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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張明富(Ming-Fu Chang) | |
dc.contributor.author | Shang-Ting Yu | en |
dc.contributor.author | 俞尚婷 | zh_TW |
dc.date.accessioned | 2021-06-13T02:16:27Z | - |
dc.date.available | 2016-10-05 | |
dc.date.copyright | 2011-10-05 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-08-01 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30807 | - |
dc.description.abstract | 原發性自體隱性畸形小頭症 (primary autosomal recessive microcephaly, MCPH) 是一種遺傳疾病,患者的大腦皮質有明顯萎縮,神經發育緩慢,最常導致此種疾病的原因即為Aspm (abnormal spindle-like, microcephaly associated) 基因突變。ASPM蛋白質在物種間具有保守性,例如哺乳類、果蠅以及線蟲。除了一開始在腦部發現,後來證實ASPM蛋白質在分裂組織中都會表現,同時在某些癌症中,例如卵巢癌、子宮頸癌,其表現量有上升現象。人類ASPM蛋白質在有絲分裂的過程中位於紡錘體相關結構,調控有絲分裂的進行,此現象與果蠅中的同源蛋白質Asp相同,但詳細的功能與機制尚未清楚。觀察果蠅Asp突變種,發現於有絲分裂中期有延遲情形,無法正常形成紡錘體中心。而在老鼠的系統中,以shRNA負調控Aspm蛋白質的表現,則會造成腦部神經細胞不對稱分裂。根據這些研究,推測人類ASPM蛋白質在細胞週期的過程中,也會參與在中心體組合與紡錘體中心形成的調控路徑上。由本實驗室先前研究,C型肝炎病毒非結構性蛋白質NS5A,透過PKR-p38的訊息傳遞路徑,抑制ASPM蛋白質表現,導致細胞週期G2/M階段延遲。另外,其他研究證實NS5A蛋白質存在下降低CDK1激脢的活性,而CDK1會磷酸化果蠅Asp蛋白質的胺基端,同時此磷酸化可能影響Asp蛋白質之後組織微小管形成星狀體之活性,推測NS5A蛋白質也可能透過影響ASPM蛋白質的磷酸化而負調控其在細胞週期中的功能。
本研究中,以免疫螢光染色法,觀察人類肝癌細胞株 Huh7,發現於有絲分裂的過程中,ASPM蛋白質於中期會位在紡錘體極,後期會位於紡錘體極與中心微小管的負極端,末期則會位於midzone,顯示隨著有絲分裂的進行,ASPM蛋白質都會參與其中,且坐落於紡錘體的各種結構。當NS5A蛋白質存在時,會造成有絲分裂多極性紡錘體極之異常;進一步探討NS5A對於細胞週期影響之可能機制,發現NS5A蛋白質會降低CDK1、cyclinB1及ASPM蛋白質的表現,已知CDK1與cyclinB1會形成複合體啟始有絲分裂,而CDK1同時會磷酸化ASPM的同源蛋白質Asp。針對磷酸化部分,以免疫沉澱實驗,證實NS5A蛋白質會抑制ASPM蛋白質胺基端區域的磷酸化程度,再以phospho-tag SDS-PAGE分析,在G2/M階段其磷酸化程度高於G0/G1階段,而G2/M階段同時也是CDK1激酶活性最高時期;加了CDK1抑制劑或是NS5A蛋白質存在下,兩組ASPM蛋白質胺基端的磷酸化都有下降且pattern相似,說明NS5A蛋白質可能透過負調控CDK1表現而抑制ASPM蛋白質胺基端區域的磷酸化。除了磷酸化修飾,發現大量表現胺基端ASPM蛋白質會使細胞週期於G2/M有延遲現象,同時造成有絲分裂中紡錘體極失去極性、染色體於分裂板異常排列等負面影響,以免疫螢光染色觀察,只具有ASPM蛋白質之胺基端區域同樣會坐落到紡錘體中的各種結構,推測當大量表現胺基端的ASPM蛋白質會佔據內生性ASPM蛋白質位置,使其無法執行功能,造成顯著性負面影響。另一方面,為了解析人類ASPM蛋白質於細胞週期中的功能,使用immortalized primary hepatocytes,模擬正常非癌化之人類肝細胞,發現ASPM蛋白質於細胞週期的G2/M階段表現量最高,並且與具活性CDK1之表現趨勢相同,符合CDK1可能磷酸化ASPM蛋白質之預期,使用shRNA降低Aspm基因與ASPM蛋白質的表現會造成細胞週期G2/M階段延遲,四套體的比例增加,最後導致aneuploidy;大量表現ASPM蛋白質之胺基端區域也會造成染色體不對稱分裂與多極性紡錘體極等異常。四套體的比例增加可能來自細胞質分裂失敗,多極性紡錘體極可能來自interphase時中心體複製有異常,顯示ASPM蛋白質除了於有絲分裂中,影響染色體於分裂板的排列以及細胞質分裂,於interphase可能也會影響中心體的複製。 | zh_TW |
dc.description.abstract | Primary autosomal recessive microcephaly (MCPH) is a genetic disorder. Patients with MCPH show a small cerebral cortex and mental retardation. One of the most common causes of MCPH is mutations in the Aspm gene. Abnormal spindle-like microcephaly associated protein ASPM is conserved among mammals, Drosophila, and nematodes. Besides brain, ASPM is widely expressed in proliferating tissues and upregulated in ovarian and uterine cancers. Human ASPM localizes to the spindle poles during mitosis, similar to its Drosophila homolog abnormal spindle protein (Asp). Asp mutants exhibit a mitotic metaphase checkpoint arrest with abnormal spindle pole organization. In mouse system, knockdown of Aspm causes asymmetric divisions of neuroepithelial cells during brain development. On the basis of these studies, the biochemical functions of human ASPM have been proposed to be involved in regulating the organization of centrosomal processes and mitotic spindle during cell cycle progression. An earlier study from our labortary has demonstrated that hepatitis C virus non-structural 5A protein (NS5A) down-regulated ASPM expression and induced aberrant mitotic cell cycle through PKR-p38 signaling pathway. In addition, NS5A down-regulated the expression of CDK1, which phosphorylated Asp in the N-terminal region. Phosphorylation may affect the activity of Asp in organizing microtubules into asters that will later form the spindle poles.
In this study, ASPM was shown by immunoflorescence staining to be involved in mitosis and associated with spindle structures in Huh7 cells. In addition, overexpression of the NS5A protein resulted in aberrant multi-polar spindle pores. NS5A down-regulated the expression of CDK1, cyclinB1 and ASPM. Immunoprecipitation and phospho-tag SDS-PAGE analysis demonstrated an inhibition of ASPM phosphorylation in the presence of NS5A or CDK1 inhibitor. These results suggest that NS5A possibly inhibited the N-terminal ASPM phosphorylation through down- regulation of CDK1. Furthermore, overexpression of the N-terminal ASPM resulted in G2/M arrest, unfocused spindle pore and abnormal chromosome alignment. These may be due to an inhibition of the functional endogenous ASPM to localize to spindle poles as confirmed by confocal microscopy. On the other hand, to dissect the function of human ASPM in mitosis, the immortalized primary hepatocytes Hus were used to mimic normal human condition. Hus cells had the highest expression level of ASPM at G2/M phase and the same expression profile on CDK1 activation, tally with the prediction of ASPM phosphorylation by CDK1. shRNA to Aspm knocked down Aspm expression in human primary hepatocytes, blocked cell cycle at the G2/M and increased the tetraploid cells that transited to aneuploidy in the end. In addition, overexpression of the N-terminal ASPM resulted in the multi-polar spindle assembly and chromosome mis-segregation. The increase of tetraploidy may be due to cytokinesis failure and the formation of multi-polar spindle pores may be a result of aberrant centrosome duplication in interphase. All of these suggest functions of ASPM in chromosome alignment and cytokinesis during mitosis and in centrosome replication during interphase. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T02:16:27Z (GMT). No. of bitstreams: 1 ntu-100-R98442006-1.pdf: 2485570 bytes, checksum: e1e2d787c17b0372e3e4487ec826f462 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | 中文摘要………………………………………………I
英文摘要………………………………………………III 縮寫表…………………………………………………V 緒論……………………………………………………1 本論文研究方向………………………………………14 材料來源………………………………………………15 實驗方法………………………………………………21 結果……………………………………………………39 討論……………………………………………………47 圖表……………………………………………………53 參考文獻………………………………………………77 | |
dc.language.iso | zh-TW | |
dc.title | C型肝炎病毒非結構性蛋白質NS5A影響ASPM磷酸化及有絲分裂之進行 | zh_TW |
dc.title | The effects of hepatitis C virus NS5A protein on ASPM phosphorylation and mitotic progression | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 張智芬(Zee-Fen Chang),張富雄(Fu-Hsiung Chang),李明學(Ming-Shyue Lee) | |
dc.subject.keyword | C型肝炎病毒,有絲分裂, | zh_TW |
dc.subject.keyword | NS5A,ASPM, | en |
dc.relation.page | 87 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-08-01 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
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