title: FoxO regulates expression of ABCA6, an intracellular ATP-binding-cassette transporter responsive to cholesterol.
abstract: 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.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Junfang
authors.initials: J
authors.lastname: Gai
authors.forename: Meiling
authors.initials: M
authors.lastname: Ji
authors.forename: Chenxi
authors.initials: C
authors.lastname: Shi
authors.forename: Wenli
authors.initials: W
authors.lastname: Li
authors.forename: Simin
authors.initials: S
authors.lastname: Chen
authors.forename: Yeyu
authors.initials: Y
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Li
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002784:Cholesterol / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: C434046:ABCA6 protein, human; D018528:ATP-Binding Cassette Transporters; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D011993:Recombinant Fusion Proteins; D002784:Cholesterol
keywords: ABC transporters; CHO; Chinese hamster ovary; Cholesterol; DTT; Endothelial cells; FITC; Forkhead box protein; GAPDH; IGF-1; PI3K; TRITC; dithiothreitol; fluorescein isothiocyanate; glyceraldehyde-3-phosphate dehydrogenase; insulin-like growth factor-1; phosphatidylinositol 3-kinase; tetramethylrhodamine isothiocyanate