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A Response Unit in the First Exon of the ß-Amyloid Precursor Protein Gene Containing Thyroid Hormone Receptor and Sp1 Binding Sites Mediates Negative Regulation by 3,5,3'-Triiodothyronine

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, 28029 Madrid, Spain

Address all correspondence and requests for reprints to: Dr. A. Pascual, Instituto de Investigaciones Biomédicas. (C.S.I.C.), Arturo Duperier 4, 28029 Madrid, Spain. E-mail: apascual{at}iib.uam.es.

Thyroid hormones repress expression of APP (ß-amyloid precursor protein) in cultured cells of neuronal origin. The effect involves binding to the nuclear thyroid hormone receptor (TR) and is mediated by DNA sequences located within the first exon of the gene. These sequences contain a thyroid hormone response element that is necessary, but not sufficient, to mediate the inhibitory effect of the thyroid hormone T₃. In this report, we show that repression by T₃ is mediated by a response unit composed by the thyroid hormone response element and 5'-flanking sequences that bind Sp1 and mediate stimulation by this transcription factor. In that unit, binding sites for TR and Sp1 overlap and a complex mechanism appears to account for the TR-mediated regulation of APP. Unliganded TR does not bind to DNA and allows Sp1 to bind to DNA and stimulate APP basal expression. Binding of ligand T₃, which increases affinity of TR by DNA, precludes binding of Sp1 to DNA and decreases the Sp1-dependent expression of APP.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Ligands:   Thyroid hormone

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