(3.238.7.202) 您好!臺灣時間:2021/03/01 22:18
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:::

我願授權國圖
: 
twitterline
研究生:伍筱梅
論文名稱:Proteasome抑制劑增加interleukin-8基因表現之訊息傳遞路徑
論文名稱(外文):Signaling pathway of proteasome inhibitor-induced interleukin-8 gene expression
指導教授:林琬琬林琬琬引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
中文關鍵詞:訊息傳遞
相關次數:
  • 被引用被引用:0
  • 點閱點閱:199
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:18
  • 收藏至我的研究室書目清單書目收藏:0
許多生化反應路徑中的訊息傳遞分子含量多經由ubiquitin-proteasome水解系統來調控。Proteasome抑制劑,例如MG132,已知可以藉由抑制IkBs之降解來抑制一些刺激劑造成的NF-kB活化,進而導致許多NF-kB所調控之基因的轉錄性受到抑制。由於interleukine-8 (IL-8)基因表現是由NF-kB及AP-1這兩種基因轉錄因子之協同作用來調控。因此,在本篇研究當中,我們嘗試去探討四種proteasome抑制劑(MG132, aLLN, lactacystin, 及MG262)對於IL-8基因表現之影響。在人類肺部上皮細胞株A549,以及人類胚胎腎臟細胞株HEK 293中,以濃度0.1 mM至30 mM之MG132處理,均可增加IL-8之釋放,且呈現濃度反應相關性。利用Boyden chamber趨化性試驗,我們證明了所釋出之IL-8能夠趨化嗜中性白血球移動。MG132所增加之IL-8可以被PD98059 (MEK抑制劑)抑制,但是另外兩個PKC抑制劑,Ro31-8220及GF109203X,以及p38抑制劑SB203580則無法影響其作用。此外,IL-8基因啟動區之報導基因試驗也印證MG132具有轉錄性促進IL-8基因誘導的作用。將IL-8基因之5’-flanking region作突變分析,顯示出啟動子區AP-1的結合位置對於MG132造成的刺激最為重要,而NF-IL-6與NF-kB的結合位置則無顯著影響。其他的proteasome抑制劑亦有類似MG132的作用,其誘導IL-8 效力強度為MG262 >> MG132 = lactacystin > aLLN。接著又發現,proteasome抑制劑能夠增加AP-1與DNA結合及AP-1報導基因的活性,但是會抑制cytokine刺激所活化之NF-kB。更進一步的實驗顯示,AP-1的活化和ERK,MEK,JNK之磷酸化作用有關,且dominant negative mutant的JNK1,JNK2,SEK,ASK,ERK2,及Ras均會抑制IL-8基因表現的活性,但是MEKK1,TAK,和p38 MAPK則沒有影響。此外,proteasome抑制劑所活化的IL-8基因及AP-1表現均可以被抗氧化劑NAC及GSH所抑制,而前處理diphenyleneiodonium (DPI),rotenone和antimycin A亦可減弱其作用,故推測可能有活性氧物種(reactive oxygen species, ROS)參與其間。使用DCFH-DA作螢光分析,確認proteasome抑制劑具有產生活性氧物種的能力。綜合上述結果,本篇研究報導了proteasome抑制劑的新作用,其可能經由ROS的產生,活化上游的訊息傳遞分子,Ras/MEK/ERK及ASK/SEK/JNK,進而造成AP-1的活化以及IL-8基因表現。

縮寫表……………………………………………………………………1
英文摘要…………………………………………………………………3
中文摘要…………………………………………………………………5
緒論………………………………………………………………………7
材料和方法……………………………………………………………..14
結果……………………………………………………………………..25
討論……………………………………………………………………..30
圖表……………………………………………………………………..37
參考文獻………………………………………………………………..54

Adams, J. (2002) Development of the proteasome inhibitor PS-341. Oncologist 7:9-16.
Boudjelal, M., Wang, Z., Voorhees, J.J. and Fisher, G.J. (2000) Ubiquitin/proteasome pathway regulates levels of retinoic acid receptor g and retinoid X receptors a in human keratinocytes. Cancer Res. 60: 2247-2252.
Callus, B.A. and Mathey-Prevot, B. (1998) Interleukin-3-induced activation of the JAK/STAT pathway is prolonged by proteasome inhibitors. Blood 91: 3182-3192.
Chadebech, P., Brichese, L., Baldin, V., Vidal, S. and Valette, A. (1999) Phosphorylation and proteasome-dependent degradation of Bcl-2 in mitotic-arrested cells after microtubule damage. Biochem. Biophys. Res. Commun. 262: 823-827.
Chen, B.C., Chen Y.H. and Lin, W.W. (1999) Involvement of p38 mitogen-activated protein kinase in lipopolysaccharide-induced iNOS and COX-2 expression in J774 macrophages. Immunology 97: 124-129.
Chen, B.C., Hsieh, S.L. and Lin, W.W. (2001) Involvement of protein kinases in the potentiation of lipopolysaccharide-induced inflammatory mediator formation by thapsigargin in peritoneal macrophages. J. Leukoc. Biol. 69: 280-288.
Chen, G., Hitomi, M., Han, J. and Stacey, D. W. (2000) The p38 pathway provides negative feedback for Ras proliferative signaling. J. Biol. Chem. 275:38973-38970.
Clerk, A., Fuller, S.J., Michae, A. and Sugden, P.H. (1998) Stimulation of “stress-regualted” mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses. J. Biol. Chem. 273: 7228-7234.
DeForge, L.E., Preston, A.M., Takeuchi, E., Kenney, J., Boxer, L.A. and Remick, D.G. (1993) Regulation of interleukin 8 gene expression by oxidant stress. J. Biol. Chem. 268: 25568-25576.
Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You, J., Slaughter, C., Pickart, C. and Chen, Z.J. (2000) Activation of the IkB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103: 351-361.
Fei, J., Viedt, C., Soto, U., Elsing, C., Jahn, L. and Kreuzer, J. (2000) Endothelin-1 and smooth muscle cells: induction of jun amino-terminal kinase through an oxygen radical-sensitive mechanism. Arterio. Throm. Vascu. Biol. 20: 1244-1249.
Finkel, T. (1998) Oxygen radicals and signaling. Curr. Opin. Cell Biol. 10: 248-253.
Floyd, Z.E. and Stephens, J.M. (2002) Interferon-g mediated activation and ubiquitin-proteasome-dependent degradation of PPAR-g in adipocytes. J. Biol. Chem. 277: 4062-4068.
Garrington, T.P. and Johnson, G.L. (1999) Organization and regulation of mitogen-activated protein kinase signalling pathways. Curr. Opin. Cell Biol. 11: 211-218.
Giasson, B.I., Bruening, W., Durham, H.D. and Mushynski, W.E. (1999) Activation of stress-activated protein kinases correlates with neurite outgrowth induced by protease inhibition in PC12 cells. J. Neurochem. 72: 1081-1087.
Guyton, K.Z., Liu, Y., Gorospe, M., Xu, Q. and Holbrook, N.J. (1996) Activation of mitogen-activated protein kinase by H2O2. J. Biol. Chem. 271: 4138-4142.
He, H., Qi, X.M., Grossmann, J. and Distelhorst, C.W. (1998) c-Fos degradation by the proteasome. J. Biol. Chem. 273: 25015- 25019.
Herlaar, E. and Brown, Z. (1999) p38 MAPK signaling cascades in inflammatory disease. Mol. Med. Today 5: 439-447.
Holtmann, H., Enninga, J., Kalble, S., Thiefes, A., Dörrie, A., Broemer, M., Winzen, R., Wilhelm, A., Ninomiya-Tsuji, J., Matsumoto, K., Resch, K. and Kracht, M. (2001) The MAPK kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation. J. Biol. Chem. 276: 3508-3516.
Jordan, N.J., Watson, M.L., Yoshimura, T. and Westwick, J. (1996) Differential effects of protein kinase C inhibitors on chemokine production in human synovial fibroblasts. Br. J. Pharmacol. 117: 1245-1253.
Kallio, P.J., Wilson, W.J., O’Brien, S., Makino, Y. and Poellinger, L. (1999) Regulation of hypoxia-inducible transcription factor 1a by the ubiqutin-proteasome pathway. J. Biol. Chem. 274: 6519-6525.
Karin, M. (1995) The regulation of AP-1 activity by mitogen-activated protein kinases. J. Biol. Chem. 270: 16483-16486.
King, R.W., Peters, J.M., Tugendreich, S., Rolfe, M., Hieter, P. and Kirschner, M.W. (1995) A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell 81: 279-288.
Kim, T.K. and Maniatis, T. (1996) Regulation of interferon-gamma-activated STAT1 by the ubiquitin-proteasome pathway. Science 273: 1717-1719.
Kopf, E., Plassat, J.L., Vivat, V., de The, H., Chambon, P. and Rochette-Egly, C. (2000) Dimerization with retinoid X receptors and phosphorylation modulate the retinoic acid-induced retinoic acid receptors a and g through the ubiquitin-proteasome pathway. J. Biol. Chem. 275: 33280-33288.
Kornitzer, D. and Ciechanover, A. (2000) Modes of regulation of ubiquitin-mediated protein degradation. J. Cell. Physiol. 182: 1-11.
Kunkel, S.L., Strieter, R.M., Lindley, I.J.D. and Westwick, J. (1995) Chemokines: new ligands, receptors and activities. Immunol. Today 16: 559-561.
Kunsch, C., Lang, R.K., Rosen, C.A. and Shannon, M.F. (1994) Synergistic transcriptional activation of the IL-8 gene by NF-kB p65 (RelA) and NF-IL6. J. Immunol. 153: 153-164.
Lakshminarayanan, V., Drab-Weiss E.A. and Roebuck, K.A. (1998) H2O2 and tumor necrosis factor-alpha induce differential binding of the redox-responsive transcription factors AP-1 and NF-kappaB to the interleukin-8 promoter in endothelial and epithelial cells. J. Biol. Chem. 273: 32670-32678.
Lali, F.V., Hunt, A.E., Tumer, S.J. and Foxwell, B.M.J. (2000) The pyridinyl imidazole inhibitor SB 203580 blocks phosphoinositide -dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independently of p38 mitogen-activated protein kinase. J. Biol. Chem. 275: 7395-7402.
Laemmli, U.K., Beguin, F. and Gujer-Kellenberger, G. (1970) A factor preventing the major head protein of bacteriophage T4 from random aggregation. J. Mol. Biol. 47:69-85.
Lander, H.M., Ogiste, J.S., Teng, K.K. and Novogrodsky, A. (1995) p21ras as a common signaling target of reactive free radicals and cellular redox stress. J. Biol. Chem. 270: 21195-21198.
Lee, D.H. and Goldberg, A.L. (1998) Proteasome inhibitors: valuable new tools for cell biologists. Trends Cell Biol. 8: 397-403.
Levine, J.S. (1995) Bronchial epithelial cell-cytokine interactions in airway inflammation. J. Invest. Med. 43: 241-249.
Lieber, M., Smith, B., Szakal, A., Nelson-Rees, W. and Todaro, G. (1976) A continuous-tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells. Int. J. Cancer 17: 62-70.
Malinin, N.L., Boldin, M.P., Kovalenko, A.V. and Wallach, D. (1997) A cytokine-responsive IkB kinase that activates the transcription factor NF-kB. Nature 385: 540-544.
Marini, M., Vittori, E., Hollemborg, J. and Mattoli, S. (1992) Expression of the potent inflammatory cytokines, granulocyte-macrophage-colony- stimulating factor and interleukin-6 and interleukin-8 in bronchial epithelial cells of patients with asthma. J. Allergy Clin. Immunol. 89: 1001-1009.
Mastronarde, J.G., Monick, M.M., Mukaida, N., Matsushima, K. and Hunninghake, G.W. (1998) Activator protein-1 is the preferred transcription factor for cooperative interaction with nuclear factor-kB in respiratory syncytial virus-induced interleukin-8 gene expression in airway epithelium. J. Infect. Dis. 177: 1275-1281.
Matsumoto, K., Hashimoto, S., Gon, Y., Nakayama, T. and Horie, T. (1998) Proinflammatory cytokine-induced and chemical mediator-induced IL-8 expression in human bronchial epithelial cells through p38 mitogen-activated protein kinase-dependent pathway. J. Allergy Clin. Immunol. 191: 825-831.
Matsusaka, T., Junikawa, K., Nishio, Y., Mukaida, N., Matsushima, K., Kishimoto, T. and Akira, S. (1993) Transcription factors NF-IL6 and NF-kB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc. Natl. Acad. Sci. USA 90: 10193-10197.
Malek, R. and Halvorsen, S.W. (1998) Ciliary neurotrophic factor and phorbol ester each decrease selected STAT3 pools in neuroblastoma cells by proteasome-dependent mechanisms. Cytokine 11: 192-199.
May, M.J. and Ghosh, S. (1998) Signal transduction through NF-kB. Immunol. Today 19: 80-88.
Meng, L., Mohan, R., Kwok, B.H.B, Elofsson, M., Sin, V. and Crews, C.M. (1999) Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo anti-inflammatory activity. Proc. Natl. Acad. Sci. USA 96: 10403-10408.
Meriin, A.B., Gabai, V.L., Yaglom, J., Shifrin, V.I. and Sherman, M.Y. (1998) Proteasome inhibitors activate stress kinases and induce Hsp72. Diverse effects on apoptosis. J. Biol. Chem. 273: 6373-6379.
Miyamoto, S., Maki, M., Schmitt, M.J., Hatanaka, M. and Verma, I.M. (1994) Tumor necrosis factor alpha-induced phosphorylation of I kappa B alpha is a signal for its degradation but not dissociation from NF-kappa B. Proc. Natl. Acad. Sci. USA 91: 12740-12744.
Mukaida, N., Okamoto, S., Ishikawa, Y. and Matsushima, K. (1994) Molecular mechanism of interleukin-8 gene expression. J. Leukocyte Biol. 56: 554-558.
Nawaz, A., Lonard, D.M., Dennis, A.P., Smith, C.L. and O’Malley, B.W. (1999) Proteasome-dependent degradation of the human estrogen receptor. Proc. Natl. Acad. Sci. USA 96: 1858-1862.
Nakayama, K., Furusu, A., Xu, Q., Konta, T. and Kitamura, M. (2001) Unexpected transcriptional induction of monocyte chemoattractant protein 1 by proteasome inhibition: involvement of the c-Jun N-terminal kinase-activator protein 1 pathway. J. Immunol. 167: 1145-1150.
Nocker, R.E., Schoonbrood, D.F. and van de Graaf, E.A. (1996) Interleukin-8 in airway inflammation in patients with asthma and chronic obstructive pulmonary disease. Int. Arch. Allergy Immunol. 109: 183-191.
Ogura, M. and Kitamura, M. (1998) Oxidant stress incites spreading of macrophages via extracellular signal-regulated kinases and p38 mitogen activated protein kinase. J. Immunol. 161: 3569-3574.
Ozes, O.N., Mayo, L.D., Gustin, J.A., Pfeffer, S.R., Pfeffer, L.M. and Donner, D.B. (1999) NF-kB avtivated by tumor necrosis factor requires the Akt serine-threonine kinase. Nature 401, 82-85.
Palombella, V.J., Rando, O.J., Goldberg, A.L. and Maniatis, T. (1994) The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78: 773-785.
Rodriguez, M.S., Desterro, J.M., Lain, S., Lane, D.P. and Hay, R.T. (2000) Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Mol. Cell. Biol. 20: 8458-8467.
Roebuck, K.A. (1999) Regulation of interleukin-8 gene expression. J. Interferon Cytokine Res. 19: 429-438.
Roebuck, K.A., Carpenter, L.R., Lakshminarayanan, S., Page, S.M., Moy, J.V. and Thomas, L.L. (1999) Stimulus-specific regulation of chemokine expression involves differential activation of the redox-responsive transcription factors AP-1 and NF-kB. J. Leukoc. Biol. 65: 291-298.
Sano, M., Jukuda, K., Sato, T., Kawaguchi, H., Suematsu, M., Matsuda, S., Koyasu S., Matsui, H., Yamauchi-Takihara, K., Harada, M., Saito, Y. and Ogawa, S. (2001) ERK and p38 MAPK, but not NF-kappaB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts. Cir. Res. 89: 661-669.
Sen, C.K. and Packer, L. (1996) Antioxidant and redox regulation of gene transcription. FASEB J. 10: 709-720.
Su, B. and Karin, N. (1996) Mitogen-activated protein kinase cascades and regulation of gene expression. Curr. Opin. Immunol. 8: 402-411.
Tobiume, K, Matsuzawa, A., Takahashi, T., Nishitoh, H., Morita, K., Takeda, K., Minowa, O., Miyazono, K., Noda, T. and Ichijo, H. (2001) ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Reports 2: 222-228.
Treier, M., Staszewski, L.M. and Bohmann, D. (1994) Ubiquitin-dependent c-Jun degradation in vivo is mediated by the delta domain. Cell 78: 787-798.
Wen, H.C. and W.W. Lin. (2000) Basal cPLA2 phosphorylation is sufficient for Ca2+-induced full activation of cPLA2 in A549 epithelial cells. J. Cell. Biochem. 79: 601-609.
Whitmarsh, A.J., Shore, P., Sharrocks, A.D. and Davis, R.J. (1995) Integration of MAP kinase signal transduction pathways at the serum response element. Science 269: 403-407.
Yamamoto, Y. and Gaynor, R.B. (2001) Therapeutic potential of inhibition of the NF-kB pathway in the treatment of inflammation and cancer. J. Clin. Invest. 107: 135-142.
You, S.A., Basu, A. and Haldar, S. (1999) Potent antitumor agent proteasome inhibitors: a novel trigger for Bcl2 phosphorylation to induce apoptosis. Int. J. Oncol. 15: 625-628.
Yu, C.L. and Burakoff, S.J. (1997) Involvement of proteasome in regulating Jak-STAT pathways upon interleukin-2 stimulation. J. Biol. Chem. 272: 14017-14020.
Zhang, H., Shi, X., Hampong, M., Blanis, L. and Pelech, S. (2001) Stress-induced inhibition of ERK1 and ERK2 by direct interaction with p38 MAP kinase. J. Biol. Chem. 276:6905-6908.

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關論文
 
系統版面圖檔 系統版面圖檔