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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 呂勝春 博士(Sheng-Chung Lee) | |
| dc.contributor.author | Yu-Ling Chen | en |
| dc.contributor.author | 陳俞伶 | zh_TW |
| dc.date.accessioned | 2021-06-13T02:15:55Z | - |
| dc.date.available | 2012-02-27 | |
| dc.date.copyright | 2007-02-27 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-02-14 | |
| dc.identifier.citation | Adam, E., Quivy, V., Bex, F., Chariot, A., Collette, Y., Vanhulle, C., Schoonbroodt, S., Goffin, V., Nguyen, T.L., Gloire, G., Carrard, G., Friguet, B., De Launoit, Y., Burny, A., Bours, V., Piette, J. and Van Lint, C. (2003) Potentiation of tumor necrosis factor-induced NF-kappa B activation by deacetylase inhibitors is associated with a delayed cytoplasmic reappearance of I kappa B alpha. Mol Cell Biol, 23, 6200-6209.
Alpert, D., Schwenger, P., Han, J. and Vilcek, J. (1999) Cell stress and MKK6b-mediated p38 MAP kinase activation inhibit tumor necrosis factor-induced IkappaB phosphorylation and NF-kappaB activation. J Biol Chem, 274, 22176-22183. Ashburner, B.P., Westerheide, S.D. and Baldwin, A.S., Jr. (2001) The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol Cell Biol, 21, 7065-7077. Baeza-Raja, B. and Munoz-Canoves, P. (2004) p38 MAPK-induced nuclear factor-kappaB activity is required for skeletal muscle differentiation: role of interleukin-6. Mol Biol Cell, 15, 2013-2026. Bevilacqua, A., Ceriani, M.C., Capaccioli, S. and Nicolin, A. (2003) Post-transcriptional regulation of gene expression by degradation of messenger RNAs. J Cell Physiol, 195, 356-372. Bohuslav, J., Kravchenko, V.V., Parry, G.C., Erlich, J.H., Gerondakis, S., Mackman, N. and Ulevitch, R.J. (1998) Regulation of an essential innate immune response by the p50 subunit of NF-kappaB. J Clin Invest, 102, 1645-1652. Bowie, A.G. and O'Neill, L.A. (2000) Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase. J Immunol, 165, 7180-7188. Brennan, C.M. and Steitz, J.A. (2001) HuR and mRNA stability. Cell Mol Life Sci, 58, 266-277. Brook, M., Tchen, C.R., Santalucia, T., McIlrath, J., Arthur, J.S., Saklatvala, J. and Clark, A.R. (2006) Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Mol Cell Biol, 26, 2408-2418. Brooks, S.A., Connolly, J.E. and Rigby, W.F. (2004) The role of mRNA turnover in the regulation of tristetraprolin expression: evidence for an extracellular signal-regulated kinase-specific, AU-rich element-dependent, autoregulatory pathway. J Immunol, 172, 7263-7271. Campbell, J., Ciesielski, C.J., Hunt, A.E., Horwood, N.J., Beech, J.T., Hayes, L.A., Denys, A., Feldmann, M., Brennan, F.M. and Foxwell, B.M. (2004) A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. J Immunol, 173, 6928-6937. Caput, D., Beutler, B., Hartog, K., Thayer, R., Brown-Shimer, S. and Cerami, A. (1986) Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci U S A, 83, 1670-1674. Carballo, E., Cao, H., Lai, W.S., Kennington, E.A., Campbell, D. and Blackshear, P.J. (2001) Decreased sensitivity of tristetraprolin-deficient cells to p38 inhibitors suggests the involvement of tristetraprolin in the p38 signaling pathway. J Biol Chem, 276, 42580-42587. Carballo, E., Lai, W.S. and Blackshear, P.J. (1998) Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science, 281, 1001-1005. Carballo, E., Lai, W.S. and Blackshear, P.J. (2000) Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability. Blood, 95, 1891-1899. Chen, C.Y., Gherzi, R., Ong, S.E., Chan, E.L., Raijmakers, R., Pruijn, G.J., Stoecklin, G., Moroni, C., Mann, M. and Karin, M. (2001) AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell, 107, 451-464. Chen, C.Y. and Shyu, A.B. (1995) AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci, 20, 465-470. Chen, L., Fischle, W., Verdin, E. and Greene, W.C. (2001) Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science, 293, 1653-1657. Chen, L.F., Mu, Y. and Greene, W.C. (2002) Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. Embo J, 21, 6539-6548. Chen, Y.L., Huang, Y.L., Lin, N.Y., Chen, H.C., Chiu, W.C. and Chang, C.J. (2006) Differential regulation of ARE-mediated TNFalpha and IL-1beta mRNA stability by lipopolysaccharide in RAW264.7 cells. Biochem Biophys Res Commun, 346, 160-168. Clark, A.R., Dean, J.L. and Saklatvala, J. (2003) Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38. FEBS Lett, 546, 37-44. Collart, M.A., Baeuerle, P. and Vassalli, P. (1990) Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B. Mol Cell Biol, 10, 1498-1506. Dean, J.L., Sully, G., Clark, A.R. and Saklatvala, J. (2004) The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation. Cell Signal, 16, 1113-1121. Dean, J.L., Wait, R., Mahtani, K.R., Sully, G., Clark, A.R. and Saklatvala, J. (2001) The 3' untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR. Mol Cell Biol, 21, 721-730. Drouet, C., Shakhov, A.N. and Jongeneel, C.V. (1991) Enhancers and transcription factors controlling the inducibility of the tumor necrosis factor-alpha promoter in primary macrophages. J Immunol, 147, 1694-1700. DuBois, R.N., McLane, M.W., Ryder, K., Lau, L.F. and Nathans, D. (1990) A growth factor-inducible nuclear protein with a novel cysteine/histidine repetitive sequence. J Biol Chem, 265, 19185-19191. El Kharroubi, A., Piras, G., Zensen, R. and Martin, M.A. (1998) Transcriptional activation of the integrated chromatin-associated human immunodeficiency virus type 1 promoter. Mol Cell Biol, 18, 2535-2544. Fan, X.C. and Steitz, J.A. (1998) Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. Embo J, 17, 3448-3460. Feldmann, M., Brennan, F.M. and Maini, R.N. (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol, 14, 397-440. Fukae, J., Amasaki, Y., Yamashita, Y., Bohgaki, T., Yasuda, S., Jodo, S., Atsumi, T. and Koike, T. (2005) Butyrate suppresses tumor necrosis factor alpha production by regulating specific messenger RNA degradation mediated through a cis-acting AU-rich element. Arthritis Rheum, 52, 2697-2707. Furia, B., Deng, L., Wu, K., Baylor, S., Kehn, K., Li, H., Donnelly, R., Coleman, T. and Kashanchi, F. (2002) Enhancement of nuclear factor-kappa B acetylation by coactivator p300 and HIV-1 Tat proteins. J Biol Chem, 277, 4973-4980. Gerritsen, M.E., Williams, A.J., Neish, A.S., Moore, S., Shi, Y. and Collins, T. (1997) CREB-binding protein/p300 are transcriptional coactivators of p65. Proc Natl Acad Sci U S A, 94, 2927-2932. Henics, T. (2003) Extending the 'stressy' edge: molecular chaperones flirting with RNA. Cell Biol Int, 27, 1-6. Hitti, E., Iakovleva, T., Brook, M., Deppenmeier, S., Gruber, A.D., Radzioch, D., Clark, A.R., Blackshear, P.J., Kotlyarov, A. and Gaestel, M. (2006) Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Mol Cell Biol, 26, 2399-2407. Hong, L., Schroth, G.P., Matthews, H.R., Yau, P. and Bradbury, E.M. (1993) Studies of the DNA binding properties of histone H4 amino terminus. Thermal denaturation studies reveal that acetylation markedly reduces the binding constant of the H4 'tail' to DNA. J Biol Chem, 268, 305-314. Hu, J. and Colburn, N.H. (2005) Histone deacetylase inhibition down-regulates cyclin D1 transcription by inhibiting nuclear factor-kappaB/p65 DNA binding. Mol Cancer Res, 3, 100-109. Ito, K., Barnes, P.J. and Adcock, I.M. (2000) Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol, 20, 6891-6903. Jalonen, U., Lahti, A., Korhonen, R., Kankaanranta, H. and Moilanen, E. (2005) Inhibition of tristetraprolin expression by dexamethasone in activated macrophages. Biochem Pharmacol, 69, 733-740. Jing, Q., Huang, S., Guth, S., Zarubin, T., Motoyama, A., Chen, J., Di Padova, F., Lin, S.C., Gram, H. and Han, J. (2005) Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell, 120, 623-634. Johnson, B.A., Stehn, J.R., Yaffe, M.B. and Blackwell, T.K. (2002) Cytoplasmic localization of tristetraprolin involves 14-3-3-dependent and -independent mechanisms. J Biol Chem, 277, 18029-18036. Jung, M. (2001) Inhibitors of histone deacetylase as new anticancer agents. Curr Med Chem, 8, 1505-1511. Keene, J.D. (1999) Why is Hu whereNULL Shuttling of early-response-gene messenger RNA subsets. Proc Natl Acad Sci U S A, 96, 5-7. Kelly, W.K., O'Connor, O.A. and Marks, P.A. (2002) Histone deacetylase inhibitors: from target to clinical trials. Expert Opin Investig Drugs, 11, 1695-1713. Kiernan, R., Bres, V., Ng, R.W., Coudart, M.P., El Messaoudi, S., Sardet, C., Jin, D.Y., Emiliani, S. and Benkirane, M. (2003) Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. J Biol Chem, 278, 2758-2766. Kontoyiannis, D., Pasparakis, M., Pizarro, T.T., Cominelli, F. and Kollias, G. (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity, 10, 387-398. Lai, W.S. and Blackshear, P.J. (2001) Interactions of CCCH zinc finger proteins with mRNA: tristetraprolin-mediated AU-rich element-dependent mRNA degradation can occur in the absence of a poly(A) tail. J Biol Chem, 276, 23144-23154. Lai, W.S., Carballo, E., Strum, J.R., Kennington, E.A., Phillips, R.S. and Blackshear, P.J. (1999) Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA. Mol Cell Biol, 19, 4311-4323. Lai, W.S., Kennington, E.A. and Blackshear, P.J. (2002) Interactions of CCCH zinc finger proteins with mRNA: non-binding tristetraprolin mutants exert an inhibitory effect on degradation of AU-rich element-containing mRNAs. J Biol Chem, 277, 9606-9613. Lai, W.S., Stumpo, D.J. and Blackshear, P.J. (1990) Rapid insulin-stimulated accumulation of an mRNA encoding a proline-rich protein. J Biol Chem, 265, 16556-16563. Lai, W.S., Thompson, M.J., Taylor, G.A., Liu, Y. and Blackshear, P.J. (1995) Promoter analysis of Zfp-36, the mitogen-inducible gene encoding the zinc finger protein tristetraprolin. J Biol Chem, 270, 25266-25272. Lee, J.Y., Kim, N.A., Sanford, A. and Sullivan, K.E. (2003) Histone acetylation and chromatin conformation are regulated separately at the TNF-alpha promoter in monocytes and macrophages. J Leukoc Biol, 73, 862-871. Levy, N.S., Chung, S., Furneaux, H. and Levy, A.P. (1998) Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J Biol Chem, 273, 6417-6423. Lin, N.Y., Lin, C.T., Chen, Y.L. and Chang, C.J. (2007) Regulation of tristetraprolin during differentiation of 3T3-L1 preadipocytes. FEBS Journal, in press. Ma, W.J., Cheng, S., Campbell, C., Wright, A. and Furneaux, H. (1996) Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J Biol Chem, 271, 8144-8151. Madrid, L.V., Mayo, M.W., Reuther, J.Y. and Baldwin, A.S., Jr. (2001) Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem, 276, 18934-18940. Mahtani, K.R., Brook, M., Dean, J.L., Sully, G., Saklatvala, J. and Clark, A.R. (2001) Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability. Mol Cell Biol, 21, 6461-6469. Marks, P., Rifkind, R.A., Richon, V.M., Breslow, R., Miller, T. and Kelly, W.K. (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer, 1, 194-202. Mukherjee, D., Gao, M., O'Connor, J.P., Raijmakers, R., Pruijn, G., Lutz, C.S. and Wilusz, J. (2002) The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements. Embo J, 21, 165-174. Ogawa, K., Chen, F., Kim, Y.J. and Chen, Y. (2003) Transcriptional regulation of tristetraprolin by transforming growth factor-beta in human T cells. J Biol Chem, 278, 30373-30381. Peng, S.S., Chen, C.Y., Xu, N. and Shyu, A.B. (1998) RNA stabilization by the AU-rich element binding protein, HuR, an ELAV protein. Embo J, 17, 3461-3470. Perkins, N.D., Felzien, L.K., Betts, J.C., Leung, K., Beach, D.H. and Nabel, G.J. (1997) Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator. Science, 275, 523-527. Perlmutter, D.H., Dinarello, C.A., Punsal, P.I. and Colten, H.R. (1986) Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. J Clin Invest, 78, 1349-1354. Place, R.F., Noonan, E.J. and Giardina, C. (2005) HDAC inhibition prevents NF-kappa B activation by suppressing proteasome activity: down-regulation of proteasome subunit expression stabilizes I kappa B alpha. Biochem Pharmacol, 70, 394-406. Richon, V.M. and O'Brien, J.P. (2002) Histone deacetylase inhibitors: a new class of potential therapeutic agents for cancer treatment. Clin Cancer Res, 8, 662-664. Roach, S.K., Lee, S.B. and Schorey, J.S. (2005) Differential activation of the transcription factor cyclic AMP response element binding protein (CREB) in macrophages following infection with pathogenic and nonpathogenic mycobacteria and role for CREB in tumor necrosis factor alpha production. Infect Immun, 73, 514-522. Rodriguez-Pascual, F., Hausding, M., Ihrig-Biedert, I., Furneaux, H., Levy, A.P., Forstermann, U. and Kleinert, H. (2000) Complex contribution of the 3'-untranslated region to the expressional regulation of the human inducible nitric-oxide synthase gene. Involvement of the RNA-binding protein HuR. J Biol Chem, 275, 26040-26049. Ryu, H., Lee, J., Olofsson, B.A., Mwidau, A., Dedeoglu, A., Escudero, M., Flemington, E., Azizkhan-Clifford, J., Ferrante, R.J. and Ratan, R.R. (2003) Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc Natl Acad Sci U S A, 100, 4281-4286. Saklatvala, J. (2004) The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr Opin Pharmacol, 4, 372-377. Saklatvala, J., Dean, J. and Clark, A. (2003) Control of the expression of inflammatory response genes. Biochem Soc Symp, 95-106. Sauer, I., Schaljo, B., Vogl, C., Gattermeier, I., Kolbe, T., Muller, M., Blackshear, P.J. and Kovarik, P. (2006) Interferons limit inflammatory responses by induction of tristetraprolin. Blood, 107, 4790-4797. Seidel, J.J. and Graves, B.J. (2002) An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors. Genes Dev, 16, 127-137. Shakhov, A.N., Collart, M.A., Vassalli, P., Nedospasov, S.A. and Jongeneel, C.V. (1990) Kappa B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J Exp Med, 171, 35-47. Shaw, G. and Kamen, R. (1986) A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell, 46, 659-667. Sheppard, K.A., Rose, D.W., Haque, Z.K., Kurokawa, R., McInerney, E., Westin, S., Thanos, D., Rosenfeld, M.G., Glass, C.K. and Collins, T. (1999) Transcriptional activation by NF-kappaB requires multiple coactivators. Mol Cell Biol, 19, 6367-6378. Stoecklin, G., Stubbs, T., Kedersha, N., Wax, S., Rigby, W.F., Blackwell, T.K. and Anderson, P. (2004) MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. Embo J, 23, 1313-1324. Su, B. and Karin, M. (1996) Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol, 8, 402-411. Suzuki, K., Nakajima, H., Ikeda, K., Maezawa, Y., Suto, A., Takatori, H., Saito, Y. and Iwamoto, I. (2003) IL-4-Stat6 signaling induces tristetraprolin expression and inhibits TNF-alpha production in mast cells. J Exp Med, 198, 1717-1727. Takahashi, N., Tetsuka, T., Uranishi, H. and Okamoto, T. (2002) Inhibition of the NF-kappaB transcriptional activity by protein kinase A. Eur J Biochem, 269, 4559-4565. Taylor, G.A., Carballo, E., Lee, D.M., Lai, W.S., Thompson, M.J., Patel, D.D., Schenkman, D.I., Gilkeson, G.S., Broxmeyer, H.E., Haynes, B.F. and Blackshear, P.J. (1996) A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity, 4, 445-454. Tchen, C.R., Brook, M., Saklatvala, J. and Clark, A.R. (2004) The stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself. J Biol Chem, 279, 32393-32400. Vanden Berghe, W., De Bosscher, K., Boone, E., Plaisance, S. and Haegeman, G. (1999) The nuclear factor-kappaB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. J Biol Chem, 274, 32091-32098. Varnum, B.C., Lim, R.W., Sukhatme, V.P. and Herschman, H.R. (1989) Nucleotide sequence of a cDNA encoding TIS11, a message induced in Swiss 3T3 cells by the tumor promoter tetradecanoyl phorbol acetate. Oncogene, 4, 119-120. Vassalli, P. (1992) The pathophysiology of tumor necrosis factors. Annu Rev Immunol, 10, 411-452. Wang, W., Furneaux, H., Cheng, H., Caldwell, M.C., Hutter, D., Liu, Y., Holbrook, N. and Gorospe, M. (2000) HuR regulates p21 mRNA stabilization by UV light. Mol Cell Biol, 20, 760-769. West, M.J., Lowe, A.D. and Karn, J. (2001) Activation of human immunodeficiency virus transcription in T cells revisited: NF-kappaB p65 stimulates transcriptional elongation. J Virol, 75, 8524-8537. Whitmarsh, A.J. and Davis, R.J. (1996) Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med, 74, 589-607. Wilson, G.M., Sutphen, K., Bolikal, S., Chuang, K.Y. and Brewer, G. (2001) Thermodynamics and kinetics of Hsp70 association with A + U-rich mRNA-destabilizing sequences. J Biol Chem, 276, 44450-44456. Yu, Q., Cok, S.J., Zeng, C. and Morrison, A.R. (2003) Translational repression of human matrix metalloproteinases-13 by an alternatively spliced form of T-cell-restricted intracellular antigen-related protein (TIAR). J Biol Chem, 278, 1579-1584. Zhang, W., Wagner, B.J., Ehrenman, K., Schaefer, A.W., DeMaria, C.T., Crater, D., DeHaven, K., Long, L. and Brewer, G. (1993) Purification, characterization, and cDNA cloning of an AU-rich element RNA-binding protein, AUF1. Mol Cell Biol, 13, 7652-7665. Zhong, H., May, M.J., Jimi, E. and Ghosh, S. (2002) The phosphorylation status of nuclear NF-kappa B determines its association with CBP/p300 or HDAC-1. Mol Cell, 9, 625-636. Zhu, W., Brauchle, M.A., Di Padova, F., Gram, H., New, L., Ono, K., Downey, J.S. and Han, J. (2001) Gene suppression by tristetraprolin and release by the p38 pathway. Am J Physiol Lung Cell Mol Physiol, 281, L499-508. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30793 | - |
| dc.description.abstract | Tristetraprolin (TTP)是一個可以結合到一些發炎相關基因的mRNA 上，而使之降解的蛋白質。其中最重要同時也被廣泛討論的是它可以造成TNF-α的mRNA 不穩定而使得發炎反應在細胞中得到適度的緩解。然而如何調控對於如此重要的發炎負調節者TTP 的轉錄作用及其表現的相關研究卻付之闕如。因此，本論文利用抑制不同訊息傳導之抑制劑來探討TTP 以及其下游基因TNF-α如何被調控。發現利用BAY 抑制NF-κB、MG132 抑制proteasome、SB203580 抑制p38 pathway 等效果皆會抑制由脂多醣引發之TTP mRNA 以及蛋白質表現。藉由ChIP 實驗證實，在脂多醣刺激巨噬細胞過程中NF-κB 這個轉錄因子可以結合到TTP 基因位於-1838~1859 的啟動子位置上。
而TTP 的啟動子活性也可被SB203580 抑制，表示p38 pathway 參與TTP 的轉錄控制。 此外在脂多醣不同時間刺激下，發現p38 pathway 對影響TTP mRNA 的穩定性有所差異。因此這些結果表示p38 pathway 能夠藉由調節轉錄以及後轉錄(post-transcription)等層面來調節TTP 的表現。另一方面，在LPS 刺激巨噬細胞中分析各種抑制劑的效果中發現TSA 這個藥物能夠很劇烈的減低TNF-α mRNA 的表現。TSA 帶有抑制HDAC酵素活性的特性，使得chromatin 結構變的鬆散而有助於轉錄作用進行。然而本論文藉由luciferase reporter 的實驗結果顯示，TSA 卻能抑制TNF-α啟動子之活性。因此進一步分析調節TNF-α啟動子上的重要轉錄因子NF-κB 之活性來深入探討是否參與其中之機制。有趣的發現是處理TSA 能夠抑制NF-κB 結合到TNF-α的啟動子上，卻不會影響NF-κB 進入到細胞核內、也不影響TNF-α mRNA 的穩定性。綜合上述，我們的實驗結果提供更多的證據來了解NF-κB 及p38 pathway 利用轉錄以及後轉錄等不同層面來調控在脂多醣刺激巨噬細胞中誘發之TTP 以及TNF-α表現。 | zh_TW |
| dc.description.abstract | Tristetraprolin (TTP) is an mRNA-destabilizing protein that negatively regulates the expression of proinflammatory mediators such as TNF-α. However, the mechanism of transcriptional regulation of TTP remains ill defined. Here we investigate the regulation of TTP as well as TNF-a expression in the mouse macrophage cell line RAW264.7. We found that pharmacological inhibition of NF-κB (BAY), proteasome (MG132) and p38 pathway (SB203580) resulted in downregulation of LPS-induced TTP mRNA and protein expression. A novel NF-κB binding element located within -1838 to -1859 relative to TTP transcription start site was identified and confirmed by ChIP experiments. Functional analysis using luciferase reporter assay demonstrated that TTP promoter activity was suppressed by SB203580 treatment. The half-life of TTP mRNA was also decreased by SB203580 treatment. These data suggest that p38 pathway regulates TTP expression at both transcriptional and post-transcriptional levels. Furthermore, the HDAC inhibitor, TSA, decreases the LPS-stimulated TNF-α mRNA expression. TSA is a general inhibitor of HDAC enzyme activity that results in chromatin structure loosening and transcriptional upregulation. In contrary, our data showed that TSA reduced the TNF-α promoter activity by luciferase reporter analysis. Interestingly, TSA disrupts NF-κB recruitment to TNF-α promoter without affecting NF-κB nuclear localization. Taken together, these results suggest that TTP mRNA transcription may be regulated by NF-κB while p38 signaling could modulate both TTP and TNF-α expression at both transcriptional and post-transcriptional levels during LPS stimulation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T02:15:55Z (GMT). No. of bitstreams: 1 ntu-96-D89242001-1.pdf: 1994703 bytes, checksum: bdde6bcd0ceab54ddd3ebd0a516f1d43 (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | 口試委員會審定書
中文摘要 英文摘要 I. INTRODUCTION 1 1.1 TTP.2 1.2 TNF-alpha .5 1.3 NF-κB .5 II. MATERIALS AND METHODS 2.1 Plasmids constructs.8 2.2 Cell culture.8 2.3 Preparation of antibodies.9 2.4 RNA isolation and RT-PCR.9 2.5 Real-time PCR.10 2.6 Preparation of cytoplasmic and nuclear extracts and Western blotting assay.10 2.7 Chromatin-immunoprecipitation (ChIP) ssay.11 2.8 Transfection, luciferase, and beta-galactosidase assay.12 2.9 Incorporation of biotin into RNA .13 2.10 RNA pull-down assay.14 2.11 In-gel digestion of gel-separated proteins, Peptide identification by mass spectrometry and bioinformatics analysis.15 III. RESULTS 3.1 The expression profile of TTP and TNF-α mRNA during LPS stimulation.16 3.2 The mRNA levels of TTP were suppressed by treatment with MG132, BAY and SB203580 .16 3.3 The expression of TNF-α mRNA were inhibited by TSA .17 3.4 The protein levels of TTP were suppressed by MG132, BAY and SB203580.17 3.5 The time frame of the MG132 effect on the production of TTP and mRNA accumulation in LPS-stimulated RAW264.7 macrophages .18 3.6 The mRNA stability of TTP in LPS-stimulated macrophages in the absence and Presence of MG132 .18 3.7 The effects of NF-κB activation on TTP mRNA accumulation in LPS-stimulated RAW264.7 cells.19 3.8 Identification of the putative NF-κB binding element in the TTP promoter ..19 3.9 The effects of p38 signaling pathway on TTP gene expression.21 3.10 SB203580 modulates TTP and its downstream target, TNF-α mRNA stability.21 3.11 Transcriptional regulation of TTP promoter by the p38 pathway .22 3.12 Activation of TTP expression by arsenite treatment.22 3.13 Identification of TTP-ARE binding proteins .23 3.14 Both HDAC inhibitors, TSA and sodium butyrate impair TNF-α production .24 3.15 Neither TSA nor sodium butyrate affect TNF-α mRNA stability..25 3.16 TSA treatment does not alter NF-κB expression and subcellular localization during LPS stimulation.25 3.17 TSA treatment reduced TNF-α -promoter activity driven by LPS stimulation.26 3.18 TSA treatment disrupts the in vivo association of NF-κB with the promoter of TNF-α in LPS-stimulated RAW264.7 cells .26 IV. DISCUSSION 4.1 Differential regulation of TTP expression by the NF-κB and p38 signaling pathways during LPS induction.28 4.2 A novel NF-κB binding site within 5’ promoter region of the ttp gene was identified .29 4.3 TTP expression was modulated by the p38 signaling pathway at both transcriptional and post-transcriptional levels .30 4.4 Heat shock proteins were associated with TTP-ARE ..31 4.5 Reduction of TNF-α expression by TSA can be attributed to down-regulated NF-κB binding to promoter .33 4.6 TTP and TNF-α expression was coordinated by NF-κB and p38 signaling pathway at both transcriptional and post-transcriptional levels ………….…….37 V. REFERENCES .38 VI. FIGURES Figure 1. Effects of various inhibitors on LPS-induced TTP mRNA expression in macrophages..47 Figure 2. Effects of various inhibitors on LPS-induced TNF-α mRNA expression in RAW264.7 cells.49 Figure 3. Effects of various inhibitors on TTP protein expression in LPS stimulated macrophages.50 Figure 4. The effect of MG132 on kinetics of TTP protein and mRNA expression in LPS stimulated macrophages.51 Figure 5. MG132 does not alter TTP mRNA stability in LPS-stimulated macrophages.52 Figure 6. Induction of TTP mRNA expression by recombinant TNF-α.52 Figure 7. NF-κB family members were recruited to TTP promoter by LPS treatment of RAW264.7 cells..53 Figure 8. Expression of multiple, phosphorylated forms of TTP could be inhibited by adding p38 inhibitor..54 Figure 9. TTP mRNA half-life were reduced by SB203580 treatment in LPS -stimulated macrophages.55 Figure 10. SB203580 treatment suppresses TTP promoter activity in LPS -stimulated macrophages.56 Figure 11. P38 MAPK signaling pathway modulates TTP expression in RAW264.7 macrophages.56 Figure 12. TTP-ARE binding protein identification.58 Figure 13. The time frame of the effect of TSA and sodium butyrate on TNF-α mRNA expression in LPS-stimulated macrophages.59 Figure 14. Effects of TSA and sodium butyrate on the turnover of TNF-α mRNA in macrophages stimulated with LPS..60 Figure 15. NF-κB expression and subcellular localization were not influenced by TSA treatment in LPS-stimulated macrophages.61 Figure 16. TSA treatment reduces LPS-stimulated TNF-α -promoter activity..62 Figure 17. TSA disrupts the interaction between p50 and the TNF-α promoter in LPS-stimulated RAW264.7 cells.63 Figure 18. Coordinative expression of TTP and TNF-α in transcriptional and post-transcriptional processes .64 VII. TABLES Table 1. Analysis of mouse TTP promoter sequence .65 Table 2. Sequence of murine TNF-α gene promoter..66 Table 3. Inhibitors of certain signaling pathways on LPS-induced TTP expression.67 Table 4. Identification of TTP-ARE binding proteins by mass spectrometry analysis .68 VIII. ABBREVIATION AND CHEMICAL SYMBOLS .70 | |
| dc.language.iso | en | |
| dc.subject | 脂多醣 | zh_TW |
| dc.subject | 巨噬細胞 | zh_TW |
| dc.subject | TNF-alpha | en |
| dc.subject | TTP | en |
| dc.subject | macrophage | en |
| dc.subject | lipopolysaccharide | en |
| dc.title | 老鼠巨噬細胞中由脂多醣誘發的基因表現之調控 | zh_TW |
| dc.title | Regulation of Lipopolysaccharide-induced Genes
Expression in Mouse Macrophages | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 張?仁 博士(Ching-Jin Chang) | |
| dc.contributor.oralexamcommittee | 果伽蘭 博士,朱善德 博士,李玉梅 博士 | |
| dc.subject.keyword | 脂多醣,巨噬細胞, | zh_TW |
| dc.subject.keyword | lipopolysaccharide,macrophage,TTP,TNF-alpha, | en |
| dc.relation.page | 70 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-02-14 | |
| 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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