title: Transcriptional regulation of human FE65, a ligand of Alzheimer's disease amyloid precursor protein, by Sp1.
abstract: FE65 is a neuronal-enriched adaptor protein that binds to the Alzheimer's disease amyloid precursor protein (APP). FE65 forms a transcriptionally active complex with the APP intracellular domain (AICD). The precise gene targets for this complex are unclear but several Alzheimer's disease-linked genes have been proposed. Additionally, evidence suggests that FE65 influences APP metabolism. The mechanism by which FE65 expression is regulated is as yet unknown. To gain insight into the regulatory mechanism, we cloned a 1.6 kb fragment upstream of the human FE65 gene and found that it possesses particularly strong promoter activity in neurones. To delineate essential regions in the human FE65 promoter, a series of deletion mutants were generated. The minimal FE65 promoter was located between -100 and +5, which contains a functional Sp1 site. Overexpression of the transcription factor Sp1 potentiates the FE65 promoter activity. Conversely, suppression of the FE65 promoter was observed in cells either treated with an Sp1 inhibitor or in which Sp1 was knocked down. Furthermore, reduced levels of Sp1 resulted in downregulation of endogenous FE65 mRNA and protein. These findings reveal that Sp1 plays a crucial role in transcriptional control of the human FE65 gene.
authors.affiliation: Department of Biochemistry (Science), The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR.
authors.forename: Hoi-Tin
authors.initials: HT
authors.lastname: Yu
authors.forename: William Wai-Lun
authors.initials: WW
authors.lastname: Chan
authors.forename: Ka-Ho
authors.initials: KH
authors.lastname: Chai
authors.forename: Chris Wing-Cheung
authors.initials: CW
authors.lastname: Lee
authors.forename: Raymond Chuen-Chung
authors.initials: RC
authors.lastname: Chang
authors.forename: Man-Shan
authors.initials: MS
authors.lastname: Yu
authors.forename: Declan M
authors.initials: DM
authors.lastname: McLoughlin
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
authors.forename: Kwok-Fai
authors.initials: KF
authors.lastname: Lau
mesh_terms: D016564:Amyloid beta-Protein Precursor; D005786:Gene Expression Regulation; D006801:Humans; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics*; D009474:Neurons; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D016329:Sp1 Transcription Factor / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor