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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 李心予(Hsinyu Lee) | |
| dc.contributor.author | Ya-Hsuan Ho | en |
| dc.contributor.author | 何亞軒 | zh_TW |
| dc.date.accessioned | 2021-06-08T01:25:27Z | - |
| dc.date.available | 2030-01-01 | - |
| dc.date.copyright | 2014-08-14 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-01 | |
| dc.identifier.citation | Abu-Remaileh, M., Gerson, A., Farago, M., Nathan, G., Alkalay, I., Zins Rousso, S., Gur, M., Fainsod, A., and Bergman, Y. (2010). Oct-3/4 regulates stem cell identity and cell fate decisions by modulating Wnt/beta-catenin signalling. The EMBO journal 29, 3236-3248.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18779 | - |
| dc.description.abstract | 紅血球與巨核細胞源自於相同的血球前驅細胞特化而成。在我們過去的研究中發現，水解磷酸脂 (Lysophosphatidic acid, LPA) 經由活化特定的水解磷酸脂受器，參與了紅血球生成的調控。因此，本篇研究進一步利用K562人類血癌細胞株來探討LPA於巨核細胞分化所扮演之角色。實驗結果顯示，在TPA (12-O-Tetradecanoylphorbol-13-acetate) 誘導K562細胞往巨核細胞分化的過程中，水解磷酸脂受器2 (LPA2) 和3 (LPA3) 的表現量會受到調控。我們進一步分析巨核細胞特定表現的膜蛋白CD61，以及核內有絲分裂 (endomitosis) 現象，發現藥劑活化LPA2會抑制TPA誘導之巨核細胞分化。反之，利用基因knockdown的方式降低LPA2的表現可以促進巨核細胞的分化。利用免疫染色，我們進一步發現β-catenin是LPA2下游的調控分子，透過進入細胞核內活化GATA-1以及FLI-1轉錄因子，負向調控巨核細胞之分化。另一方面，我們將細胞以LPA1/3的拮抗劑處理抑制了巨核細胞分化，而藥劑活化LPA3則促進巨核細胞分化。利用基因knockdown方式降低LPA3的表現也使巨核細胞之分化受到抑制。我們更證明LPA3是透過產生reactive oxygen species (ROS)，影響FLI-1轉錄因子的表現，因而正向調控巨核細胞分化。這些結果顯示，LPA2 與LPA3在K562的系統內，可能存在彼此拮抗的關係，並扮演著分子開關的角色反向調控巨核細胞之分化。 | zh_TW |
| dc.description.abstract | Erythrocytes and megakaryocytes (MK) are derived from a common progenitor that undergoes lineage specification. Lysophosphatidic acid (LPA), a lipid growth factor abundant in serum, was shown to be a regulator for erythropoietic process through activating LPA receptor 3 (LPA3). However, whether LPA affects megakaryopoiesis remains unclear. In this study, we used K562 leukemia cell line as a model to investigate the roles of LPA in MK differentiation. We demonstrated that K562 cells express both LPA receptor 2 (LPA2) and LPA3, and the expression levels of LPA2 are higher than LPA3. Treatment with phorbol 12-myristate 13-acetate (TPA), a commonly used megakaryopoiesis inducer, reversely regulates the expressions of LPA2 and LPA3. By pharmacological blockers and knockdown experiments, we revealed that LPA2 suppressed while LPA3 promotes MK differentiation in K562. The LPA2-mediated inhibition is dependent on β-catenin translocation, whereas reactive oxygen species (ROS) generation is a downstream signal for activation of LPA3. Furthermore, hematopoietic transcriptional factors (TFs), including GATA-1 and FLI-1, may involve in these regulatory mechanisms. Taken together, our results suggested that LPA2 and LPA3 may function as a molecular switch and play antagonistic roles during megakaryopoiesis of K562 cells. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T01:25:27Z (GMT). No. of bitstreams: 1 ntu-103-R01b41006-1.pdf: 2633267 bytes, checksum: e2fe2d0d46ad9dba0f8b99a559b2941f (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | Contents
論文口試委員審定書 i 致謝 ii 中文摘要 iii Abstract iv Introduction 1 Megakaryopoiesis and erythropoiesis 1 Transcription factors (TF) and MEP lineage commitment 2 K562 myeloid leukemia cell line 3 Lysophosphatidic acid (LPA) 3 Wnt/β-catenin pathway 4 Reactive oxygen species (ROS) 5 Rationale 7 Materials and methods 7 Cell culture and pharmacological treatment 8 LPA3 siRNA transfection 9 Lentivirus packaging and LPA2 shRNA transfection 9 RNA extraction and quantitative real-time PCR reaction 10 Flow cytometry 10 Immunofluorescence staining 11 Statistical analysis 11 Results 13 Induction of MK surface marker CD61 and endomitosis of K562 cells by TPA 13 Expression patterns of LPA receptors during TPA-induced megakaryopoiesis 13 Activation of LPA2 suppresses megakaryopoiesis 14 LPA3 signaling enhances megakaryopoiesis 16 Knockdown of LPA2 and LPA3 inversely regulate MK differentiation 17 Exogenous LPA does not affect MK differentiation 18 β-catenin translocation is involved in LPA2-mediated MK differentiation 19 ROS generation is involved in LPA3-mediated MK differentiation 20 Discussion 23 Reference 27 Tables & Figures 46 Table 1 Chemicals 46 Table 2 Real-time PCR primers (human) 47 Fig. 1 Induction of megakaryopoiesis by TPA 48 Fig. 2 mRNA expression of LPA receptors 49 Fig. 3 Pharmacological activation of LPA2 suppresses megakaryopoiesis 52 Fig. 4 Pharmacological blockade of LPA1/3 inhibits MK differentiation 54 Fig. 5 Pharmacological activation of LPA3 enhances megakaryopoiesis 56 Fig. 6 Knockdown of LPA2 and LPA3 have opposite effects on MK differentiation 59 Fig. 7 Exogenous LPA has no effect on MK differentiation 61 Fig. 8 The involvement of β-catenin in LPA2-mediated MK differentiation 65 Fig. 9 The involvement of ROS in LPA3-mediated MK differentiation 67 Fig. 10 Working model 68 | |
| dc.language.iso | zh-TW | |
| dc.title | 水解磷酸脂受器於K562血癌細胞株調控巨核細胞分化之研究 | zh_TW |
| dc.title | LPA receptor 2 and 3 reversely regulate megakaryopoiesis of K562 human erythroleukemia cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陸振翮(Jenher Lu),陳俊宏(Jiun-Hong Chen),姚少凌(Chao-Ling Yao) | |
| dc.subject.keyword | K562血癌細胞株,巨核細胞,水解磷酸脂,水解磷酸脂受器,核內有絲分裂, | zh_TW |
| dc.subject.keyword | K562,megakaryocyte (MK),megakaryopoiesis,CD61,lysophosphatidic acid (LPA),LPA receptor, | en |
| dc.relation.page | 68 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2014-08-01 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生命科學系 | zh_TW |
| dc.date.embargo-terms | 2030-01-01 | |
| Appears in Collections: | 生命科學系 | |
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| ntu-103-1.pdf Restricted Access | 2.57 MB | Adobe PDF |
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