Ana Villa, Maria Jesús Latasa, and Angel Pascual
نویسندگان
چکیده
Nerve growth factor modulates the expression and secretion of -amyloid precursor protein through different mechanisms in PC12 cells. ABSTRACT The -amyloid protein, component of the senile plaques found in Alzheimer brains is proteolytically derived from the -amyloid precursor protein (APP), a larger membrane-associated protein that is expressed in both neural and nonneural cells. Overexpression of APP might be one of the mechanisms that more directly contributes to the development of Alzheimer disease. APP gene expression is regulated by a number of cellular mediators including nerve growth factor (NGF) and other ligands of tyrosine kinase receptors. We have previously described that NGF increases APP mRNA levels In PC12 cells. However, the molecular mechanisms and the precise signaling patways that mediate its regulation are not yet well understood. In the present study we present evidence that NGF, and to a lesser extent fibroblast growth factor (FGF) and epidermal growth factor (EGF), stimulate APP promoter activity in PC12 cells. This induction is mediated by DNA sequences located between the nucleotides-307 and-15, and involves activation of the Ras-MAP kinase signaling pathway. In contrast, we have also found that NGF-induced secretion of soluble fragments of APP into the culture medium is mediated by a Ras independent mechanism. Running title: NGF regulate synthesis and secretion of APP by different mechanisms.
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A response unit in the first exon of the beta-amyloid precursor protein gene containing thyroid hormone receptor and Sp1 binding sites mediates negative regulation by 3,5,3'-triiodothyronine.
Thyroid hormones repress expression of APP (beta-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 ...
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