臺灣博碩士論文加值系統

血球細胞形成之過程是非常複雜, 由一小群幹細胞製造成較大群的成熟細胞, 這些成熟細胞主要分為八個系譜o 幹細胞於培養基中需要多種細胞激素才能生長, 但是由幹細胞分化成的系譜委任母細胞其生長僅需要單一細胞激素o 幹細胞的生長對於細胞激素需要的不同與細胞激素受體表現量有關, 然而細胞激素調控這些細胞分化與生長的機制並不是很清楚o 在這個實驗, 我們發現顆粒性白血球及巨噬細胞聚落叢集刺激素 (granulocyte-macrophage colony stimulating factor, GM-CSF) 不論有無幹細胞因子 (stem cell factor, SCF) 存在皆可以適當的活化血癌細胞TF-1的生長, 然而IL-5需要和SCF一同刺激才可以使細胞生長良好o 如此的協助作用效果部分是因為SCF的抗細胞凋亡之活性o 於細胞大量表現IL-5受體a次單位也可以使抗細胞凋亡活性增強而使細胞生長良好o 表現外來的抗細胞凋亡蛋白, Bcl-2, 也可使細胞成為依賴IL-5生長的現象o 這些結果建議只有當細胞的IL-5受體表現量低, 而IL-5訊息傳遞缺乏抗細胞凋亡時才需要SCF的協助作用o 為了了解IL-5和SCF的抗細胞凋亡傳遞因子, 首先我們分析Bcl-2家族成員包括Bcl-2, Mcl-1和Bax的表達與TF-1和JYTF-1細胞是否凋亡的關係o SCF對於這兩種細胞可以有效誘導Mcl-1的表現, 然而IL-5對Mcl-1在這兩種細胞中有不同的誘導表現量, 且與其抗細胞凋亡之活性有所關聯o IL-5對於TF-1細胞的抗細胞凋亡的缺陷與JAK1缺乏酪氨酸的磷酸化及顯著降低JAK2, STAT5, MAPK和PKB/Akt的磷酸化有關, 但是SCF的協助作用可以活化MAPK和PKB/Akt的磷酸化, 而卻不會活化STAT5的磷酸化o 將JYTF-1細胞處理MEK抑制劑和PI-3K抑制劑, 即可分別去除MAPK和PKB/Akt的活性, 並且降低Mcl-1的表現和細胞生長的活性o 因此這些結果建議Mcl-1是SCF與IL-5抗細胞凋亡活性的共同標的, 並且皆經由MAPK和PKB/Akt的傳遞途徑調控Mcl-1表現和預防細胞凋亡o 前面實驗建議, JAK1和JAK2於細胞激素之訊息傳遞扮演一個重要的角色, 且對於GM-CSF/IL-3/IL-5所依賴的存活效果, JAK1和JAK2同時活化可能是必需的o 為了了解JAK1和JAK2調控特定訊息傳遞途徑扮演的角色, 我們建立一個有條件的JAK活化系統o 我們構築可以製造結合體的質體, 此結合體含有CD16膜外範圍, CD7膜間區域和JAK做為質內範圍o 這些質體被送入Ba/F3細胞株並且分離出已穩定表現結合體蛋白之細胞株o 這些細胞株包含表現JAK1 (CDJAK1)或JAK2 (CDJAK2) 以及同時表現JAK1和JAK2 (CDJAK1+2)o 我們成功地利用抗CD16抗體做抗體交叉聯集, 可以使結合體蛋白聚集並誘導此蛋白自動磷酸化和STAT5酪氨酸磷酸化o 我們將繼續分析這些受活化的結合體蛋白對生命性質特別是對於依賴細胞激素之細胞的生存活性的影響o

Hematopoiesis is a complex process in which a small population of stem cells is needed to generate continuously large populations of mature cells in eight major lineages. In vitro proliferation of hematopoietic stem cells requires costimulation by multiple cytokines whereas expansion of lineage-committed progenitor cells generated by stem cells usually requires only a single factor. The distinct requirement of factors for proliferation coincides with the differential temporal expression of the subunits of cytokine receptors during early stem cell differentiation. However, the underlying molecular mechanism of the hierarchical response of the cells to cytokine during the differentiation and prliferation program is not yet clear. In this study, we found that GM-CSF optimally activated proliferation of TF-1 cells regardless of the presence or absence of SCF. However, IL-5 alone sustained survival of TF-1 cells and required costimulation of SCF for optimal proliferation. The synergistic effect of SCF was partly due to its anti-apoptosis activity. Over-expression of the IL5Ra in TF-1 cells also resumed optimal proliferation due to correction of the defect in apoptosis suppression. Exogenous expression of an oncogenic anti-apoptosis protein, Bcl-2, conferred on TF-1 cells an IL-5-dependent phenotype. These data suggest SCF costimulation is only necessary when the expression level of IL5Ra is low and apoptosis suppression is defective in the signal transduction of IL-5. To understand the signaling components of IL-5 and SCF involved in anti-apoptosis, we first detected some Bcl-2 family members, including Bcl-2, Mcl-1 and Bax, in response to cytokine stimulation in TF-1 and JYTF-1 cells whose optimal growth requires or does not require SCF costimulation, respectively. The Mcl-1 was highly inducible by SCF in both cell lines, however was differentially induced by IL-5 and closely correlated with the ability of IL-5 to suppress apoptosis. The defect of IL-5 in apoptosis suppression was also associated with lack of induction of tyrosine phosphorylation of JAK1 and markedly reduction of phosphorylation of JAK2, STAT5, MAPK and PKB/Akt, while SCF costimulation activated the phosphorylation of MAPK and PKB/Akt, but not STAT5 in TF-1 cells. Treatment of JYTF-1 cells with the MEK inhibitor and the PI-3K inhibitor rendered a loss of the downstream MAPK and PKB/Akt activities, respectively, and resulted in the reduction of Mcl-1 expression and loss of cell viability. Therefore, our data suggested that Mcl-1 is a common target of both IL-5 and SCF for their apoptosis prevention activity and that both MAPK and PKB/Akt signaling pathways are crucial in regulation of Mcl-1 expression and apoptosis prevention. In our study, JAK1 and JAK2 was suggested to play a central role in transducing signals of cytokines and the simultaneous activation of both JAK1 and JAK2 may be essential for optimizing the GM-CSF/IL-3/IL-5-dependent survival effect. To explore the role of JAK1 and JAK2 in the regulation of specific signal transduction pathways, we established a conditional activation system for JAK activation. We constructed plasmids encoding fusion proteins with a CD16 external domain, a CD7 transmembrane region, and JAK1 (CD16/7/JAK1) or JAK2 (CD16/7/JAK2) as a cytoplasmic domain. These plasmids were transfected into Ba/F3 cell line and then stable expressing subclones were isolated. We established cell lines not only expressing JAK1 (CDJAK1) or JAK2 (CDJAK2) alone, but also expressing JAK1 and JAK2 together (CDJAK1+2). Clustering of these chimeric proteins by antibody cross-linking with anti-CD16 antibody induced autophosphorylation of the chimeric kinase proteins and tyrosine phosphorylation of STAT5. We will continue to analyze the biological outcomes resulting from activating these chimeric kinase proteins, especially on the survival effect in cytokine-dependent cells.

COVER
Contents
Figure
Appendix
Summary
中文摘要
Chapter I:General introduction
References
Chapter II:Optimal proliferation of a hematopoietic progenitor cell line requires either costimulation with stem cell factor or increase of receptor expression that can be replaced by overexpression of Bcl-2
Abstract
Introduction
Materials and Mehtod
Results
Discrssion
Figrue Legends
References
Chapter III:mcl-1 is a common target of intrleukin 5 and stem cell factor for the apoptosis prevention in hematopoietic progenitor cells
Abstract
Introduction
Materials and Mehtod
Results
Discrssion
Figrue Legends
References
Chapter IV:Conditional Activation of Janus Kinase (JAK) and Functional Characterization in Interleukin-3-Dependent Cells
Abstract
Introduction
Materials and Mehtod
Results
Discrssion
Figrue Legends
References

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91. Kitamura, T., Tange, T., Terasawa, T., Chiba, S., Kuwaki, T., Miyagawa, K., Piao, Y.F., Miyazono, K., Urabe, A., Takaku, F. Establishment and characterization of a unique human cell line that proliferates dependently on GM-CSF, IL-3, or erythropoietin. J. Cell Physiol. 140:323-334, 1989.
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17. Duronio, V., Welham, M.J., Abraham, S., Dryden, P., Schrader, J.W. p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein. Proc. Natl. Acad. Sci. U. S. A. 889:1587-1591, 1992.
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