FoxO regulates expression of ABCA6, an intracellular ATP-binding-cassette transporter responsive to cholesterol
FoxO regulates expression of ABCA6, an intracellular ATP-binding-cassette transporter responsive to cholesterol
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FoxO 调节 ABCA6 的表达，ABCA6 是一种对胆固醇有反应的细胞内 ATP 结合盒转运蛋白
DOI：
10.1016/j.biocel.2013.08.020
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发表时间：
2013-11-01
影响因子：
4
通讯作者：
Li, Hao
中科院分区：
文献类型：
--
作者：
Gai, Junfang;Ji, Meiling;Li, Hao
ATP结合盒（ABC）蛋白已被认为是细胞生理运输过程中的关键球员。ABC转运蛋白A6（ABCA 6）是ABC亚家族A的成员。虽然它在10多年前被克隆，但其表达调控，亚细胞定位和生理功能仍然很大程度上未知。我们在此证明ABCA 6在人内皮细胞系EA.hy926和人脐静脉内皮细胞中的表达是叉头盒O（FoxO）依赖性的。在ABCA 6启动子中鉴定了两个功能性FoxO响应元件，并对其进行了详细表征。胰岛素样生长因子-1可抑制ABCA 6 mRNA的表达，促进FoxOs的磷酸化和失活，而磷脂酰肌醇3-激酶抑制剂则相反。通过免疫荧光和共聚焦显微镜，ABCA 6蛋白主要定位于细胞内区室，可能代表高尔基体。ABCA 6 mRNA被证明对人内皮细胞中的胆固醇负荷以及3-羟基-3-甲基-戊二酰-CoA（HMG-CoA）还原酶抑制剂有响应。我们的数据为FoxO蛋白在人血管内皮细胞ABCA 6转录中的重要作用提供了证据。基于其胆固醇反应性，ABCA 6可能参与细胞内脂质转运过程。皇冠版权所有（C）2013由爱思唯尔有限公司出版。保留所有权利。
ATP-binding-cassette (ABC) proteins have been recognized as key players in cellular physiological transport processes. ABC transporter A6 (ABCA6) is a member of the ABC subfamily A. Although it was cloned more than 10 years ago, its expression regulation, subcellular localization, and physiologic function remain largely unknown. We here demonstrated that expression of ABCA6 was Forkhead box O (FoxO)-dependent in human endothelial cell line EA.hy926 and human umbilical vein endothelial cells. Two functional FoxO-responsive elements were identified in ABCA6 promoter and characterized in detail. ABCA6 mRNA was suppressed by insulin-like growth factor-1 which stimulates the phosphorylation and inactivation of FoxOs while inhibitor of phosphatidylinositol 3-kinase had the opposite effect. By immunofluorescence and confocal microscopy, ABCA6 protein is localized primarily in an intracellular compartment, likely representing the Golgi apparatus. ABCA6 mRNA was demonstrated to be responsive to cholesterol loading as well as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors in human endothelial cells. Our data provide evidence for an essential role of FoxO proteins in the transcription of ABCA6 in human vascular endothelial cells. Based on its cholesterol responsiveness, a potential involvement of ABCA6 in intracellular lipid transport processes may be anticipated. Crown Copyright (C) 2013 Published by Elsevier Ltd. All rights reserved.