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dc.contributor.authorHsia, Jiun-Yien_US
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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.titleThe Function of SLAN and its Relationship with Lung Canceren_US
dc.typeThesis and Dissertationzh_TW
item.openairetypeThesis and Dissertation-
item.fulltextno fulltext-
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