文名稱(外文):Functional analysis of Kaposi’s Sarcoma-associated Herpesvirus K15 proteins
指導教授:王學偉王學偉引用關係
指導教授(外文):Hsei-wei Wang
學位類別:博士
校院名稱:國立陽明大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:84
中文關鍵詞:卡波西氏瘤疱疹病毒細胞移動性微型核醣核酸
外文關鍵詞:Kaposi’s Sarcoma-associated HerpesvirusKSHV K15migrationmicroRNA
相關次數:
  • 被引用被引用:0
  • 點閱點閱:112
  • 評分評分:
  • 下載下載:16
  • 收藏至我的研究室書目清單書目收藏:0
卡波西氏瘤相關疱疹病毒(KSHV)是造成卡波西氏瘤(KS)的主要原因,在臨床上卡波西氏瘤會隨著病程發展而呈現全身性的病灶,甚至轉移到肺臟或淋巴系統。而在過去的實驗中也發現KSHV會促進內皮細胞侵犯的能力。K15基因是KSHV特有的基因,會表現出具有trans-membrane domain的膜蛋白。K15蛋白在不同的的病毒株中發現有不同的亞型,目前主要發現的有predominant (P) form及minor (M) form兩種(分別命名為K15P and K15M)。K15基因與EBV(Epstein-Barr Virus)的LMP2A基因在基因體的分布位置上相似,所表現出的蛋白結構也十分類似。另外K15蛋白與另一EB病毒之LMP1蛋白同樣具有特殊的蛋白質序列片段。因此KSHV的K15蛋白似乎是LMP2A及LMP1兩個蛋白的混合體,同時具有兩者之許多特色。過去的研究也指出LMP2A及LMP1蛋白都具有促進細胞移動或促進轉移的能力,因此我們想了解K15蛋白是否也具有相同的能力。在本論文研究中,我們發現K15P及K15M都可以增進細胞的移動性;同時在剔除內生性的表現時,也可以觀察到KSHV所導致的細胞移動能力會因為喪失K15蛋白表現而降低。在機制上,發現兩者促進細胞移動的機制不盡相同。K15P蛋白主要藉由與Hax-1蛋白的結合而促進細胞移動,同時C端上Y481氨基酸亦會影響細胞的移動。而在K15M方面,其C端上的Y490氨基酸的磷酸化是主要影響細胞移動的因子。K15M上的Y490氨基酸會促進microRNA31及microRNA21的表現,並藉由調控microRNA的表現促進細胞的移動。就本研究結果,我們認為KSHV所表現的K15蛋白,不論是P-form或是M-form都會促進細胞的移動性,但所利用的機轉不盡相同。這樣的結論也在治療KSHV相關的腫瘤上提供了新的可能性。
Kaposi’s sarcoma (KS) associated herpesvirus (KSHV) is the etiological agent of KS. In vivo KS is a tumor capable of spreading throughout the body and pulmonary metastasis is observed clinically. In vitro KSHV induces the invasiveness of endothelial cells. The KSHV ORF K15 is a KSHV-specific gene encoding a transmembrane protein. Two highly divergent forms of K15, the predominant (P) and minor (M) forms (K15P and K15M, respectively) have been identified in different KSHV strains. The two K15 alleles resemble the LMP2A gene of Epstein-Barr virus (EBV) in their genomic locations and protein topology. Also, both K15 proteins have similar motifs to those found in EBV LMP1 protein. K15 therefore appears to be a hybrid of a distant evolutionary relative of EBV LMP1 and 2A. Since both LMP1 and LMP2A proteins are capable of inducing cell motility, we questioned whether K15 posses similar abilities. In this study, we show that both K15P and K15M can induce cell migration ability. Knockdown of either form of K15 protein can abolish KSHV induced cell migration in PEL cells or KSHV infected HMEC-1 cells indicate that both K15P and K15M contribute in KSHV induced cell migration. Although both form of K15 protein can induce cell migration but different mechanism is applied in P or M form K15 induced cell migration. In our data, K15P induce migration via Hax-1 mediated mechanism, and phosphorylation of Y481 residue of YEEV SH2-B motif is also involved. In the case of K15M, phosphorylation of Y490 of SH2-B motif is involved in K15M induced cell migration. We also demonstrate that miR-31 and miR-21 play roles in K15M induced cell migration and are mediated by K15M Y490 phosphorylation. Collectively, our data suggest that KSHV encoded K15 protein can induce cell migration in both P and M form but through different mechanism. Therefore, the targeting of K15 or the downstream regulators may represent novel therapies for treatment of KSHV-associated neoplasia.
摘要 ------------------------------------------------------------------------------------------------2
ABSTRACT ---------------------------------------------------------------------------------------3
序論 ------------------------------------------------------------------------------------------------4
材料與方法 -------------------------------------------------------------------------------------16
結果 ----------------------------------------------------------------------------------------------30
討論 ---------------------------------------------------------------------------------------------40
參考文獻 ---------------------------------------------------------------------------------------44
圖表 ---------------------------------------------------------------------------------------------56
附錄 ---------------------------------------------------------------------------------------------74
Alagiozoglou, L., F. Sitas and L. Morris (2000). "Phylogenetic analysis of human herpesvirus-8 in South Africa and identification of a novel subgroup." J Gen Virol 81(Pt 8): 2029-38.

Arvanitakis, L., E. A. Mesri, R. G. Nador, J. W. Said, A. S. Asch, D. M. Knowles and E. Cesarman (1996). "Establishment and characterization of a primary effusion (body cavity-based) lymphoma cell line (BC-3) harboring kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) in the absence of Epstein-Barr virus." Blood 88(7): 2648-54.

Asangani, I. A., S. A. K. Rasheed, D. A. Nikolova, J. H. Leupold, N. H. Colburn, S. Post and H. Allgayer (2007). "MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer." Oncogene 27(15): 2128-2136.

Barozzi, P., M. Luppi, F. Facchetti, C. Mecucci, M. Alù, R. Sarid, V. Rasini, L. Ravazzini, E. Rossi, S. Festa, B. Crescenzi, D. G. Wolf, T. F. Schulz and G. Torelli (2003). "Post-transplant Kaposi sarcoma originates from the seeding of donor-derived progenitors." Nat Med 9(5): 554-61.

Boshoff, C., T. F. Schulz, M. M. Kennedy, A. K. Graham, C. Fisher, A. Thomas, J. O. McGee, R. A. Weiss and J. J. O'Leary (1995). "Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells." Nat Med 1(12): 1274-8.

Brinkmann, M. M., M. Glenn, L. Rainbow, A. Kieser, C. Henke-Gendo and T. F. Schulz (2003). "Activation of mitogen-activated protein kinase and NF-kappaB pathways by a Kaposi's sarcoma-associated herpesvirus K15 membrane protein." J Virol 77(17): 9346-58.

Brinkmann, M. M., M. Pietrek, O. Dittrich-Breiholz, M. Kracht and T. F. Schulz (2007). "Modulation of host gene expression by the K15 protein of Kaposi's sarcoma-associated herpesvirus." J Virol 81(1): 42-58.

Cesarman, E., P. S. Moore, P. H. Rao, G. Inghirami, D. M. Knowles and Y. Chang (1995). "In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DNA sequences." Blood 86(7): 2708-14.

Cesarman, E., R. G. Nador, K. Aozasa, G. Delsol, J. W. Said and D. M. Knowles (1996). "Kaposi's sarcoma-associated herpesvirus in non-AIDS related lymphomas occurring in body cavities." Am J Pathol 149(1): 53-7.

Chang, Y., E. Cesarman, M. S. Pessin, F. Lee, J. Culpepper, D. M. Knowles and P. S. Moore (1994). "Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma." Science 266(5192): 1865-9.

Cheung, L. and S. G. Rockson (2005). "The lymphatic biology of Kaposi's sarcoma." Lymphatic research and biology 3(1): 25-35.
Cho, W. C. (2007). "OncomiRs: the discovery and progress of microRNAs in cancers." Mol Cancer 6: 60.

Choi, J. K., B. S. Lee, S. N. Shim, M. Li and J. U. Jung (2000). "Identification of the novel K15 gene at the rightmost end of the Kaposi's sarcoma-associated herpesvirus genome." J Virol 74(1): 436-46.

Cook, P. M., D. Whitby, M. L. Calabro, M. Luppi, D. N. Kakoola, H. Hjalgrim, K. Ariyoshi, B. Ensoli, A. J. Davison and T. F. Schulz (1999). "Variability and evolution of Kaposi's sarcoma-associated herpesvirus in Europe and Africa. International Collaborative Group." AIDS 13(10): 1165-76.

Damania, B. (2004). "Oncogenic gamma-herpesviruses: comparison of viral proteins involved in tumorigenesis." Nat Rev Microbiol 2(8): 656-68.

Du, M. Q., H. Liu, T. C. Diss, H. Ye, R. A. Hamoudi, N. Dupin, V. Meignin, E. Oksenhendler, C. Boshoff and P. Isaacson (2001). "Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders." Blood 97(7): 2130-6.

Dupin, N., C. Fisher, P. Kellam, S. Ariad, M. Tulliez, N. Franck, E. van Marck, D. Salmon, I. Gorin, J. P. Escande, R. A. Weiss, K. Alitalo and C. Boshoff (1999). "Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma." Proc Natl Acad Sci USA 96(8): 4546-51.
Ensoli, B., G. Barillari, S. Z. Salahuddin, R. C. Gallo and F. Wong-Staal (1990). "Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients." Nature 345(6270): 84-6.

Foreman, K. E. (2001). "Kaposis sarcoma: the role of HHV-8 and HIV-1 in pathogenesis." Expert reviews in molecular medicine 2001: 1-17.

Gaidano, G. and A. Carbone (2001). "Primary effusion lymphoma: a liquid phase lymphoma of fluid-filled body cavities." Adv Cancer Res 80: 115-46.

Gill, P. S., Y. C. Tsai, A. P. Rao, C. H. Spruck, T. Zheng, W. A. Harrington, T. Cheung, B. Nathwani and P. A. Jones (1998). "Evidence for multiclonality in multicentric Kaposi's sarcoma." Proc Natl Acad Sci USA 95(14): 8257-61.

Glenn, M., L. Rainbow, F. Auradé, A. Davison and T. F. Schulz (1999). "Identification of a spliced gene from Kaposi's sarcoma-associated herpesvirus encoding a protein with similarities to latent membrane proteins 1 and 2A of Epstein-Barr virus." J Virol 73(8): 6953-63.

Grandadam, M., N. Dupin, V. Calvez, I. Gorin, L. Blum, S. Kernbaum, D. Sicard, Y. Buisson, H. Agut, J. P. Escande and J. M. Huraux (1997). "Exacerbations of clinical symptoms in human immunodeficiency virus type 1-infected patients with multicentric Castleman's disease are associated with a high increase in Kaposi's sarcoma herpesvirus DNA load in peripheral blood mononuclear cells." J Infect Dis 175(5): 1198-201.

Green, I., E. Espiritu, M. Ladanyi, R. Chaponda, R. Wieczorek, L. Gallo and H. Feiner (1995). "Primary lymphomatous effusions in AIDS: a morphological, immunophenotypic, and molecular study." Mod Pathol 8(1): 39-45.

Hayward, G. S. and J. C. Zong (2007). "Modern evolutionary history of the human KSHV genome." Curr Top Microbiol Immunol 312: 1-42.

Hengge, U. R., T. Ruzicka, S. K. Tyring, M. Stuschke, M. Roggendorf, R. A. Schwartz and S. Seeber (2002). "Update on Kaposi's sarcoma and other HHV8 associated diseases. Part 2: pathogenesis, Castleman's disease, and pleural effusion lymphoma." The Lancet infectious diseases 2(6): 344-52.

Herndier, B. and D. Ganem (2001). "The biology of Kaposi's sarcoma." Cancer Treat Res 104: 89-126.

Huang, L. M., S. Y. Huang, M. Y. Chen, M. F. Chao, C. Y. Lu, H. F. Tien, C. Y. Lee and K. T. Jeang (2000). "Geographical differences in human herpesvirus 8 seroepidemiology: a survey of 1,201 individuals in Asia." J Med Virol 60(3): 290-3.

Im, S. S., S. P. Wilczynski, R. A. Burger and B. J. Monk (2003). "Early stage cervical cancers containing human papillomavirus type 18 DNA have more nodal metastasis and deeper stromal invasion." Clin Cancer Res 9(11): 4145-50.

Jenner, R. G. and C. Boshoff (2002). "The molecular pathology of Kaposi's sarcoma-associated herpesvirus." Biochim Biophys Acta 1602(1): 1-22.
Kaposi, M. (1872). "Idiopathisches multiples pigmentsarkom her haut." Arch Dermatol Shypilol 4: 8.

Katano, H., Y. Sato, T. Kurata, S. Mori and T. Sata (2000). "Expression and localization of human herpesvirus 8-encoded proteins in primary effusion lymphoma, Kaposi's sarcoma, and multicentric Castleman's disease." Virology 269(2): 335-44.

Lagos-Quintana, M., R. Rauhut, W. Lendeckel and T. Tuschl (2001). "Identification of novel genes coding for small expressed RNAs." Science 294(5543): 853-8.

Lu, J., H. H. Chua, S. Y. Chen, J. Y. Chen and C. H. Tsai (2003). "Regulation of matrix metalloproteinase-1 by Epstein-Barr virus proteins." Cancer Res 63(1): 256-62.

Ma, L. and R. A. Weinberg (2008). "Micromanagers of malignancy: role of microRNAs in regulating metastasis." Trends Genet 24(9): 448-56.

Meng, Y. X., T. J. Spira, G. J. Bhat, C. J. Birch, J. D. Druce, B. R. Edlin, R. Edwards, C. Gunthel, R. Newton, F. R. Stamey, C. Wood and P. E. Pellett (1999). "Individuals from North America, Australasia, and Africa are infected with four different genotypes of human herpesvirus 8." Virology 261(1): 106-19.

Monini, P., S. Colombini, M. Stürzl, D. Goletti, A. Cafaro, C. Sgadari, S. Buttò, M. Franco, P. Leone, S. Fais, P. Leone, G. Melucci-Vigo, C. Chiozzini, F. Carlini, G. Ascherl, E. Cornali, C. Zietz, E. Ramazzotti, F. Ensoli, M. Andreoni, P. Pezzotti, G. Rezza, R. Yarchoan, R. C. Gallo and B. Ensoli (1999). "Reactivation and persistence of human herpesvirus-8 infection in B cells and monocytes by Th-1 cytokines increased in Kaposi's sarcoma." Blood 93(12): 4044-58.

Moore, P. S. and Y. Chang (1998). "Antiviral activity of tumor-suppressor pathways: clues from molecular piracy by KSHV." Trends Genet 14(4): 144-50.

Mrazek, J., S. B. Kreutmayer, F. A. Grasser, N. Polacek and A. Huttenhofer (2007). "Subtractive hybridization identifies novel differentially expressed ncRNA species in EBV-infected human B cells." Nucleic Acids Res 35(10): e73.

Nador, R. G., E. Cesarman, A. Chadburn, D. B. Dawson, M. Q. Ansari, J. Sald and D. M. Knowles (1996). "Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus." Blood 88(2): 645-56.

Nakamura, H., M. Lu, Y. Gwack, J. Souvlis, S. L. Zeichner and J. U. Jung (2003). "Global changes in Kaposi's sarcoma-associated virus gene expression patterns following expression of a tetracycline-inducible Rta transactivator." J Virol 77(7): 4205-20.

Neipel, F., J. C. Albrecht and B. Fleckenstein (1997). "Cell-homologous genes in the Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity?" J Virol 71(6): 4187-92.

Parravicini, C., B. Chandran, M. Corbellino, E. Berti, M. Paulli, P. S. Moore and Y. Chang (2000). "Differential viral protein expression in Kaposi's sarcoma-associated herpesvirus-infected diseases: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease." Am J Pathol 156(3): 743-9.

Pegtel, D. M., A. Subramanian, T. S. Sheen, C. H. Tsai, T. R. Golub and D. A. Thorley-Lawson (2005). "Epstein-Barr-virus-encoded LMP2A induces primary epithelial cell migration and invasion: possible role in nasopharyngeal carcinoma metastasis." J Virol 79(24): 15430-42.

Pfeffer, S., M. Zavolan, F. A. Grässer, M. Chien, J. J. Russo, J. Ju, B. John, A. J. Enright, D. Marks, C. Sander and T. Tuschl (2004). "Identification of virus-encoded microRNAs." Science 304(5671): 734-6.
Poliseno, L., A. Tuccoli, L. Mariani, M. Evangelista, L. Citti, K. Woods, A. Mercatanti, S. Hammond and G. Rainaldi (2006). "MicroRNAs modulate the angiogenic properties of HUVECs." Blood 108(9): 3068-71.

Poole, L. J., J. C. Zong, D. M. Ciufo, D. J. Alcendor, J. S. Cannon, R. Ambinder, J. M. Orenstein, M. S. Reitz and G. S. Hayward (1999). "Comparison of genetic variability at multiple loci across the genomes of the major subtypes of Kaposi's sarcoma-associated herpesvirus reveals evidence for recombination and for two distinct types of open reading frame K15 alleles at the right-hand end." J Virol 73(8): 6646-60.

Qian, L. W., J. Xie, F. Ye and S. J. Gao (2007). "Kaposi's sarcoma-associated herpesvirus infection promotes invasion of primary human umbilical vein endothelial cells by inducing matrix metalloproteinases." J Virol 81(13): 7001-10.

Rabkin, C. S., R. J. Biggar and J. W. Horm (1991). "Increasing incidence of cancers associated with the human immunodeficiency virus epidemic." Int J Cancer 47(5): 692-6.

Rabkin, C. S., S. Janz, A. Lash, A. E. Coleman, E. Musaba, L. Liotta, R. J. Biggar and Z. Zhuang (1997). "Monoclonal origin of multicentric Kaposi's sarcoma lesions." N Engl J Med 336(14): 988-93.

Radhika, V., D. Onesime, J. H. Ha and N. Dhanasekaran (2004). "Galpha13 stimulates cell migration through cortactin-interacting protein Hax-1." J Biol Chem 279(47): 49406-13.

Russo, J. J., R. A. Bohenzky, M. C. Chien, J. Y. Chen, M. Yan, D. Maddalena, J. P. Parry, D. Peruzzi, I. S. Edelman, Y. Chang and P. S. Moore (1996). "Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8)." Proc Natl Acad Sci USA 93(25): 14862-7.

Samaniego, F., P. D. Markham, R. Gendelman, R. C. Gallo and B. Ensoli (1997). "Inflammatory cytokines induce endothelial cells to produce and release basic fibroblast growth factor and to promote Kaposi's sarcoma-like lesions in nude mice." J Immunol 158(4): 1887-94.

Sharp, T. V., H. W. Wang, A. Koumi, D. Hollyman, Y. Endo, H. Ye, M. Q. Du and C. Boshoff (2002). "K15 protein of Kaposi's sarcoma-associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function." J Virol 76(2): 802-16.

Soulier, J., L. Grollet, E. Oksenhendler, P. Cacoub, D. Cazals-Hatem, P. Babinet, M. F. d'Agay, J. P. Clauvel, M. Raphael and L. Degos (1995). "Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease." Blood 86(4): 1276-80.

Stebbing, J., D. Bourboulia, M. Johnson, S. Henderson, I. Williams, N. Wilder, M. Tyrer, M. Youle, N. Imami, T. Kobu, W. Kuon, J. Sieper, F. Gotch and C. Boshoff (2003). "Kaposi's sarcoma-associated herpesvirus cytotoxic T lymphocytes recognize and target Darwinian positively selected autologous K1 epitopes." J Virol 77(7): 4306-14.

Vieira, J. and P. M. O'Hearn (2004). "Use of the red fluorescent protein as a marker of Kaposi's sarcoma-associated herpesvirus lytic gene expression." Virology 325(2): 225-40.

Wang, H. W. and C. Boshoff (2005). "Linking Kaposi virus to cancer-associated cytokines." Trends in molecular medicine 11(7): 309-12.

Wang, L., M. M. Brinkmann, M. Pietrek, M. Ottinger, O. Dittrich-Breiholz, M. Kracht and T. F. Schulz (2007). "Functional characterization of the M-type K15-encoded membrane protein of Kaposi's sarcoma-associated herpesvirus." J Gen Virol 88(Pt 6): 1698-707.

Wang, L., N. Wakisaka, C. C. Tomlinson, S. M. DeWire, S. Krall, J. S. Pagano and B. Damania (2004). "The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) K1 protein induces expression of angiogenic and invasion factors." Cancer Res 64(8): 2774-81.

Whitby, D., V. A. Marshall, R. K. Bagni, C. D. Wang, C. J. Gamache, J. R. Guzman, M. Kron, P. Ebbesen and R. J. Biggar (2004). "Genotypic characterization of Kaposi's sarcoma-associated herpesvirus in asymptomatic infected subjects from isolated populations." J Gen Virol 85(Pt 1): 155-63.

Wong, E. L. and B. Damania (2006). "Transcriptional regulation of the Kaposi's sarcoma-associated herpesvirus K15 gene." J Virol 80(3): 1385-92.

Zong, J., D. M. Ciufo, R. Viscidi, L. Alagiozoglou, S. Tyring, P. Rady, J. Orenstein, W. Boto, H. Kalumbuja, N. Romano, M. Melbye, G. H. Kang, C. Boshoff and G. S. Hayward (2002). "Genotypic analysis at multiple loci across Kaposi's sarcoma herpesvirus (KSHV) DNA molecules: clustering patterns, novel variants and chimerism." J Clin Virol 23(3): 119-48.

Zong, J. C., D. M. Ciufo, D. J. Alcendor, X. Wan, J. Nicholas, P. J. Browning, P. L. Rady, S. K. Tyring, J. M. Orenstein, C. S. Rabkin, I. J. Su, K. F. Powell, M. Croxson, K. E. Foreman, B. J. Nickoloff, S. Alkan and G. S. Hayward (1999). "High-level variability in the ORF-K1 membrane protein gene at the left end of the Kaposi's sarcoma-associated herpesvirus genome defines four major virus subtypes and multiple variants or clades in different human populations." J Virol 73(5): 4156-70.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊