TY - JOUR
T1 - Transcriptional regulation of human FE65, a ligand of Alzheimer's disease amyloid precursor protein, by Sp1
AU - Yu, Hoi Tin
AU - Chan, William Wai Lun
AU - Chai, Ka Ho
AU - Lee, Chris Wing Cheung
AU - Chang, Raymond Chuen Chung
AU - Yu, Man Shan
AU - McLoughlin, Declan M.
AU - Miller, Christopher C.J.
AU - Lau, Kwok Fai
PY - 2010/3/1
Y1 - 2010/3/1
N2 - 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.
AB - 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.
KW - Amyloid precursor protein
KW - FE65
KW - Promoter
KW - Sp1
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U2 - 10.1002/jcb.22457
DO - 10.1002/jcb.22457
M3 - Article
C2 - 20091743
AN - SCOPUS:77749311404
SN - 0730-2312
VL - 109
SP - 782
EP - 793
JO - Journal of supramolecular structure and cellular biochemistry
JF - Journal of supramolecular structure and cellular biochemistry
IS - 4
ER -