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dc.contributor.advisorHo Linen_US
dc.contributor.authorLin, Li-Lingen_US
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dc.description.abstract雄性激素受體 (AR) 對於攝護腺癌的生長及發育相當重要,許多蛋白質激酶會藉由磷酸化AR絲氨酸或蘇氨酸而調控AR的活性。然而研究指出,cyclin D1會直接和AR結合抑制AR的轉錄活性,並抑制雄性激素所調控的攝護腺癌細胞增生。本研究欲探討的Cdk5蛋白屬於cyclin-dependent kinase (Cdk) 家族的成員之ㄧ,是ㄧ種絲氨酸-蘇氨酸蛋白激酶,其專一的活化蛋白為p35。有異於其他Cdk家族成員,截至目前的研究尚未發現Cdk5具有直接調控細胞週期的能力。本實驗室的研究首先發現Cdk5和AR有交互作用的情況,並有正向調控AR的能力,除此之外,和cyclin D1結構相似的p35蛋白也和AR有交互作用。有趣的是,利用質體DNA轉染的方式表現Cdk5及p35蛋白會干擾cyclin D1和AR的交互作用,進ㄧ步的研究發現,cyclin D1會抑制AR下游調控蛋白PSA的表現,然而Cdk5和AR間的交互作用使細胞內PSA蛋白的表現以及PSA蛋白的分泌有顯著增加的情形,若利用RNA干擾技術降低Cdk5的表現,則發現PSA蛋白的表現及分泌受到抑制。因此推測Cdk5會藉由干擾cyclin D1和AR間的交互作用而調控AR的活性。綜合上述的研究,Cdk5對於AR活性的調控在攝護腺癌細胞中扮演重要的角色,而Cdk5及AR相關的基礎研究可能對未來攝護腺癌的治療開啟ㄧ個新方向。zh_TW
dc.description.abstractThe androgen receptor (AR) is important for the development of prostate cancer. Several protein kinases have been shown to regulate AR transactivation by phosphorylating serine or threonine residues in AR. On the other hand, cyclin D1 harbors a distinct anti-mitogenic function and inhibits androgen-dependent proliferation in prostatic adenocarcinoma. In which, cyclin D1 was reported to directly interact with AR and negatively regulate AR transactivation. Cdk5 protein, the main focus in this study, is a member of serine/threonine cyclin-dependent kinase (CDK) family and its regulator is p35 protein. In contrast to other members of the CDK family, Cdk5 is not directly involved in cell cycle modulation. Our previous results indicated that Cdk5 could associate with AR and performed a positive regulation of AR. In addition, based on the homology between cyclin D1 and p35, the protein interaction between p35 and AR was also identified. Interestingly, we found that overexpression of Cdk5 or p35 in prostate cancer cells significantly decreased the association of cyclin D1 and AR. The ability of the AR to activate endogenous target gene expression was inhibited in the presence of cyclin D1. However, the interaction between Cdk5 and AR significantly increased endogenous PSA expression and PSA secretion. Furthermore, Cdk5 inhibition by siRNA decreased the expression of PSA protein. In conclusion, we suggest that Cdk5 might modulate AR transactivation in prostate cancer through competition with cyclin D1. Therefore, Cdk5 becomes a future candidate of therapeutic target for prostate cancer.en_US
dc.description.tableofcontents中文摘要………………………………………………………………i 英文摘要………………………………………………………………ii 目次……………………………………………………………………iii 圖表目次………………………………………………………………v 第一章、 前言………1 一、 背景………1 (一) 攝護腺及攝護腺癌………1 (二) 雄性激素及雄性激素受體………2 (三) 雄性激素對攝護腺癌的重要性………5 (四) 攝護腺特異抗原 (prostate specific antigen, PSA)………5 (五) 細胞週期調節蛋白cyclin D1的調控………6 (六) 細胞週期調節蛋白cyclin D1與惡性腫瘤………8 (七) cyclin D1與雄性激素受體………8 (八) The cyclin D1b variant protein………10 (九) Cdk5 (cyclin-dependent kinase 5)………11 (十) Cdk5活化蛋白………13 (十一) Cdk5和攝護腺癌………14 二、 研究動機及目的………15 第二章、 材料與方法………17 一、 細胞培養 (cell culture)………17 二、 細胞冷凍保存 (cryopreservation)………18 三、 細胞生長曲線測定 (growth curve)………18 四、 細胞週期分析 (cell cycle analysis)………18 (一) 酒精固定法………18 (二) Propidium iodide (PI) 染色………19 五、 質體DNA轉染技術 (plasmid DNA transfection)………19 六、 RNA干擾技術 (RNA interference)………19 七、 蛋白質免疫螢光染色 (immunofluorescence stain)………20 八、 蛋白質萃取 (protein extraction)………21 九、 細胞核質分離 (fractionation)………21 十、 蛋白質免疫沉澱 (immunoprecipitation, IP)………22 十一、 聚丙烯胺膠體電泳 (SDS-polyacrylamide gel electrophoresis)………22 十二、 西方墨點法 (immunoblotting, western blot)………23 (一) 半乾式轉漬法 (semi-dry)………23 (二) 全濕式轉漬法 (immersion)………23 十三、 ㄧ級抗體 (primary antibody)………24 十四、 二級抗體 (secondary antibody)………25 十五、 Methyltrienolone (R1881)………25 十六、 Roscovitine (RV)………26 第三章、 結果………27 一、 攝護腺癌細胞株之生長狀況及蛋白質表現………27 二、 攝護腺癌細胞中cyclin D1與Cdk5的生化交互作用………28 三、 cyclin D1和p35蛋白競爭和Cdk5的交互作用………28 四、 Cdk5、p35和AR蛋白的交互作用………29 五、 Cdk5及p35干擾cyclin D1和AR的結合………29 六、 cyclin D1干擾Cdk5及p35和AR的交互作用………30 七、 cyclin D1影響AR在細胞核及細胞質的分佈………30 八、 cyclin D1影響AR下游調控基因PSA蛋白的表現………31 九、 Cdk5對AR下游調控基因PSA表現之影響………31 十、 Cdk5對AR下游調控基因PSA分泌之調控………32 十一、異種移植的攝護腺腫瘤中,Cdk5影響AR的表現及磷酸化………32 第四章、 討論………33 一、 Cdk5及cyclin D1的交互作用在惡性腫瘤中所扮演的角色………33 二、 Cdk5、p35及AR的交互作用………35 三、 Cdk5與AR活性的探討………35 第五章、 總結………37 第六章、 參考文獻………61zh_TW
dc.subjectcyclin D1en_US
dc.subjectAndrogen Receptoren_US
dc.subjectcyclin D1zh_TW
dc.titleCdk5蛋白藉由干擾cyclin D1調控雄性激素受體活性zh_TW
dc.titleCdk5 Interferes Cyclin D1-Dependent Activation of Androgen Receptoren_US
dc.typeThesis and Dissertationzh_TW
item.openairetypeThesis and Dissertation-
item.fulltextno fulltext-
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