Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23493
DC FieldValueLanguage
dc.contributor何素鵬zh_TW
dc.contributor洪耀欽zh_TW
dc.contributor.advisor周寬基zh_TW
dc.contributor.advisorKuan-Chih Chowen_US
dc.contributor.author吳夢珊zh_TW
dc.contributor.authorWu, Meng-Shanen_US
dc.contributor.other中興大學zh_TW
dc.date2011zh_TW
dc.date.accessioned2014-06-06T07:20:31Z-
dc.date.available2014-06-06T07:20:31Z-
dc.identifierU0005-1708201020284100zh_TW
dc.identifier.citationNeil A. Campbell 原著,偉明圖書,台灣培生教育合作出版:生物學/第5版 。2005 台灣癌症臨床研究合作組織肺癌研究委員會。肺癌臨床指引,National Cancer Institute。台北。2004 科學發展,350期:52-55頁。2002 國家衛生研究院-癌症研究組。肺癌診治共識。台北。1998 Antoni L, Sodha N, Collins I, Garrett MD. CHK2 kinase:cancer susceptibility and cancer therapy-two sides of the same coin? Nat Cancer Rev. 7: 925-36.(2007) Ahn J, Urist M, Prives C. Questioning the role of checkpoint .J Biol Chem. 278: 20480-9(2003) Aktas D, Arno MJ, Rassool F, Mufti G.Analysis of CHK2 in patients with myelodysplastic syndromes. Leuk Res. 26: 985-7(2002) Bartek J, Lukas J.Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 3: 421-9(2003) Ben-Yehoyada M, Wang LC, Kozekov ID, Rizzo CJ, Gottesman ME, Gautier J. Checkpoint Signaling from a single DNA Interstrand Crosslink. Mol Cell. 35: 704-15(2009) Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DAHeterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 286: 2528-31(1999) Buscemi G, Zannini L, Fontanella E, Lecis D, Lisanti S, Delia D. The Shelterin Protein TRF2 Inhibits Chk2 Activity at Telomeres in the Absence of DNA Damage. Curr Biol. 19: 874-9(2009) Cai Z, Chehab NH, Pavletich NP. Structure and Activation Mechanism of the CHK2 DNA Damage Checkpoint Kinase. Mol Cell. 35: 818-29.(2009) Castedo M, Perfettini JL, Roumier T, Yakushijin K, Horne D, Medema R, Kroemer G. The cell cycle checkpoint kinase Chk2 is a negative regulator of mitotic catastrophe. Oncogene. 23: 4353-61(2004) Chou WC, Wang HC, Wong FH, Ding SL, Wu PE, Shieh SY, Shen CY. Chk2-dependent phosphorylation of XRCC1 in the DNA damage response promotes base excision repair. EMBO J. 27: 3140-50(2008) Chen MS, Hurov J, White LS, Woodford-Thomas,T. and Piwnica- Worms H. Absence of apparent phenotype in mice lacking Cdc25C protein phosphatase. Mol Cell Biol. 21: 3853-3861(2001) Dodson GE, Shi Y, Tibbetts RS.DNA Replication Defects, Spontaneous DNA Damage, and ATM-dependent Checkpoint Activation in Replication Protein A-deficient Cells. J Biol Chem. 279: 34010-4(2004) Dong X, Wang L, Taniguchi K, Wang X, Cunningham JM, McDonnell SK, Qian C, Marks AF, Slager SL, Peterson BJ, Smith DI, Cheville JC, Blute ML, Jacobsen SJ, Schaid DJ, Tindall DJ, Thibodeau SN, Liu W. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 72: 270-80(2003) Haruki N, Saito H, Tatematsu Y, Konishi H, Harano T, Masuda A, Osada H, Fujii Y, Takahashi T. Histological type-selective, tumorpredominant expression of a novel CHK1 isoform and infrequent in vivo somatic CHK2 mutation in small cell lung cancer. Cancer Res. 60: 4689-92(2000) Hiroyuki Niida and Makoto Nakanishi.DNA damage checkpoints in mammals. Mutagenesis. 21: 3-9(2006) Huen MS, Chen J.The DNA damae response pathway:at the crossroad of protein modifications. Cell Res. 18: 8-16(2008) Kim DS, Kim MJ, Lee JY, Lee SM, Choi JE, Lee SY, Park JY.Epigenetic inactivation of checkpoint kinase 2 gene in non-small cell lung cancer and its relationship with clinicopathological features. Lung Cancer. 65: 247-50(2009) Laurent Antoni, Nayanta Sodha, Ian Collins and Michelle D.Garrett.CHK2 kinase: cancer susceptibility and cancer therapy-two sides of the same coin? Nature Reviews. 7: 925-936.(2007) Lincoln AJ, Wickramasinghe D, Stein P, Schultz R M , Palko M E, De Miguel, M.P., TessarolloL and Donovan PJ.Cdc25b phosphatase is required for resumption of meiosis during oocyte maturation. Nat Genet. 30: 446-449(2002) Lukas C, Bartkova J, Latella L, Falck J, Mailand N, Schroeder T, Sehested M, Lukas J, Bartek J. DNA Damage-activated Kinase Chk2 Is Independent of Proliferation or Differentiation Yet Correlates with Tissue. Biology Cancer Res. 61: 4990-3(2001) Lukas C, Falck J, Bartkova J, Bartek J, Lukas J. Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage. Nat Cell Biol. 5: 255-60(2003) Matsuoka S, Nakagawa T, Masuda A, Haruki N, Elledge SJ, Takahashi T.Reduced expression and impaired kinase activity of a Chk2 mutant identified in human lung cancer. Cancer Res.61: 5362-5(2001) Miller CW, Ikezoe T, Krug U, Hofmann WK, Tavor S, Vegesna V, Tsukasaki K, Takeuchi S, Koeffler HP.Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors. Genes Chromosomes Cancer. 33: 17-21(2002) Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR.CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 31: 55-9(2002) Oldenburg RA, Kroeze-Jansema K, Kraan J, Morreau H, Klijn JG, Hoogerbrugge N, Ligtenberg MJ, van Asperen CJ, Vasen HF, Meijers C, Meijers-Heijboer H, de Bock TH, Cornelisse CJ, Devilee P.The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res. 63: 8153-7(2003) Olsen BB, Larsen MR, Boldyreff B, Niefind K, Issinger OG.Explorong the intramolecular phosphorylation site in human chk2. Mutat Res. 646: 50-9(2008) Shackelford RE, Kaufmann WK, Paules RS.Cell cycle control, checkpoint mechanisms,and genotoxic stress. Environ Health Perspect. 107: 5-24(1999) Sherr CJ.Mammalian G1 cyclins and cells cycle progression . Proc Assoc Am Physicians. 107: 181-6(1995) Stevens C, Smith L, La Thangue NB.Chk2 activates E2F-1 in response to DNA damage. Nat Cell Biol. 5: 401-9(2003) Taylor WR, Stark GR.Regulation of the G2/M transition by p53. Oncogene. 20: 1803-15.(2001) Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, Kilpivaara O, Tamminen A, Kononen J, Aittomaki K, Heikkila P, Holli K, Blomqvist C, Bartek J, Kallioniemi OP, Nevanlinna H.A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 71: 432-8(2002) Wei JH, Chou YF, Ou YH, Yeh YH, Tyan SW, Sun TP, Shen CY, Shieh SY. TTK/hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on Thr68. J Biol Chem. 280: 7748-57(2005) Williams LH, Choong D, Johnson SA, Campbell IG.Genetic and Epigenetic Analysis of CHEK2 in Sporadic Breast, Colon, and Ovarian. Clin Cancer Res.12: 6967-72(2006) Xiao Z, Xue J, Sowin TJ, Zhang H.Differential roles of checkpoint kinase 1, checkpoint kinase 2, and mitogen-activated protein kinase-activated protein kinase 2 in mediating DNA damage-induced cell cycle arrest:implications for cancer therapy. Mol Cancer Ther. 5: 1935-43(2006) Xu X, Tsvetkov LM, Stern DF.Chk2 Activation and Phosphorylation-Dependent Oligomerization. Molecular and cellular biology. 22: 4419-32.(2002) Yang J, Yu Y, Hamrick HE, Duerksen-Hughes PJ.ATM, ATR and DNA-PK:initiators of the cellular genotoxic stress sponses. Carcinogenesis. 24: 1571-80(2003) Yang S, Kuo C, Bisi JE, Kim MK.PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nat Cell Biol. 4: 865-70 (2002) Yang X, Wood PA , Hrushesky WJ .Mannalian TIMELESS is required for ATM-dependent CHK2 activation and G2/M checkpoint control. J Biol Chem. 285: 3030-4(2010) Zhang P, Wang J, Gao W, Yuan BZ, Rogers J, Reed E.CHK2 kinase expression is down-regulated due to promoter methylation in non-small cell lung cancer . Mol Cancer. 3: 14(2004) Zhou BB, Elledge SJ.The DNA damage response:putting checkpoint in perspective. Nature. 408: 433-9(2000) Zhu H, Miao ZH, Huang M, Feng JM, Zhang ZX, Lu JJ, Cai YJ, Tong LJ, Xu YF, Qian XH, Ding J.Naphthalimides induce G (2) arrest through the ATM-activated Chk2-executed pathway in HCT116 cells. Neoplasia. 11: 1226-34(2009) Campbell Neil A, Reece JB., Biology ., 6th ed. 2005 http://www.cancer.org/downloads/STT/500809web.pdf http://www.biocarta.com/pathfiles/h_plk3Pathway.aspzh_TW
dc.identifier.urihttp://hdl.handle.net/11455/23493-
dc.description.abstract在許多國家中,肺癌一直都是致死率高治愈率極低的癌症。許多專家學者也皆致力於肺癌研究無非希望能找到標靶細胞來治療肺癌。當人體細胞受到紫外線、放射線以及環境致癌因子等因素的傷害時,細胞便會啟動ATR-Chk1(Ataxia telangiectasia mutated and Rad3-related-checkpoint kinase 1)和ATM-Chk2(Ataxia telangiectasia mutated-checkpoint kinase 2)兩大監測系統來修復DNA的損傷。細胞週期檢查點(cell-cycle-checkpoint kinase 2)Chk2參與著DNA損傷機制重要的訊息傳遞。本研究中,我們利用反轉錄聚合酶鏈反應偵測Chk2 mRNA在肺癌細胞株肺癌患者患者檢體的表現(13.33%),以西方墨漬法偵測Chk2蛋白在肺癌細胞株及肺癌患者檢體的表現(68%),更以免疫組織化學染色法偵測Chk2在肺癌病理組織切片中的表現(84.75%)以及Tissue-array肺癌患者檢體的表現(65%),結果顯示,Chk2蛋白在肺癌腫瘤組織中呈現穩定度增加以及大量表現的結果。zh_TW
dc.description.abstractLung cancer is the leading cause of cancer death in many developed country including Taiwan. Many doctors and scientists have focused their time towards the prevention and treatment of lung cancer. However, the effect is minimal. Chk2 kinase is an important cell cycle regulator in the DNA damage response pathway. In response to exogenous or endogenous DNA damage agents, both ATR-Chk1(Ataxia telangiectasia mutated and Rad3-related-checkpoint kinase 1)and ATM-Chk2(Ataxia telangiectasia mutated-checkpoint kinase 2 )are activated.Chk2 is mainly phosphorylated and activated by ATM kinase. In this study, we detected the expression of Chk2 mRNA by RT-PCR(13.33%), the expression of Chk2 protein in lung cancer cell lines and patients' samples by Western blotting(68%), and that of Chk2 in lung cancer pathology tissue(84.75%)and tissue-array(65%)by Immunohistochemistry. Our results showed that Chk2 protein is highly expressed in lung cancer tissue and cell line.en_US
dc.description.tableofcontents摘要 I Summary II 圖表目次 III 第一章 緒論 - 1 - 一、細胞週期(cellcycle) - 1 - (一) 細胞週期 - 1 - (二) 有絲分裂 - 2 - (三) 細胞週期檢查點 - 3 - 二、細胞檢查點激酶2( Checkpoint2) - 5 - (一) Checkpoint 2 生物現象 - 5 - (二) Checkpoint 2與癌症的關係 - 8 - (三) P53 - 9 - 三、肺癌簡介 - 10 - (一) 肺癌之臨床分型 - 11 - (二) 非小細胞肺癌之臨床分期 - 13 - (三) 肺癌預防 - 14 - (四) 未來期望 - 14 - 四、研究動機與目標 - 15 - 第二章 材料與方法 - 16 - 一、材料來源 - 16 - (一)肺癌檢體來源 - 16 - (二)細胞株 - 16 - (三)抗體 - 16 - (四)設計之引子對 - 16 - (五)藥品試劑 - 17 - (六)緩衝溶液 - 17 - (七)儀器 - 17 - 二、實驗方法 - 17 - (一)免疫組織染色法(Immunohistochemistry;IHC) - 17 - (二)聚炳烯胺凝膠電泳(SDS-polyacrylamide gel electrophoresis,SDS-PAGE)及西方墨點法(Western Blot) - 19 - (三)反轉錄聚合酶連鎖反應 (Reverse transcription-polymerase chain reaction;RT-PCR) - 20 - (四)、DNA序列分析 - 23 - 第三章 實驗結果 - 24 - 一、Chk2於肺癌患者檢體內之表現與分佈情形 - 24 - 二、Chk2蛋白於肺癌、子宮頸癌細胞株之表現情形 - 24 - 三、Chk2蛋白於肺癌患者組織檢體之表現情形 - 25 - 四、Chk2於各肺癌細胞株及子宮頸癌細胞株mRNA之表現情形 - 25 - 五、Chk2於肺癌患者組織檢體mRNA之表現情形 - 25 - 六、比較分析肺癌細胞株H1437以及A549之DNA序列 - 26 - 第四章 討論 - 27 - 第五章 結論 - 31 - 第六章 實驗結果圖表 - 32 - 圖一、Chk2於肺癌患者檢體內之表現與分佈情形 - 32 - 圖二、Chk2於肺癌組織Tissue-array之表現與分佈情形 - 34 - 圖三、Chk2蛋白於肺癌與子宮頸癌細胞株中表現 - 35 - 圖四、Chk2蛋白於肺癌患者檢體中之表現情形 - 36 - 圖五、Chk2於各肺癌細胞株及子宮頸癌細胞株mRNA之表現情形 - 37 - 圖六、Chk2於肺癌患者mRNA之表現情形 - 38 - 表一、設計之引子對 - 39 - 表二、Chk2蛋白於50對肺癌患者中表現量 - 39 - 表三、Chk2 mRNA在15對肺癌患者中表現量 - 39 - 表四、使用PSORT軟體預測Chk2蛋白分布情況 - 40 - 表五、Chk2 Phosphorylation sites predicted - 41 - 表六、利用ExPASY網站預測Chk2可能進行磷酸化(Phosphorylation)修飾之位置 - 43 - 表七、PsortⅡ預測分析Chk2分布情形 - 44 - 表八、肺癌細胞株H1437序列 - 48 - 表九、Chk2序列 - 50 - 表十、肺癌細胞株1437 和原始Chk2 序列blast結果 - 52 - 第七章 附錄 - 56 - 第八章 參考文獻 - 63-zh_TW
dc.language.isoen_USzh_TW
dc.publisher生命科學院碩士在職專班zh_TW
dc.relation.urihttp://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-1708201020284100en_US
dc.subjectCHK2en_US
dc.subject非小細胞肺癌zh_TW
dc.subjectLung canceren_US
dc.subjectDNA repairen_US
dc.subjectDNA修復zh_TW
dc.titleCHK2在非小細胞肺癌的病理意義zh_TW
dc.titleThe Pathological Significance of Chk2 in Non-Small Cell Lung Canceren_US
dc.typeThesis and Dissertationzh_TW
item.grantfulltextnone-
item.openairetypeThesis and Dissertation-
item.languageiso639-1en_US-
item.fulltextno fulltext-
item.cerifentitytypePublications-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
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