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© 1995 Oxford University Press

RESEARCH-ARTICLE

The upstream stimulatory factor functionally interacts with the Alzheimer amyloid ß-protein precursor gene

Dora M. Kovacs, Wilma Wasco, Johanna Witherby, Kevin M. Felsenstein1, Franck Brunei2, Robert G. Roeder2 and Rudolph E. Tanzi*

Genetics and Aging Unit, Massachusetts General Hospital, Harvard Medical School Boston, MA 02129 1Bristol-Myers Squibb Wallingford, CT 06492 2Laboratory of Biochemistry and Molecular Biology, The Rockefeller University New York, NY 10021, USA

*To whom correspondence be addressed

Received April 11, 1995; Revised June 2, 1995; Accepted June 2, 1995

The amyloid ß-protein precursor (APP) gives rise to the Aß 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 ß-amyloid.


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