Please use this identifier to cite or link to this item:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95726
Title: | 探討哺乳動物肌苷酸脫氫酶細胞蛇於細胞代謝之角色 Investigating Roles of IMPDH Cytoophidium in Mammalian Cell Metabolism |
Authors: | 彭敏 Min Peng |
Advisor: | 宋麗英 Li-Ying Sung |
Keyword: | 細胞蛇,肌苷酸脫氫酶,胚胎幹細胞,癌細胞,糖解作用,核苷酸生合成,細胞代謝, Cytoophidium,IMPDH,Embryonic stem cells,Cancer cells,Glycolysis,Nucleotide biosynthesis, |
Publication Year : | 2024 |
Degree: | 博士 |
Abstract: | 細胞蛇 (cytoophidium) 為細胞中由代謝酶多聚體聚合形成之新型無膜細胞器,可能調控組成代謝酶之活性、穩定度等特性。肌苷酸脫氫酶 (inosine monophosphate dehydrogenase, IMPDH) 負責催化細胞鳥苷三磷酸 (guanosine triphosphate, GTP) 生合成的速率限制步驟,為調節細胞內 GTP 濃度的關鍵蛋白。哺乳動物細胞內 IMPDH 已被證實可於體內、外環境形成細胞蛇,其細胞蛇之可能功能為促進 GTP 合成,進而平衡細胞在不同生理狀態下對 GTP 的需求與生產。IMPDH 細胞蛇已被證實與免疫細胞、癌細胞及多能性幹細胞 (pluripotent stem cell) 的快速增殖特性有關。這些細胞對於糖解作用 (glycolysis) 的共同偏好,意味著細胞蛇與增殖細胞內之代謝狀態具有相關性。然而,過去礙於缺乏適當之細胞及動物模型,無法對 IMPDH 細胞蛇的功能及重要性提出直接證據。因此,本研究旨在透過點突變抑制 IMPDH 聚合化,調查細胞蛇參與於哺乳動物細胞代謝之調控。在小鼠胚胎發育過程以及多能性幹細胞中,IMPDH 細胞蛇的形成與細胞代謝之活化呈正相關。利用 IMPDH2 點突變建立無法形成細胞蛇之胚胎幹細胞 (embryonic stem cell) 模型,發現細胞蛇在維持糖解作用所衍生之核苷酸 (nucleotide) 生合成當中具有極其重要的作用。此外,在多種人類癌細胞組織切片中可觀察到 IMPDH 細胞蛇的表現,特別是與子宮頸癌 (cervical cancer) 的發生具有顯著相關性。透過建立無法形成細胞蛇之 IMPDH2 點突變癌細胞株,證明細胞蛇對於子宮頸癌細胞以及子宮內膜癌 (endometrial cancer) 細胞內糖解作用以及核苷酸生合成的維持至關重要。綜上所述,此研究揭示細胞蛇於快速生長且依賴糖解作用的細胞代謝當中扮演著調節角色。有鑒於 IMPDH 對免疫及腫瘤代謝的重要臨床價值,本研究結果可為 IMPDH 相關之臨床應用提供重要資訊。 The cytoophidium is an evolutionarily conserved subcellular structure formed by metabolic enzymes. In mammals, inosine monophosphate dehydrogenase (IMPDH), which catalyzes the rate-limiting step in guanosine triphosphate (GTP) biosynthesis, is one of the well-studied cytoophidium-forming enzymes. Forming cytoophidium prevents feedback inhibition of IMPDH, facilitating nucleotide production in hyperproliferating cells such as developing thymocytes, pluripotent stem cells, and cancer cells. The shared preference for glycolysis among these cells implies a link between the cytoophidium and the metabolic status of proliferating cells. However, direct evidence for the physiological significance of IMPDH cytoophidium has been lacking due to the lack of appropriate models in the past. Therefore, this study aims to investigate how cytoophidium is involved in the coordination of mammalian cell metabolism by hindering IMPDH filamentation. The formation of IMPDH cytoophidium is positively correlated with the active cell metabolism in mouse embryo development and pluripotent stem cells. By using IMPDH2 point mutation embryonic stem cell models, which are unable to form the cytoophidium, the utmost importance of the cytoophidium in maintaining the glycolysis-derived nucleotide synthesis is revealed. Furthermore, IMPDH cytoophidia are observed in various human cancer tissues, notably in almost half of the cervical carcinoma samples but not in normal cervical tissues. The essential role of the cytoophidium in supporting nucleotide synthesis via glycolysis is demonstrated in cervical and uterine cancer through the establishment of mutant cancer cell lines with IMPDH2 point mutation that impedes polymerization. Collectively, these findings suggest a regulatory role of cytoophidium in the metabolism of rapidly growing and glycolytic-reliant cells. Given that IMPDH is a potential drug target for autoimmune, infectious diseases, and cancer, this insight may shed light on new avenues in cell biology and medicine. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95726 |
DOI: | 10.6342/NTU202403679 |
Fulltext Rights: | 未授權 |
Appears in Collections: | 生物科技研究所 |
Files in This Item:
File | Size | Format | |
---|---|---|---|
ntu-112-2.pdf Restricted Access | 35.79 MB | Adobe PDF |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.