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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 胡忠怡 | |
dc.contributor.author | Mao-Hua Wang | en |
dc.contributor.author | 王茂華 | zh_TW |
dc.date.accessioned | 2021-06-08T06:20:31Z | - |
dc.date.copyright | 2006-09-18 | |
dc.date.issued | 2006 | |
dc.date.submitted | 2006-08-28 | |
dc.identifier.citation | 1. Ware, C. F. 2003. The TNF superfamily. Cytokine Growth Factor Rev 14:181-184.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/25598 | - |
dc.description.abstract | Tumor necrosis factor (TNF) -related apoptosis-inducing ligand (TRAIL) 是新近被發現的腫瘤壞死因子家族的成員,與Fas ligand具有很高的相似度。因為TRAIL可以殺死許多種類的腫瘤細胞,但在細胞培養和實驗動物中不會傷害正常細胞,現在被認為有希望將TRAIL發展成為強有力的癌症治療藥物。在許多正常的組織中TRAIL和TRAIL receptors廣泛的表現,可以推測TRAIL在生理中扮演的角色較引起癌症細胞進行細胞凋亡更加複雜。關於這方面,其他的研究顯示TRAIL參與在血液生成作用中,在正常和疾病引起的情況下TRAIL減少紅血球生成,並在HL60細胞株與正常CD34衍生骨髓性白血球細胞中促進單核球分化成熟。某些研究表示受到維他命D3或phorbol esters刺激的白血病細胞株與正常單核球前驅細胞,在單核球分化時會增強mitogen-activated protein (MAP) kinase活化。並且受MAP kinase調控的轉錄因子像是 CCAAT enhancer binding proteins β (C/EBP β) and activating protein-1 (AP-1) 皆參與在單核球分化中。在本篇論文中,我們利用TRAIL處理HL60人類白血病細胞株來調查發生單核球分化中相關的訊息傳遞路徑。
TRAIL處理HL60細胞後會造成迅速的細胞毒性伴隨著存活細胞朝向單核球系成熟。在TRAIL處理的細胞藉由細胞表面CD14表現顯著的增加,並獲得與典型的成熟單核球細胞形態特徵,證實朝向單核球系分化。在細胞內訊息路徑的調查中,TRAIL明顯的刺激 extracellular signal-regulated kinase 1/2 (ERK1/2)及p38磷酸化增加,但對 c-Jun N-terminal kinase (JNK) 路徑沒有影響。利用ERK路徑的藥物抑制劑U0126使得TRAIL在HL60細胞表面引起的CD14表現量降低,一致的證實ERK1/2在調控TRAIL誘發的單核球分化扮演關鍵的角色。此外,在TRAIL處理後p90Rsk的活化增加,在抑制劑U0126作用下TRAIL引起分化的能力被抑制,ERK1/2與p90Rsk的磷酸化也明顯減少。根據結果顯示ERK1/2-p90Rsk路徑在TRAIL誘發的單核球分化中扮演相當重要的角色。未來TRAIL將有機會應用在白血病的引導治療 (induction therapy) 上。 | zh_TW |
dc.description.abstract | Tumor necrosis factor (TNF) -related apoptosis-inducing ligand (TRAIL), a recently disclosed TNF family member, shares high digree of similarity with Fas ligand. Currently, TRAIL is under development as a potential cancer therapeutic agent because it kills many types of tumor cells but spares normal cells in cell culture and experiment animals. The wide expression of TRAIL and TRAIL receptors in many normal tissus suggests that physiologic role of TRAIL is more complex than induction of apoptosis in cancer cells. In this respect, other studies shown that TRAIL involves in modulation of hematopoiesis. TRAIL was reported to impair erythropoiesis in normal and pathological conditions, and to promote monocytic maturation in the HL60 leukemic cell line as well as primary CD34-derived myeloid cells. Some studies have described increased mitogen-activated protein (MAP) kinase activity during monocytic differentiation of leukemic cell lines and normal monocytic precursors in response to vitamin D3 or phorbol esters. Moreover, the transcription factors modulated by MAP kinase, such as CCAAT enhancer binding proteins β (C/EBP β) and activating protein-1 (AP-1) complex, involves in monocytic differentiation. In this study, the signaling pathway involved in TRAIL-induced monocytic differentiation in HL60 leukimic cell line was investigated.
Treatment of the HL60 cells with TRAIL resulted in rapid cytotoxicity and accompanied with progressive maturation of the surviving cells along the monocytic lineage. The occurrence of monocytic differentiation was demonstrated by a significant increase of CD14 surface expression, and the acquisition of typically morphologic features of mature monocytes in TRAIL-treated culture. Among the intracellular pathways investigated, TRAIL significantly stimulated the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 but not the c-Jun N-terminal kinase (JNK) pathway. Consistently with a key role of ERK1/2 in mediating the positive effect of TRAIL-induced monocytic differentiation, U0126, a pharmacologic inhibitor of the ERK pathway, decreased the surface expression of CD14 of TRAIL on HL60 cells. Furthermore, activation of p90Rsk was increased by treatment of TRAIL. The potentiation of differentiation by TRAIL was inhibited by inhibitor U0126, and ERK1/2 and p90Rsk phosphorylation was significantly decreased. The results indicate that ERK1/2-p90Rsk pathway has an important role in TRAIL-induced monocytic differentiation. TRAIL should be further evaluated for use in induction therapy of acute myeloid leukimia. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T06:20:31Z (GMT). No. of bitstreams: 1 ntu-95-R93424017-1.pdf: 1064666 bytes, checksum: 92f48994b3cb54a5a847d9c2e6cb5c7d (MD5) Previous issue date: 2006 | en |
dc.description.tableofcontents | 目錄 I
中文摘要 IV 英文摘要 VI 縮寫對照表(依字母排列) VIII 第一章 緒論 1 壹、腫瘤壞死因子與其受體超級家族 (TNF and TNFR superfamilies) 1 貳、腫瘤壞死因子與其受體結構 (The structure of TNF/TNFR) 1 參、TRAIL與TRAIL受體 (TRAIL and TRAIL receptors) 2 肆、TRAIL的訊息傳遞路徑 (The signaling pathway of TRAIL) 3 伍、 TRAIL在生理中的角色 (physiological roles) 與其生物效應 (biological effects) 5 陸、TRAIL在血液生成作用扮演的角色 6 柒、造血 (hematopoiesis) 與造血細胞的轉分化 (transdifferentiation) 現象 7 捌、研究目的 8 第二章 材料與方法 9 第一節、材料 9 一、藥品與試劑 9 二、溶液 11 三、重要儀器與分析軟體 15 第二節、實驗方法 15 一、細胞株與細胞培養 15 二、細胞凋亡 (apoptosis) 與細胞分化 (differentiation) 分析 16 三、訊息傳遞路徑分析 18 第三章 實驗結果 23 第一節、TRAIL可快速引發部份HL60細胞進行細胞凋亡 23 第二節、TRAIL誘使HL60細胞進行單核細胞分化 23 一、以TRAIL處理HL60細胞誘使其細胞表面表現單核球特有表面抗原 23 二、TRAIL促使HL60細胞形態改變與胞內表現非特異性酯酶 24 第三節、TRAIL經由調控ERK1/2的活化誘使HL60細胞朝單核球分化 25 一、以TRAIL刺激HL60細胞促使ERK1/2與p38活化 25 二、抑制ERK1/2造成TRAIL無法誘使HL60細胞朝單核球系分化 26 第四節、TRAIL刺激HL60細胞會經由ERK1/2活化下游p90Rsk 27 一、TRAIL刺激HL60促使p90Rsk活化 27 二、抑制ERK1/2使TRAIL引起的p90Rsk磷酸化減弱 28 第四章、討論 29 參考文獻 34 圖表 43 圖一A、 TRAIL可引發HL60白血病細胞株部份細胞凋亡 44 圖一B、 TRAIL可引發HL60白血病細胞株部份細胞凋亡 45 圖二A、TRAIL誘發HL60白血病細胞進行單核細胞分化 46 圖二B、TRAIL誘發HL60白血病細胞進行單核細胞分化 47 圖三、經TRAIL處理後HL60的細胞形態變化與細胞內NSE的表現 48 圖四、 以TRAIL刺激HL60細胞促使ERK1/2與p38活化 49 圖五A、加入MEK1/2抑制劑U0126使TRAIL誘發的單核球分化減少 50 圖五B、加入MEK1/2抑制劑U0126使TRAIL誘發的單核球分化減少 51 圖六、MEK1/2抑制劑U0126抑制ERK1/2的磷酸化 52 圖七、TRAIL刺激HL60細胞會使得p90Rsk磷酸化增加 53 圖八、MEK1/2抑制劑U0126造成p90Rsk的磷酸化減弱 54 圖九、TRAIL誘發單核球分化的訊息傳遞路徑 55 表一、HL60細胞經TRAIL處理後細胞死亡與CD14表現 56 表二、MEK1/2抑制劑U0126抑制TRAIL在HL60細胞表面引發的CD14表現 57 附錄 58 附錄一 59 | |
dc.language.iso | zh-TW | |
dc.title | TRAIL誘發HL60白血病細胞株分化為單核球之訊息傳遞路徑研究 | zh_TW |
dc.title | Investigating signaling pathway of TRAIL induced-monocytic differentiation in HL60 leukemic cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 94-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林亮音,林東燦,楊雅倩,呂健惠 | |
dc.subject.keyword | 白血病,單核球分化, | zh_TW |
dc.subject.keyword | TRAIL,acute myeloid leukemia (AML),mitogen-activated protein (MAP) kinase,monocytic differentiation, | en |
dc.relation.page | 59 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2006-08-29 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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ntu-95-1.pdf 目前未授權公開取用 | 1.04 MB | Adobe PDF |
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