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標題: | 探討N端乙醯基轉移酶在癌細胞移行及轉移過程中之角色 The Role of N-α-Acetyltransferase 10 Protein (Naa10p) in Cancer Cell Mobility and Metastasis |
作者: | Kuo-Tai Hua 華國泰 |
指導教授: | 郭明良 |
關鍵字: | N端乙醯基轉移酶,淋巴轉移,細胞移行,鳥糞嘌呤核苷,酸轉換因子, Naa10p,metastasis,migration,PIX, |
出版年 : | 2011 |
學位: | 博士 |
摘要: | 蛋白質N端乙醯化修飾普遍的發生在百分之八十至九十的新生蛋白質分子上,並且經由特定的N端乙醯基轉移酶來催化反應,然而N端乙醯基轉移酶在細胞中到底扮演何種功能仍不清楚,近來此類N端乙醯基轉移酶已被發現參與在如胚胎發育、神經疾病以及癌症等重要的生理過程中。乙醯基轉移酶複合體 A (Nat A)最早在酵母菌中被發現,由Naa10p與Naa15p兩個蛋白質分子共同組成負責許多新生蛋白質的N端乙醯化修飾,其中Naa10p具催化N端乙醯化修飾的能力為酵素反應催化次單元。Naa10p已知參與包含細胞周期及凋亡等重要細胞功能的調控,雖然許多腫瘤組織中已經發現Naa10p的表現,但是在癌細胞中Naa10p扮演何種角色仍不清楚。在我們的研究中發現腫瘤組織中Naa10p表現量的多寡顯著的與癌細胞淋巴轉移及癌症病患的預後有高度相關性,此外在細胞模式中Naa10p的高表現也顯著的抑制細胞移行、腫瘤生長及轉移的能力,我們很意外的發現Naa10p的乙醯基轉移酶活性並不參與在上述的現象中,反之,Naa10p能藉由結合在鳥糞嘌呤核苷酸轉換因子PIX上的GIT結合位置進而影響GIT-PIX-Paxillin複合體的形成,導致細胞內Cdc42/Rac1無法被激活而抑制細胞移行的能力,而將PIX表現在已過量表現Naa10p的細胞中能增加其原本受抑制的細胞移行及轉移能力。我們的研究結果顯示Naa10p是一個腫瘤轉移抑制因子,並且主要作用在干擾促使細胞移動的GIT-PIX-Paxillin複合體的形成,亦為一個GIT-PIX-Paxillin複合體調控分子。 80%–90% of eukaryotic proteins are N-α-terminally acetylated. They are mediated by specific N-α-acetyltransferases. However, the biological importance of these N-α-acetyltransferases remains largely unknown. Recently, these N-α-acetyltransferases have been recognized as important characters in many biological processes, including embryonic development, neuron disease and cancer. N-α-acetyltransferase A (Nat A) was first characterized in yeast, it composed of Naa10p, also known as hARD1 (human Arrest defective 1), and Naa15p, also known as NATH (N-acetyl transferase human), are responsible for the N-α-acetylation of majority proteins in mammalian cells. Naa10p is known to be involved in cell cycle control and apoptosis. However, the role of Naa10p in human cancers is elusive. In this study, we found that elevated Naa10p levels are associated with less metastasis to lymph nodes and better prognosis of cancer patients. Naa10p significantly suppressed migration, tumor growth, and metastasis independent of its enzymatic activity. Instead, Naa10p binds to the GIT-binding domain of PIX, thereby preventing the formation of the GIT-PIX-Paxillin complex, resulting in reduced intrinsic Cdc42/Rac1 activity and decreased cell migration. Forced expression of PIX in Naa10-transfected tumor cells restored the migration and metastasis ability. We suggest that Naa10p functions as a tumor metastasis suppressor by disrupting the migratory complex, PIX-GIT- Paxillin, in cancer cells. Our study not only highlights the potential of Naa10p as a therapeutic target for tumor metastasis, but also identifies Naa10p as a regulatory component of the migration complex PIX-GIT-Paxillin. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48603 |
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顯示於系所單位: | 毒理學研究所 |
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