探討致癌蛋白Aurora-A以及其下游受質HURP對於細胞增生以及高基氏體組成之調控

Aurora-A與HURP為兩個具細胞轉型(cell transformation)活性的因子，高量表現在多種癌症組織中；此兩蛋白功能多元，參與在包括細胞週期調控等多種細胞生理的調節過程。本博士論文主旨在揭露Aurora-A與HURP新的細胞功能。論文架構分為兩大面向，一是Aurora-A透過磷酸化下游受質Astrin與HURP調控細胞週期的進行，另一是HURP經由調控穩定性微管(stable microtubule，stable MT)促進高基氏體的組裝。Aurora-A於mitosis磷酸化Astrin，藉此促進Astrin與相關M期調控蛋白的交互作用，進而保證mitosis的順利進行。此外，Aurora-A亦透過磷酸化HURP來活化p38與NF-?B，接著刺激Cyclin-E1的表現與加速G1/S 的行進。另一方面，HURP也同時經由NF-?B轉錄調控了CCP1與αTAT1此兩個stable MT生成酵素的表現，以製造stable MT，繼而維持高基氏體的彩帶型(Golgi ribbon)的結構。

關鍵字

磷酸化；細胞週期；細胞增生；高基氏體；微管

並列摘要

Aurora-A and HURP play roles in cell transformation. The two versatile proteins govern numerous cellular physiological functions, such as cell cycle progression. The new cellular functions of Aurora-A and HURP are revealed in this doctoral dissertation. The conceptual framework of this study is divided into two major parts. First, Aurora-A phosphorylates Astrin and HURP to regulate cell cycle progression. Second, HURP direct Golgi assembly by regulating stable microtubules (stable MTs). Aurora-A phosphorylates Astrin in mitosis and facilitates the interaction between Astrin and various mitosis regulating proteins to ensure the mitosis progression. Besides, Aurora-A phosphorylates HURP and the phospho-HURP activates p38 and NF-?B. HURP/NF-?B elevates the expression level of cyclin E1 to accelerate G1/S transition. Furthermore, HURP transcriptionally regulates the expression of Golgi assembly factors, such as GRASP65, GRASP55 and Golgin160, and CCP1 and αTAT1, which are the two stable microtubules generating enzymes, thereby maintaining the Golgi ribbon structure.