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Thyroid hormone negatively regulates the transcriptional activity of the β-amyloid precursor protein gene

AuthorsBelandia, Borja ; Latasa, María Jesús ; Villa, Ana; Pascual, Ángel
Issue Date1998
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 273(46): 30366-30371 (1998)
AbstractThe expression of the β-amyloid precursor protein (APP), which plays a key role in the development of Alzheimer's disease, is regulated by a variety of cellular mediators in a cell-dependent manner. In the present study, we present evidence that thyroid hormones negatively regulate the expression of the APP gene in neuroblastoma cells. Transient transfection studies using plasmids that contain progressive deletions of the 5' region of the gene demonstrate that triiodothyronine (T3), the more active form of the thyroid hormones, represses APP promoter activity by a mechanism that requires binding of the nuclear T3 receptor (TR) to a specific sequence located in the first exon. The unliganded receptor increases promoter activity, and T3 reverses that activity to basal levels. The repressive effect of T3 does not exhibit TR isoform specificity, and it is equally mediated by TRα and TRβ. Gel mobility shift assays using in vitro synthesized nuclear receptors and nuclear extracts led to the identification of a negative thyroid hormone response element, at nucleotide position +80/+96, that preferentially binds heterodimers of TR with the retinoid X receptor. Insertion of sequences containing this element confers negative regulation by T3 to a heterologous TK promoter, thus indicating the functionality of the element.
DescriptionEl pdf del artículo es la versión de autor.
Publisher version (URL)http://dx.doi.org/10.1074/jbc.273.46.30366
Identifiersdoi: 10.1074/jbc.273.46.30366
issn: 0021-9258
e-issn: 1083-351X
Appears in Collections:(IIBM) Artículos
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