The upstream stimulatory factor functionally interacts with the Alzheimer amyloid beta-protein precursor gene.
The amyloid beta-protein precursor (APP) gives rise to the A beta peptide, which is deposited in the brains of patients with Alzheimer's disease and Down's syndrome. Overexpression of APP due to a third copy of the gene appears to correlate with very early onset of Alzheimer's disease neuropathology in the brains of Down's syndrome patients. Thus, the identification of the factors involved with transcriptional regulation of the APP gene could provide critical clues regarding the events leading to the formation of amyloid deposits. An overlapping AP-1/AP-4 site in the proximal promoter region (-39 to -49) of the human APP gene has previously been shown to increase transcription 4-fold. Here we identify the factor binding specifically to this element as the upstream stimulatory factor USF, unrelated to the c-fos/c-jun complex or the AP-4 factor. In vitro transcription and co-transfection studies show that USF activates transcription from the APP promoter and that the AP-1/AP-4 element participates in this activation. Modulation of APP expression via regulation of USF could potentially ameliorate the production of Alzheimer-augmented beta-amyloid.
Genetics and Aging Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02129, USA.
D M
DM
Kovacs
W
W
Wasco
J
J
Witherby
K M
KM
Felsenstein
F
F
Brunel
R G
RG
Roeder
R E
RE
Tanzi
D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D004247:DNA; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051720:Upstream Stimulatory Factors
D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; D004247:DNA