Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/22265
DC FieldValueLanguage
dc.contributor陳健尉zh_TW
dc.contributor周寬基zh_TW
dc.contributor曹昌堯zh_TW
dc.contributor陳志毅zh_TW
dc.contributor.advisor楊秋英zh_TW
dc.contributor.author夏君毅zh_TW
dc.contributor.authorHsia, Jiun-Yien_US
dc.contributor.other中興大學zh_TW
dc.date2012zh_TW
dc.date.accessioned2014-06-06T07:17:35Z-
dc.date.available2014-06-06T07:17:35Z-
dc.identifierU0005-2308201117255900zh_TW
dc.identifier.citationReferences 1 Yeang CH, McCormick F, Levine A. Combinatorial patterns of somatic gene mutations in cancer. FASEB J 2008;22:2605-2622. 2 Simpson AJ. Sequence-based advances in the definition of cancer-associated gene mutations. Curr Opin Oncol 2009;21:47-52. 3 Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer: looking to the future. J Clin Oncol 2005;23:3175-3185. 4 Youlden DR, Cramb SM, Baade PD. The international epidemiology of lung cancer: geographical distribution and secular trends. J Thorac Oncol 2008; 3:819-831. 5 Ewart-Toland A, Dai Q, Gao YT, et al. Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis 2005;26:1368-1373. 6 Gu J, Gong Y, Huang M, Lu C, et al. Polymorphisms of STK15 (Aurora-A) gene and lung cancer risk in Caucasians. Carcinogenesis 2007;28:350-355. 7 Ogawa E, Takenaka K, Katakura H, et al. Perimembrane Aurora-A expression is a significant prognostic factor in correlation with proliferative activity in non-small-cell lung cancer (NSCLC). Ann Surg Oncol 2008;15:547-554. 8 Agnese V, Bazan V, Fiorentino FP, et al. The role of Aurora-A inhibitors in cancer therapy. Ann Oncol 2007;6:vi47-52. 9 Boss DS, Beijnen JH, Schellens JH. Clinical experience with aurora kinase inhibitors: a review. Oncologist 2009;14:780-793. 10 Carvajal RD, Tse A, Schwartz GK. Aurora kinases: new targets for cancer therapy. Clin Cancer Res 2006;12:6869-6875. 11 Cheung CH, Coumar MS, Hsieh HP, et al. Aurora kinase inhibitors in preclinical and clinical testing. Expert Opin Investig Drugs 2009;18:379-398. 12 Coumar MS, Cheung CH, Chang JY, et al. Advances in Aurora kinase inhibitor patents. Expert Opin Ther Pat 2009; 19:321-356. 13 Gautschi O, Heighway J, Mack PC, et al. Aurora kinases as anticancer drug targets. Clin Cancer Res 2008;14:1639-1648. 14 Kitzen JJ, de Jonge MJ, Verweij J. Aurora kinase inhibitors. Crit Rev Oncol Hematol 2010;73:99-110. 15 Moore AS, Blagg J, Linardopoulos S, et al. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia 2010;24:671-678. 16. Copeland PR, Driscoll DM. RNA binding proteins and selenocysteine. Biofactors 2001;14:11-16. 17 Mudge J, Miller NA, Khrebtukova I, et al. Genomic Convergence Analysis of Schizophrenia: mRNA Sequencing Reveals Altered Synaptic Vesicular Transport in Post-Mortem Cerebellum. PLoS ONE 2008;3:e3625. 18 Hawse JR, Hejtmancik JF, Huang Q, et al. Identification and functional clustering of global gene expression differences between human age-related cataract and clear lenses. Mol Vis 2003;9:515-537. 19 Cahill S, Smyth P, Finn SP, et al. Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer 2006;5:70. 20 Yu JX, Sieuwerts AM, Zhang Y,et al. Pathway analysis of gene signatures predicting metastasis of node-negative primary breast cancer. BMC Cancer 2007; 7:182. 21 Bischoff JR, Anderson L, Zhu Y, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 1998; 17:3052-3065. 22 Zhou H, Kuang J, Zhong L Kuo WL, et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 1998;20:189-193. 23 Wang X, Zhou YX, Qiao W Tominaga Y, et al. Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene 2006;25:7148-7158. 24 Crane R, Gadea B, Littlepage L, et al. Aurora A, meiosis and mitosis. Biol Cell 2004;96:215-229. 25 Marumoto T, Zhang D, Saya H. Aurora-A - a guardian of poles. Nat Rev Cancer 2005;59:42-450. 26 Barr AR, Gergely F. Aurora-A: the maker and breaker of spindle poles. J Cell Sci 2007;120:2987-2996. 27 Su LJ, Chang CW, Wu YC, et al. Selection of DDX5 as a novel internal control for Q-RT-PCR from microarray data using a block bootstrap re-sampling scheme. BMC Genomics 2007;8:140. 28 Lin YS, Su LJ, Yu CT, et al. Gene expression profiles of the aurora family kinases. Gene Expr 2006;13:15-26. 29 Tsai MY, Wang S, Heidinger JM, et al. A mitotic lamin B matrix induced by RanGTP required for spindle assembly. Science 2006;311:1887-1893. 30 Walker DL, Wang D, Jin Y, et al. Skeletor, a novel chromosomal protein that redistributes during mitosis provides evidence for the formation of a spindle matrix. J Cell Biol 2000;151:1401-1412. 31 Caban K, Copeland PR. Size matters: a view of selenocysteine incorporation from the ribosome. Cell Mol Life Sci 2006;63:73-81. 32 Yu CT, Hsu JM, Lee YC, et al. Phosphorylation and stabilization of HURP by Aurora-A: implication of HURP as a transforming target of Aurora-A. Mol Cell Biol 2005;25:5789-5800. 33 Arbitrario JP, Belmont BJ, Evanchik MJ, et al. SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer Chemother Pharmacol 2009;65:707-717. 34 Benten D, Keller G, Quaas A, et al. Aurora kinase inhibitor PHA-739358 suppresses growth of hepatocellular carcinoma in vitro and in a xenograft mouse model. Neoplasia 2009;11:934-944. 35 Lin ZZ, Hsu HC, Hsu CH, et al. The Aurora kinase inhibitor VE-465 has anticancer effects in pre-clinical studies of human hepatocellular carcinoma. J Hepatol 2009;50:518-527. 36 Ochi T, Fujiwara H, Yasukawa M. Aurora-A kinase: a novel target both for cellular immunotherapy and molecular target therapy against human leukemia. Expert Opin Ther Targets 2009;13:1399-1410. 37 VanderPorten EC, Taverna P, Hogan JN, et al. The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model. Mol Cancer Ther 2009;8:930-939.en_US
dc.identifier.urihttp://hdl.handle.net/11455/22265-
dc.description.abstractIn an attempt to search for genes with abnormal expression in cancers, SLAN (Suppressed in lung cancer, also known as KIAA0256) is found underexpressed in human lung cancer tissues by quantitative real-time PCR (Q-RT-PCR). SLAN and its deletion mutants are localized to many subcellular locations such as endoplasmic reticulum (ER), nucleus, nucleolus, spindle pole and midbody, suggesting SLAN may function as a multifunctional protein. Overexpression of SLAN per se or its short hairpin RNAs (shRNAs) inhibits or accelerates cell proliferation through prolonging or shortening mitosis. Time-lapse microscopic recording reveals that cells overexpressing exogenous SLAN are arrested in mitosis or cannot undergo cytokinesis. SLAN 2-551 mutants drastically arrest cells in mitosis, where α- and γ-tubulin are disorganized. SLAN employs C-terminal to interact with Aurora-A, a key mitosis regulator and an oncogenic kinase associated with a wide range of human cancers. SLAN negatively regulates the activity of Aurora-A by directly inhibiting kinase activity in vitro or reducing the level of active Aurora-A in cells. SLAN is frequently reduced in lung cancer tissues overexpressing Aurora-A, arguing for the necessity to suppress SLAN during the Aurora-A-associated cancer formation. Taken together, we have identified a novel protein SLAN downregulated in lung caner and able to inhibit cell proliferation and Aurora-A.en_US
dc.description.abstract為了嚐試尋找在癌症組織中不正常表現的基因,我們以肺癌作為研究的目標,經由Q-RT-PCR之方法,發現在人類肺癌組織中,SLAN (Suppressed in Lung cANcer,又稱為KIAA0256)這個尚未被充分研究的新的基因有表現偏低的現象。這個研究的目的,即在於探討SLAN分子在細胞內的功能及與肺癌的關係。 本研究利用SLAN 之 full length或是各種的deletion mutants,或是SLAN 的shRNA,表現在293T或各種肺癌的cell lines中,進而研究它們對於細胞增生,細胞週期,細胞分裂的進行,及紡綞絲排列之影響。 在本研究中,我們發現SLAN及它的各種deletion mutants分布在細胞內的許多位置,包括內質網,細胞核,核仁,極紡綞體等,顯示SLAN可能是一個具有多種功能的蛋白質。將SLAN基因過度表現,會經由延長有絲分裂而抑制細胞增生。反之,以SLAN之shRNA作用後,會經由縮短有絲分裂而加速細胞增生。連續定時之顯微鏡觀察顯示,細胞過度表現外來的SLAN時,會使細胞停止在有絲分裂或不能進行細胞質分裂。SLAN 2-551這個deletion mutant讓細胞停止在有絲分裂期的比例最高,同時呈現α及γ-tubulin混亂的排列。Aurora-A,是一個關鍵的有絲分裂調控者,並與多種人類癌症相關的致癌激酶。SLAN以C端與Aurora-A交互作用。同時SLAN會直接抑制激酶活動而反向調控Aurora-A的活性,或在細胞內降低具有活性的Aurora-A。在過度表現Aurora-A的肺癌組織中,SLAN時常會降低表現,也使得在與Aurora-A相關的癌症形成中,抑制SLAN基因的機轉值得進一步探討。 總之,在本研究中,我們確認了一個在肺癌中會降低表現的新蛋白質SLAN,具有包括在紡綞絲基質及中心體的多種細胞內的位置,並會抑制細胞增生及Aurora-A的功能。zh_TW
dc.description.tableofcontentsAbstract ii 1. Introduction 1 2. Materials and Methods 3 2.1. Tissue procurement, total RNA preparation, and reverse transcription 3 2.2. Quantitative-RT-PCR (Q-RT-PCR) 3 2.3. Cell culture 4 2.4. Preparation of cell extracts, Western blot analysis and immunocoprecipitation 5 2.5. Indirect immunofluorescence analysis 5 2.6. Flowcytometric analysis and mitotic index 6 2.7. Construction of SLAN expression vectors 6 2.8. Knockdown of SLAN 7 2.9. Cell proliferation assay 8 3. Results 9 3.1. SLAN is downregulated in collected lung cancer tissues 9 3.2. Motif prediction and subcellular localization of SLAN 9 3.3. SLAN is associated with spindle matrix-like structure 10 3.4. SLAN retards cell proliferation by disturbing mitosis 11 3.5. SLAN binds and inactivates Aurora-A 12 3.6. Underexpression of SLAN and overexpression of Aurora-A are detected in lung cancer tissues 12 4. Discussion 14 Reference 17en_US
dc.language.isoen_USzh_TW
dc.publisher分子生物學研究所zh_TW
dc.relation.urihttp://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-2308201117255900en_US
dc.subjectSLANen_US
dc.subject肺癌zh_TW
dc.subjectSLANzh_TW
dc.titleSLAN分子功能的探討及與肺癌之關係zh_TW
dc.titleThe Function of SLAN and its Relationship with Lung Canceren_US
dc.typeThesis and Dissertationzh_TW
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.languageiso639-1en_US-
item.openairetypeThesis and Dissertation-
item.grantfulltextnone-
item.fulltextno fulltext-
item.cerifentitytypePublications-
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