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.

Genome-wide pathway analysis of memory impairment in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks

“…We found that a preponderance of the most highly-represented genes in our enriched pathways were constituents of a transcriptional regulation network driven by the SP1 transcription factor (Figure 4). The SP1 transcription factor has known binding regions in the promoters of genes related to beta-amyloid precursor protein (Yu et al 2010; Rossner et al 2006), tau protein (Santpere et al 2006), and APOE . In particular, SP1 has been proposed as a regulator of APOE promoter activity in relation to two promoter polymorphisms with significant association to AD (Maloney et al 2010).…”

Multicenter study identified molecular blood‐born protein signatures for Wilms Tumor

“…This clone was reactive with 52% of WT sera collected by SIOP but only with 12% of sera from non‐WT controls. The protein that is a member of the Fe65 protein family interacts with the amyloid precursor protein and downregulates thymidylate synthase expression in Alzheimer's disease 41…”

Possible roles of amyloid intracellular domain of amyloid precursor protein

“…Overexpression of 14-3-3γ by Gal4-AICD fusion protein enhances Fe65-dependent gene transactivation by two-fold in mouse neuroblastoma-2a cells (53). Recently, Sp1 was reported to play a crucial role in transcriptional regulation of human Fe65 (54). In contrast, X11α has an inhibitory effect on AICD-mediated gene transactivation by trapping AICD in the cytoplasm (42).…”