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系統識別號 U0026-0812200913445288
論文名稱(中文) 前列腺環素致效劑抑制PMA誘導HEL細胞分化為巨核細胞之研究
論文名稱(英文) Prostacyclin Receptor (IP) Agonists Inhibit PMA Induced Megakaryocytopoiesis in Human Erythroleukemia Cells
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 95
學期 2
出版年 96
研究生(中文) 林慧君
研究生(英文) Hui-chun Lin
電子信箱 protein1115@yahoo.com.tw
學號 S2694412
學位類別 碩士
語文別 英文
論文頁數 61頁
口試委員 指導教授-簡偉明
口試委員-簡伯武
口試委員-呂增宏
中文關鍵字 巨核細胞  分化  前列腺環素 
英文關鍵字 prostacyclin  Megakaryocyte  differentiation 
學科別分類
中文摘要 人體內的血小板(platelets)為凝血過程中的主要角色,並且也參與調節血液系統的平衡,它在體內的生成是由骨髓中成熟的巨核細胞(megakaryocytes; MKs)所裂解(fragmentation)釋放出來的。巨核細胞在分化過程中會進入一核內分裂的過程稱為”endomitosis”,不同於一般細胞所進行的cell cycle,它會略過anaphase B及cytokinesis,使得染色體套數不斷增加(ployploidization)但細胞卻不分裂,造成細胞體積明顯增加。過去研究巨核細胞的分化過程(megakaryocytopoiesis)多利用老鼠骨髓幹細胞、臍帶血細胞或具有分化能力的megakaryocytic cell lines例如HEL、K562及MEG-01等,以megakaryocytes所必須的cytokine—TPO或者phorbol diester (PMA)來誘導其分化;並且已知在PMA的處理下可誘導HEL cells產生megakaryocytic features如細胞體積變大、染色體套數多倍化及特定表面抗原CD41/61的表現的增加。據文獻指出,在immature megakaryocytes或megakaryocytic cell lines都被發現有prostacyclin receptor的表現;由於prostacyclin在體內主要是由內皮細胞分泌,藉由抑制血小板凝集及放鬆心血管平滑肌細胞來微幅調控血液平衡狀態,因此我們便有興趣探討,prostacyclin對於血小板的前驅細胞—megakaryocytes扮演了什麼角色? 我們利用PMA誘導HEL cells分化的模式,在處理prostacyclin receptor (IP)agonists後,從我們的實驗結果發現,在IP agonists作用下,可抑制細胞體積變大、抑制染色體套數多倍化及明顯減少特定表面抗原CD41/61的表現;另外我們利用cAMP analogue及adenylyl cyclase activator來mimic prostacyclin receptor活化後造成增加的cAMP,結果也發現同樣的抑制現象。最後利用Western blot也發現,IP agonists及cAMP elevating agents所抑制的megakaryocytes differentiation,的確減少了megakaryocytopoiesis中所必須的G1/S progression protein—cyclin D3的表現。而在PKA抑制劑、PI3K抑制劑、Raf抑制劑以及MEK抑制劑的作用下,均無法阻擋IP agonist的抑制作用;因此由以上實驗結果我們推測,prostacyclin可經由活化prostacyclin receptor增加細胞內cAMP,但不透過活化PKA、PI3K及Raf/ MEK/ ERK而達到抑制megakaryocytes differentiation的作用。
英文摘要 Prostacyclin is an important mediator in the regulation of the homeostasis of vascular system via the relaxation of vascular smooth cells and inhibition of platelets aggregation. It is reported that prostacyclin receptors appear in megakaryocytes (MKs), the precursor cells of platelets. But the functional role of prostacyclin in megakaryocytes remains unknown. The erythroleukemia cell line (HEL) differentiates into megakaryocytes when treated with Phorbol diester (PMA). PMA induced megakaryocyte is characterized by the enlargement in cell size, nuclear polyploidization and expression of specific specific cell surface marker, CD41/61. Here we reported that the differentiation was inhibited in the presence of prostacyclin receptor (IP) agonist, BMY45778. We found adenylyl cyclase activator forskolin attenuated PMA-induced megakaryocytic differentiation in HEL cells. Moreover, through prostacyclin receptor, IP agonists and adenylyl cyclase activator attenuated the expression of G1/S progression regulatory, protein cyclin D3 that is a key regulator for megakaryocytic endomitosis. The inhibitory effect could not be reversed by PKA, PI3K, Raf-1 and MEK/ERK inhibitors. These findings indicated that IP agonists have a negative regulatory effect dependent of cAMP but not PKA, PI3K and Raf/ MEK/ ERK pathways on megakaryocytic differentiation through the activation of prostacyclin receptor in HEL cells.
論文目次 考試合格證明 -----------------II
Abstract -------------------------III
Abstract in Chinese ------------IV
Index-----------------------------VIII
Abbreviation --------------------X
Introduction
I.Megakaryocyte development from HSC -------------1
II.Aspects of megakaryocyte differentiation and maturation ---------------------------------------------------------------3
III.Signal transduction involved in megarkaryocytopoiesis ---------------------------------------------------------------5
IV.Prostacyclin (PGI2) -----------------------------------7
V.Prostacyclin receptor (IP) and its signaling ---------8
VI.The effect of IP agonist on PMA-stimulated megakaryocytopoiesis in HEL cells ---------------------------------------------------------------10
Materials and Methods
I.Materials -------------------------------------------------12
II.Methods
1.Cell culture ----------------------------------------------15
2.Immunolabeling for flow cytometry ----------------15
3.Enumeration of cells ----------------------------------16
4.Western blotting analysis -----------------------------17
Results
1.Prostacyclin receptor agonist inhibits megakaryocytic differentiation upon PMA stimulation in HEL cells---------------------------------20
2.IP agonist induced inhibition of megakaryocytopoiesis is via cAMP dependent mechanism ------------------------------------------------22
3.IP agonist blocks MKs endomitosis and is associated with cyclin D3 decrease --------------------------------------------------------------23
4.The effects of pharmacologic inhibitors on IP agonist down-regulation of cyclin D3 expression-------------------------------------------------24
Discussion ------------------------------------------------26
References -----------------------------------------------32
Curriculum vitae --------------------------------------------------------------61
Table 1 Surface Antigen phenotype in HEL cells------41
Fig. 1 The megakaryocytic developmental pathway ----- 42
Fig. 2 Overview of megakaryocyte production of platelets --- 43
Fig. 3 The endomitotic cell cycle in megakaryocytes ---------- 44
Fig. 4 Pathway of prostaglandin production --------------------- 45
Fig. 5 Secondary structure of human prostacyclin receptor ---- 46
Fig. 6 Non-prostanoid prostacyclin mimetic ---------------------- 47
Fig. 7 Effect of IP agonist on the morphology of HEL cells differentiation
induced by PMA --------------------------------------------------------48
Fig. 8 Inhibition of the cell size enlargement ---------------------- 49
Fig. 9 Flow cytometry analysis on the DNA content of megakaryocytes -------- 50
Fig. 10 Flow cytometric analysis of megakaryocytic marker, CD41/61 ----------- 51
Fig. 11 The inhibition induced by IP agonist involved in blocking endomitosis
of megakaryocytes -------------------------------------------------------52
Fig. 12 The inhibition of megakaryocytic differentiation induced by IP agonist
was involved in blocking endomitosis and associated with cyclin D3 decrease -------------------------------------------------------------------------------53
Fig. 13 The decrease of cyclin D3 mediated by BMY45778 and Forskolin ------ 54
Fig. 14 The inhibition of cyclin D3 expression induced by IP agonis was
independent of protein kinase A (PKA) on PMA-pretreated HEL cells ------------55
Fig. 15 The inhibition of cyclin D3 expression induced by IP agonist was
independent of PI3 kinase on PMA-pretreated HEL cells ----------------------------56
Fig. 16 The inhibition of cyclin D3 expression induced by IP agonist was
independent of c-raf kinase on PMA-pretreated HEL cells ---------------------------57
Fig. 17 The inhibition of cyclin D3 expression induced by IP agonist was
independent of MEK kinase on PMA-pretreated HEL cells -------------------------58
Fig. 18 The expression of cyclin D3 was inhibited by δPKC-inhibitor on
PMA-pretreated HEL cells ----------------------------------------------------------------59
Fig. 19 The proposed mechanism of inhibitory effect by prostacyclin on
megakaryocyte differentiation ------------------------------------------------------------60
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