請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/6549
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張?仁(Ching-Jin Chang) | |
dc.contributor.author | Kuan-Ting Wang | en |
dc.contributor.author | 王冠婷 | zh_TW |
dc.date.accessioned | 2021-05-17T09:14:36Z | - |
dc.date.available | 2014-02-21 | |
dc.date.available | 2021-05-17T09:14:36Z | - |
dc.date.copyright | 2013-02-21 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2013-01-24 | |
dc.identifier.citation | [1] B. Varnum, Q. Ma, T. Chi, and B. Fletcher, “The TIS11 primary response gene is a member of a gene family that encodes proteins with a highly conserved sequence containing an unusual Cys-His repeat.,” Mol Cell Biol., vol. 11, no. 3, pp. 1754-1758, 1991.
[2] W. S. Lai, J. Stumpos, and P. J. Blacksheart, “Rapid insulin-stimulated accumulation of an mRNA encoding a proline-rich protein.,” J Biol Chem., vol. 265, no. 27, pp. 16556-16563, 1990. [3] R. N. DuBois, M. W. McLane, K. Ryder, L. F. Lau, and D. Nathans, “A growth factor-inducible nuclear protein with a novel cysteine/histidine repetitive sequence.,” J Biol Chem., vol. 265, no. 31, pp. 19185-19191, Nov. 1990. [4] P. Blackshear, R. Phillips, and S. Ghosh, “Zfp36l3, a rodent X chromosome gene encoding a placenta-specific member of the Tristetraprolin family of CCCH tandem zinc finger proteins.,” Biol Reprod., vol. 73, no. 2, pp. 297-307, Aug. 2005. [5] G. Taylor, E. Carballo, D. Lee, and W. Lai, “A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency.,” J Immunol., vol. 4, no. 5, pp. 445-454, 1996. [6] E. Carballo et al., “Bone marrow transplantation reproduces the tristetraprolin-deficiency syndrome in recombination activating gene-2 (-/-) mice. Evidence that monocyte/macrophage progenitors may be responsible for TNFalpha overproduction.,” J Clin Invest., vol. 100, no. 5, pp. 986-995, 1997. [7] E. Carballo, “Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin.,” Science., vol. 281, no. 5379, pp. 1001-1005, Aug. 1998. [8] S. Sanduja, F. F. Blanco, and D. a Dixon, “The roles of TTP and BRF proteins in regulated mRNA decay.,” Wiley Interdiscip Rev RNA., vol. 2, no. 1, pp. 42-57, 2011. [9] D. J. Stumpo et al., “Chorioallantoic fusion defects and embryonic lethality resulting from disruption of Zfp36L1, a gene encoding a CCCH tandem zinc finger protein of the Tristetraprolin family.,” Mol Cell Biol., vol. 24, no. 14, pp. 6445-6455, 2004. [10] D. J. Stumpo et al., “Targeted disruption of Zfp36l2, encoding a CCCH tandem zinc finger RNA-binding protein, results in defective hematopoiesis.,” Blood., vol. 114, no. 12, pp. 2401-2410, Jul. 2009. [11] S. B. V. Ramos, “The CCCH tandem zinc-finger protein Zfp36l2 is crucial for female fertility and early embryonic development.,” Development., vol. 131, no. 19, pp. 4883-4893, Oct. 2004. [12] D. Hodson, M. Janas, A. Galloway, and S. Bell, “Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia.,” Nat Immunol., vol. 11, no. 8, pp. 717-724, Aug. 2010. [13] W. S. Lai, “Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to Au-rich elements and destabilization of mRNA.,” J Biol Chem., vol. 275, no. 23, pp. 17827-17837, Apr. 2000. [14] W. Lai and D. Carrick, “Influence of nonameric AU-rich tristetraprolin-binding sites on mRNA deadenylation and turnover.,” J Biol Chem., vol. 280, no. 40, pp. 34365-34377, Oct. 2005. [15] J. Lykke-Andersen, “Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1.,” Genes Dev., vol. 19, no. 3, pp. 351-361, 2005. [16] H. Sandler, J. Kreth, H. T. M. Timmers, and G. Stoecklin, “Not1 mediates recruitment of the deadenylase Caf1 to mRNAs targeted for degradation by tristetraprolin.,” Nucleic Acids Res., vol. 39, no. 10, pp. 4373-4786, May 2011. [17] M. Fenger-Gron, C. Fillman, B. Norrild, and J. Lykke-Andersen, “Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping.,” Mol Cell., vol. 20, no. 6, pp. 905-915, Dec. 2005. [18] C. Chen, R. Gherzi, S. Ong, and E. Chan, “AU binding proteins recruit the exosome to degrade ARE-containing mRNAs.,” Cell, vol. 107, no. 4, pp. 451-464, 2001. [19] M. Baou, A. Jewell, and J. J. Murphy, “TIS11 family proteins and their roles in posttranscriptional gene regulation.,” J Biomed Biotechnol., vol. 2009, pp. 1-11, Jan. 2009. [20] Q. Jing, S. Huang, S. Guth, T. Zarubin, and A. Motoyama, “Involvement of microRNA in AU-rich element-mediated mRNA instability.,” Cell., vol. 120, no. 5, pp. 623-634, Mar. 2005. [21] Y. M. Schichl, U. Resch, R. Hofer-Warbinek, and R. de Martin, “Tristetraprolin impairs NF-kappaB/p65 nuclear translocation.,” J Cell Biochem., vol. 284, no. 43, pp. 29571-29581, Oct. 2009. [22] J. Liang, T. Lei, Y. Song, N. Yanes, Y. Qi, and M. Fu, “RNA-destabilizing factor tristetraprolin negatively regulates NF-kappaB signaling.,” J Biol Chem., vol. 284, no. 43, pp. 29383-29390, Oct. 2009. [23] D. Benjamin, M. Schmidlin, L. Min, B. Gross, and C. Moroni, “BRF1 protein turnover and mRNA decay activity are regulated by protein kinase B at the same phosphorylation sites.,” Mol Cell Biol., vol. 26, no. 24, pp. 9497-9507, Dec. 2006. [24] S. L. Clement, C. Scheckel, G. Stoecklin, and J. Lykke-Andersen, “Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment.,” Mol Cell Biol., vol. 31, no. 2, pp. 256-266, Jan. 2011. [25] M. Brook et al., “Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways.,” Mol Cell Biol., vol. 26, no. 6, pp. 2408-2418., 2006. [26] S. Maitra, C. Chou, C. Luber, K.-yeol Lee, and M. Mann, “The AU-rich element mRNA decay-promoting activity of BRF1 is regulated by mitogen-activated protein kinase-activated protein kinase 2.,” RNA., vol. 14, no. 5, pp. 950-959, 2008. [27] M. Schmidlin et al., “The ARE-dependent mRNA-destabilizing activity of BRF1 is regulated by protein kinase B.,” EMBO J., vol. 23, no. 24, pp. 4760-4769, Dec. 2004. [28] J. Mendell, “When the message goes awry: disease-producing mutations that influence mRNA content and performance.,” Cell., vol. 107, no. 4, pp. 411-414, Nov. 2001. [29] L. E. Young, S. Sanduja, K. Bemis-Standoli, E. a Pena, R. L. Price, and D. a Dixon, “The mRNA binding proteins HuR and tristetraprolin regulate cyclooxygenase 2 expression during colon carcinogenesis.,” Gastroenterology., vol. 136, no. 5, pp. 1669-1679, May 2009. [30] S. Lee, S. Kim, J. Kim, and C. Moon, “Butyrate response factor 1 enhances cisplatin sensitivity in human head and neck squamous cell carcinoma cell lines.,” Int J Cancer., vol. 117, no. 1, pp. 32-40, Oct. 2005. [31] C. Dong, R. J. Davis, and R. a Flavell, “MAP kinases in the immune response.,” Annu Rev Immunol., vol. 20, pp. 55-72, Jan. 2002. [32] L. Chang, “Mammalian MAP kinase signalling cascades.,” Nature., vol. 410, no. 6824, pp. 37-40, Mar. 2001. [33] H. T. Lu et al., “Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice.,” EMBO J., vol. 18, no. 7, pp. 1845-1857, Apr. 1999. [34] J. Beech, L. Hayes, and A. Denys, “A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis.,” J Immunol., vol. 173, no. 11, pp. 6928-6937, Dec. 2004. [35] D. Kontoyiannis, A. Kotlyarov, and E. Carballo, “Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology.,” EMBO J., vol. 20, no. 14, pp. 3760-3770, Jul. 2001. [36] C. Dumitru, J. Ceci, C. Tsatsanis, and D. Kontoyiannis, “TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway.,” Cell., vol. 103, no. 7, pp. 1071-1083, Dec. 2000. [37] Y. Liu, E. G. Shepherd, and L. D. Nelin, “MAPK phosphatases--regulating the immune response.,” Nat Rev Immunol., vol. 7, no. 3, pp. 202-212, Mar. 2007. [38] P. Chen, J. Li, and J. Barnes, “Restraint of proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages.,” J Immunol., vol. 169, no. 11, pp. 6408-6416, Dec. 2002. [39] S. Hao and D. Baltimore, “The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules.,” Nat Immunol., vol. 10, no. 3, pp. 281-288, Mar. 2009. [40] J. Sanghera and S. Weinstein, “Activation of multiple proline-directed kinases by bacterial lipopolysaccharide in murine macrophages.,” J Immunol., vol. 11, no. 27, pp. 4457-4465, 1996. [41] C. R. Tchen, M. Brook, J. Saklatvala, and A. R. Clark, “The stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself.,” J Biol Chem., vol. 279, no. 31, pp. 32393-32400, Jul. 2004. [42] F. Kratochvill et al., “Tristetraprolin-driven regulatory circuit controls quality and timing of mRNA decay in inflammation.,” Mol Syst Biol., vol. 7, p. 560, Jan. 2011. [43] S. A. Brooks, J. E. Connolly, and W. F. C. Rigby, “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., vol. 172, no. 12, pp. 7263-7271, 2004. [44] B. a Johnson, J. R. Stehn, M. B. Yaffe, and T. K. Blackwell, “Cytoplasmic localization of tristetraprolin involves 14-3-3-dependent and -independent mechanisms.,” J Biol Chem., vol. 277, no. 20, pp. 18029-18036, May 2002. [45] K. S. a Khabar, “Post-transcriptional control during chronic inflammation and cancer: a focus on AU-rich elements.,” Cell Mol Life Sci., vol. 67, no. 17, pp. 2937-2955, Sep. 2010. [46] D. N. Slack, O. M. Seternes, M. Gabrielsen, and S. M. Keyse, “Distinct binding determinants for ERK2/p38alpha and JNK map kinases mediate catalytic activation and substrate selectivity of map kinase phosphatase-1.,” J Biol Chem., vol. 276, no. 19, pp. 16491-16500, May 2001. [47] K. R. Mahtani, M. Brook, J. L. E. Dean, J. Saklatvala, A. R. Clark, and G. Sully, “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., vol. 21, no. 19, pp. 6461-6469, 2001. [48] J. Liang, W. Song, G. Tromp, P. E. Kolattukudy, and M. Fu, “Genome-wide survey and expression profiling of CCCH-zinc finger family reveals a functional module in macrophage activation.,” PLoS One., vol. 3, no. 8, p. e2880, Jan. 2008. [49] H. Cao, J. F. U. Jr, and R. A. Anderson, “Cinnamon polyphenol extract affects immune responses by regulating anti- and proinflammatory and glucose transporter gene expression in mouse macrophages.,” J Nutr., vol. 138, no. 5, pp. 833-840, 2008. [50] N. Lin and C. Lin, “Modulation of immediate early gene expression by tristetraprolin in the differentiation of 3T3-L1 cells.,” Biochem Biophys Res Commun., vol. 365, no. 1, pp. 69-74, Jan. 2008. [51] F. Marra et al., “Differential requirement of members of the MAPK family for CCL2 expression by hepatic stellate cells.,” Am J Physiol Gastrointest Liver Physiol., vol. 287, no. 1, pp. G18-26, Jul. 2004. [52] W. S. Lai, J. S. Parker, S. F. Grissom, D. J. Stumpo, and P. J. Blackshear, “Novel mRNA targets for tristetraprolin (TTP) identified by global analysis of stabilized transcripts in TTP-deficient fibroblasts.,” Mol Cell Biol., vol. 26, no. 24, pp. 9196-9208, Dec. 2006. [53] S. Ryser, A. Massiha, I. Piuz, and W. Schlegel, “Stimulated initiation of mitogen-activated protein kinase phosphatase-1 (MKP-1) gene transcription involves the synergistic action of multiple cis-acting elements in the proximal promoter.,” Biochem J., vol. 378, no. Pt 2, pp. 473-484, Mar. 2004. [54] J. Brondello, “Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation.,” Science., vol. 286, no. 5449, pp. 2514-2517, Dec. 1999. [55] R. Davis, “The mitogen-activated protein kinase signal transduction pathway,” J Biol Chem., vol. 268, no. 20, pp. 14553-14556, 1993. [56] G. S. Wu, “Role of mitogen-activated protein kinase phosphatases (MKPs) in cancer.,” Cancer Metastasis Rev., vol. 26, no. 3–4, pp. 579-585, Dec. 2007. [57] Z. Wang, J. Xu, J.-Y. Zhou, Y. Liu, and G. S. Wu, “Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance.,” Cancer Res., vol. 66, no. 17, pp. 8870-8877, Sep. 2006. [58] N. Al-Souhibani, W. Al-Ahmadi, J. E. Hesketh, P. J. Blackshear, and K. S. a Khabar, “The RNA-binding zinc-finger protein tristetraprolin regulates AU-rich mRNAs involved in breast cancer-related processes.,” Oncogene., vol. 29, no. 29, pp. 4205-4215, Jul. 2010. [59] S. E. Brennan, Y. Kuwano, N. Alkharouf, P. J. Blackshear, M. Gorospe, and G. M. Wilson, “The mRNA-destabilizing protein tristetraprolin is suppressed in many cancers, altering tumorigenic phenotypes and patient prognosis.,” Cancer Res., vol. 69, no. 12, pp. 5168-5176, Jun. 2009. [60] I. Amit, A. Citri, T. Shay, Y. Lu, M. Katz, and F. Zhang, “A module of negative feedback regulators defines growth factor signaling.,” Nat Genet., vol. 39, no. 4, pp. 503-512, Apr. 2007. [61] X. H. Liu and D. P. Rose, “Differential expression and regulation of cyclooxygenase-1 and -2 in two human breast cancer cell lines.,” Cancer Res., vol. 56, no. 22, pp. 5125-5127, Nov. 1996. [62] A. Ristimaki et al., “Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer.,” Cancer Res., vol. 62, no. 3, pp. 632-635, 2002. [63] C. Liu, S. Chang, K. Narko, and O. Trifan, “Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice.,” J Biol Chem., vol. 276, no. 21, pp. 18563-18569, May 2001. [64] G. Davies, J. Salter, M. Hills, L.-ann Martin, and N. Sacks, “Correlation between cyclooxygenase-2 expression and angiogenesis in human breast cancer.,” Clin Cancer Res., vol. 9, no. 7, pp. 2651-2656, 2003. [65] K. Phillips, N. Kedersha, and L. Shen, “Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis.,” Proc Natl Acad Sci U S A., vol. 101, no. 7, pp. 2011-2016, Feb. 2004. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/6549 | - |
dc.description.abstract | 先天免疫反應的基因表達受到嚴密調控。絲裂原活化蛋白激酶(MAPK)在先天免疫反應中扮演關鍵腳色,它透過磷酸化下游轉錄因子和RNA結合蛋白,可活化炎性細胞因子(proinflammatory cytokines)的合成。MAPK磷酸酶(MKP)藉由去磷酸化作用使MAPK失去活性。目前研究指出Mkp-1是一個重要的負調控因子,它可以關閉炎性細胞因子的生產。我們已經證明Tristetraprolin(Ttp)可以藉由與具有特殊的多腺嘌呤-尿嘧啶序列(AU-rich element, ARE)的Mkp-1 mRNA結合,並透過後轉錄機制將Mkp-1 mRNA降解。TTP家族包含三個主要成員,Ttp,Zfp36l1和Zfp36l2。本論文的目標即在了解其他TTP家族蛋白在先天免疫反應中扮演的角色。首先我們觀察TTP家族蛋白的mRNA與蛋白質表達。在受到脂多醣(Lipopolyssacharide, LPS)刺激的老鼠巨噬細胞RAW264.7中,TTP的mRNA和蛋白質被高度誘導,但Zfp36l1和Zfp36l2的mRNA表現降低,而蛋白質表現則保持一致。利用Zfp36l1和Zfp36l2的knockdown分析,我們發現兩個受到Zfp36l1和Zfp36l2調控的目標mRNA:Mkp-1和Cox-2。減少Zfp36l1和Zfp36l2的表現,可延長目標mRNA的半衰期,進而使目標mRNA增加。當細胞內Mkp-1的表達增加時,會抑制p38 MAPK的活性,使老鼠巨噬細胞對LPS刺激的敏感度下降。此外,我們還發現高度磷酸化的Zfp36l1會與支架蛋白14-3-3結合,並使Mkp-1 mRNA不被降解。綜合上述,我們的研究結果顯示Zfp36l1和Zfp36l2的表現與磷酸化修飾,可調控老鼠巨噬細胞RAW264.7受脂多醣刺激時,Mkp-1 mRNA的表現,這也說明Zfp36l1和Zfp36l2是先天免疫反應中重要的調控因子。 | zh_TW |
dc.description.abstract | Gene expressions are tightly controlled in the innate immune response. Mitogen-activated protein kinases (MAPKs) play critical roles in the innate immune response through phosphorylating downstream transcription factors and RNA binding proteins to elicit the biosynthesis of proinflammatory cytokines. Inactivation of MAPKs is done by MAPK phosphatases (MKPs) through dephosphorylation. The previous studies strongly suggested that Mkp-1 was a critical negative regulator for switching off the production of proinflammatory cytokines. We had demonstrated that Mkp-1 mRNA containing AU-rich element (ARE) was post-transcriptionally regulated by an ARE-binding protein Tristetraprolin (Ttp). The TTP family contains three major members, Ttp, Zfp36l1 and Zfp36l2. To examine whether other family proteins also play roles in the innate immune response, their expression profiles were determined. The mRNA and protein of Ttp were highly induced by Lipopolyssacharide (LPS) in mouse macrophage RAW264.7 cells, whereas the mRNAs of Zfp36l1 and Zfp36l2 were down-regulated and their proteins were maintained in the consistent levels in the period of LPS-stimulation. By knockdown analysis, we found that Mkp-1 and Cyclooxygenase-2 (Cox-2) were the mRNA targets of Zfp36l1 and Zfp36l2 in the resting condition. Knockdown of Zfp36l1 and Zfp36l2 increased the basal levels of target mRNAs by prolonging their half-lives. Increasing the expression of Mkp-1 repressed the activity of p38 MAPK, and the sensitivity to LPS-stimulation was decreased. Furthermore, we found that hyper-phosphorylation of Zfp36l1 stabilized Mkp-1 expression by forming a complex with adapter protein 14-3-3. Our findings imply the expression and phosphorylation of Zfp36l1 and Zfp36l2 might play roles in modulating the mRNA level of Mkp-1 to control p38 MAPK activity in LPS-stimulation, and both Zfp36l1 and Zfp36l2 are important regulators in the innate immune response. | en |
dc.description.provenance | Made available in DSpace on 2021-05-17T09:14:36Z (GMT). No. of bitstreams: 1 ntu-101-R99b46004-1.pdf: 3273170 bytes, checksum: f7a16d888f025a1b33c5bcf6d44949fa (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | Contents
誌謝 i 中文摘要 iii Abstract iv Contents vi Abbreviations ix 1. Introduction 1 1.1 TTP Family Proteins 1 1.1.1 Identification of TTP Family Proteins 1 1.1.2 Function of TTP Family Proteins 2 1.1.3 TTP Family Proteins Mediate ARE-containing mRNA Decay 3 1.1.4 Ttp in the Transcriptional Regulation 4 1.1.5 The Phosphorylation Modification of TTP Family Proteins 5 1.1.6 TTP family Proteins in Cancers 6 1.2 Innate Immune Response 7 1.2.1 Mitogen-activated Protein Kinase (MAPK) in the Innate Immune Response 7 1.2.2 Mitogen-activated Protein Kinase Phosphatases (MKPs) in the Innate Immune Response 7 1.2.3 TTP Family Proteins in the Innate Immune Response 8 2. Materials and Methods 10 2.1 Plasmid Constructs 10 2.2 Cell Culture 11 2.3 Preparation Whole Cell Extracts and Cytoplasmic/Nuclear Extracts 12 2.4 Alkaline Phosphatase, Calf Intestinal (CIP) Treatment 13 2.5 Western Blot Assay and Antibodies 13 2.6 RNA Extraction and Reverse-transcription 14 2.7 Real-time PCR 15 2.8 RNA Pull-down Assay 16 2.9. Dual Luciferase Reporter Assay 17 2.10 Short-hairpin RNA (shRNA) 17 2.11. Lentivirus Knockdown 18 2.12. Co-immunoprecipitaion (Co-IP) 19 2.13. GST Fusion Protein Production and GST Pull-down Assay 19 2.14 Statistical Analysis 21 3. Specific Aims 22 4. Results 23 4.1 The Consistent Expression and Protein Phosphorylation of Zfp36l1 and Zfp36l2 in the Period of LPS-stimulation in RAW264.7 Cells. 23 4.2 Zfp36l1 and Zfp36l2 Destabilize MAPK Phosphotase-1 (Mkp-1) and Cyclooxygenase-2 (Cox-2) mRNAs in Resting RAW264.7 Cells. 24 4.3 Zfp36l1 and Zfp36l2 Down-regulate the Mkp-1 and Cox-2 3’UTR-mediated Luciferase Reporter Activity and Interact with Deadenylase Caf1a. 25 4.4 Regulation of Mkp-1 mRNA Stability by Phosphorylation of Zfp36l1. 27 4.5 The Induction of Mkp-1 mRNA in Early LPS-stimulation is Post-transcriptionally Modulated by Zfp36l1 and Zfp36l2. 29 4.6 p38 MAPK Activity is Regulated by Zfp36l1 and Zfp36l2 Through Mkp-1. 30 5. Discussion 32 6. Figures 39 Figure 1. The consistent expression and protein phosphorylation of Zfp36l1 and Zfp36l2 during the period of LPS-stimulation in RAW264.7 cells. 39 Figure 2. Zfp36l1 and Zfp36l2 destabilize MAPK phosphotase-1 (Mkp-1) and cyclooxygenase-2 (Cox-2) mRNAs in resting RAW264.7 cells. 42 Figure 3. Zfp36l1 and Zfp36l2 down-regulate the Mkp-1 and Cox-2 3’UTR -mediated luciferase reporter activity and interact with deadenylase Caf1a. 46 Figure 4. Regulation of Mkp-1 mRNA stability by phosphorylation of Zfp36l1. 49 Figure 5. The induction of Mkp-1 mRNA in early LPS-stimulation is post-transcriptionally modulated by Zfp36l1 and Zfp36l2. 52 Figure 6. p38 MAPK activity is regulated by Zfp36l1 and Zfp36l2 through Mkp-1. 54 Figure 7. Hypothesized regulatory networks between Zfp36l1, Zfp36l2, Mkp-1, and p38 MAPK in RAW264.7 cells. 56 7. Tables 57 Table 1. Primers for PCR 57 Table 2. Primers for real-time PCR 58 8. Appendix 59 Appendix 1. mRNA targets of human TTP family proteins. 59 Appendix 2. The pathway of ARE-mediated mRNA decay. 60 Appendix 3. Mammalian MAP kinase pathways. 60 Appendix 4. Classification of MAPK phosphatases 61 Appendix 5. The three types of gene expression profiles in Tnf-α activated genes. 61 9. References 62 | |
dc.language.iso | en | |
dc.title | Tristetraprolin家族蛋白在小鼠巨噬細胞功能之研究 | zh_TW |
dc.title | Functional Characterization of Tristetraprolin Family Proteins in Mouse Macrophages | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 張震東(Geen-Dong Chang),余榮熾(Lung-Chih Yu),朱善德(Sin-Tak Chu) | |
dc.subject.keyword | mRNA 穩定性,Tristetraprolin,先天免疫反應,磷酸化,絲裂原活化蛋白激酶, | zh_TW |
dc.subject.keyword | mRNA stability,Tristetraprolin,Innate immune response,Phosphorylation,Mitogen-activated protein kinase, | en |
dc.relation.page | 69 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2013-01-24 | |
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 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-101-1.pdf | 3.2 MB | Adobe PDF | 檢視/開啟 |
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。