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    請使用永久網址來引用或連結此文件: http://ir.cmu.edu.tw/ir/handle/310903500/47682


    題名: 探討CDK1或微管蛋白所引發的有絲分裂風暴在蔓荊子黃素 (Casticin)誘導的人類結腸直腸癌HT-29細胞凋亡中扮演的角色
    作者: 鍾景光(Jing-Gung Chung)
    貢獻者: 生命科學院生物科技學系;中國附醫醫學研究部
    關鍵詞: CCCH 鋅指基因;Zc3h12a;Zc3hav1L;發炎體;TNFα;pyroptosis;CCCH zinc finger gene;Zc3h12a;Zc3hav1L;inflammasomes;TNFα;pyroptosis
    日期: 2012-02-29
    上傳時間: 2013-01-25 13:57:29 (UTC+8)
    摘要: 近?研究發現人?有55 種新穎CCCH 鋅指基因(novel CCCH zinc finger gene),這些基因可能?與 細胞的各種過程,如增殖、分化、凋亡、抗病毒、免疫和發炎反應。先前我們篩選T3 期的人?結腸 直腸癌組織檢體,發現許多CCCH 鋅指基因?常表現,如Zc3h12a 基因在腫瘤組織中表現低下;而 Zc3hav1L 基因在腫瘤組織中表現顯著上升。 Zc3h12a (=MCPIP1, MCP-1-induced protein 1)是單核球細胞受到發炎激素MCP-1 (monocyte hemotactic protein-1)活化後誘導表現出?的一種轉?因子,具有RNase 及deubiquitinase 活性,可經由 抑制NF-B 活性,?低發炎反應。我們初步的研究發現大?表現Zc3h12a,其細胞生長受到抑制;? 處以TNF,發現大?表現Zc3h12a 的細胞,其凋亡比?顯著增加;相反的,將Zc3h12a 做定點突變 (D141N),發現其無法抑制細胞生長,也無法增強TNF所誘導的細胞凋亡。已知TNFα 與其受體(TNF receptor, TNFR)結合後,會誘導受體形成TNFR complex I 及TNFR complex II。complex I 的形成與活 化NF-B ?徑有關;而complex II 的形成與活化caspase-8 有關。此外有些文獻指出TNFR complex 的形成也與caspase-1 或caspase-4 活化有關,且caspase-1 及caspase-4 活化是TNFα 誘導caspase cascade 的最上游。發炎體(Inflammasomes)是發炎激素所誘導形成的細胞內蛋白質聚合體,與引起發炎反應及 活化caspase-1 有關,活化後的caspase-1 負責?割pro-IL-1,形成活化態IL-1,而依賴caspase-1 的 死亡方式稱為pyroptosis。我們初步發現caspase-1 抑制劑可以防止Zc3h12a/TNFα 所活化的caspase cascade 及細胞凋亡,因此我們認為Zc3h12a 可能?與發炎體及pyroptosis。另一方面,Zc3hav1-like 基因(Zc3hav1L)相似於Zc3hav1 基因,已知Zc3hav1 蛋白質具有分解病毒RNA 的活性,因此具有抗病 毒功能,然而Zc3hav1L 卻鮮少被研究過。我們初步的研究發現?低Zc3hav1L 基因的表現,可抑制細 胞增生及轉移,而大?表現Zc3hav1L 基因,可增加細胞增生及轉移。 基於我們的初步結果,我們將在三?內完成下?目標: 第一?、探討Zc3h12a 增強TNF所誘導 細胞凋亡的機制: 再確認Zc3h12a 增強TNF所誘導的細胞凋亡現象; 試驗Zc3h12a 是否影響TNFα 所 誘導的FADD/caspase-8 凋亡?徑; 試驗Zc3h12a 是否影響TNF所誘導的NF-B 存活與JNK 凋亡訊 息?徑。第二?、探討Zc3h12a 在TNFR complex I & II, 發炎體及pyroptosis 所扮演的角色: 試驗 caspase-1 或caspase-4 是否?與Zc3h12a/TNFα 所誘導的細胞凋亡; 試驗Zc3h12a 是否影響TNFR complex I 及complex II 的形成; 試驗Zc3h12a 是否影響發炎體的形成及是否?與pyroptosis。第三?、 探討Zc3h12a 及Zc3hav1L 調控結腸直腸癌細胞生長之機制: 試驗過?表現Zc3h12a 基因是否影響結腸 直腸癌細胞生長、細胞週期及凋亡;試驗抑制或過?表現Zc3hav1L 基因是否影響結腸直腸癌細胞生 長、轉移及凋亡。

    Recent research have found 55 novel CCCH-type zinc finger genes in human, those genes potentially participate in several cellular processes including proliferation, differentiation, apoptosis, anti-virus, immunity and inflammation. We have found several CCCH-type zinc finger genes were abnormally expressed in human colorectal cancer tissues, such as downregulation of Zc3h12a and upregulation of Zc3hav1L in tumor. Zc3h12a (also named MCPIP1) was identified as a transcription factor in monocyte chemotactic protein-1 (MCP-1)-activated monocytes. It exhibits RNase and deubiquitinase activities, and can inhibit inflammation through decrease of NF-B activity. Our preliminary results found overexpression of wild type Zc3h12a resulted in inhibiting cell proliferation and enhanced the TNF-induced cell apoptosis. However, mutant Zc3h12a (D141N) did not inhibit cell proliferation and enhance TNF-induced cell apoptosis. It has been known that TNFα binds to its receptor and subsequently forms TNFR complex I and TNFR complex II, which are associated with the activation of NF-B and caspase-8, respectively. The formation of TNFR complex might contribute to the activation of caspase-1 or caspase-4, which might be the most upstream events in TNFα-induced caspase cascade. Inflammasomes are intracellular protein complexes induced by inflammatory cytokines, which aims to activate caspase-1 and then in turn to cleave pro-IL-1 into IL-1. The “pyroptosis” is a new term to describe the caspase-1-dependent cell death. Our preliminary results found the caspase-1 inhibitor could reverse the Zc3h12a- and TNFα-induced the activation of caspase cascade and apoptosis. Therefore, we thought the Zc3h12a might involve in the inflammasomes and pyroptosis. Zc3hav1 protein has been known that exhibits anti-virus activity by degradation of viral RNA. Another CCCH-type zinc finger gene Zc3hav1-like gene (Zc3hav1L) is similar to Zc3hav1 gene , but it has been little studied previously. Our preliminary results also found knockdown Zc3hav1L significantly inhibited cell proliferation and migration, however overexpression of Zc3hav1L increases cell proliferation and migration. Based on our recent findings and hypothesis, we would like to fully understand the molecular mechanisms of Zc3h12a and Zc3hav1L on the regulation of cell proliferation, apoptosis, migration/metastasis, inflammation, or pyroptosis, and hope to achieve the following Specific Goals. 1. To investigate the molecular mechanisms about Zc3h12a enhances TNF-induced cell apoptosis: to confirm the effects of Zc3h12a enhances TNF-induced cell apoptosis; to examine whether Zc3h12a affects TNF-induced FADD/caspase-8 death pathway; to examine whether Zc3h12a affects TNF-induced NF-B survival pathway and JNK death pathway. 2. To investigate the role of Zc3h12a on the formation of TNFR complex I, complex II, and inflammasomes and pyroptosis: to examine whether Zc3h12a affects the formation of TNFR complex I and complex II; to examine whether Zc3h12a affects inflammasomes and involves in the pyroptosis. 3. To investigate the role of Zc3h12a and Zc3hav1L on the regulation of cell growth in colorectal cancer cells: to examine whether overexpression of Zc3h12a affects cell proliferation, cell cycle progression and apoptosis in colorectal cancer cells; to examine whether decrease or overexpression of Zc3hav1L affects cell growth, migration/metastasis, and apoptosis in colorectal cancer cells.
    顯示於類別:[生物科技學系暨碩士班] 研究計畫

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