Transcriptional regulation of human FE65, a ligand of Alzheimer's disease amyloid precursor protein, by Sp1.
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.
Yu
Hoi-Tin
HT
Department of Biochemistry (Science), The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR.
Chan
William Wai-Lun
WW
Chai
Ka-Ho
KH
Lee
Chris Wing-Cheung
CW
Chang
Raymond Chuen-Chung
RC
Yu
Man-Shan
MS
McLoughlin
Declan M
DM
Miller
Christopher C J
CC
Lau
Kwok-Fai
KF
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
C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor