The tumor suppressor p53 regulates the expression of the beta-amyloid precursor protein.
Biochem J. 2008 Dec 3;
Authors: Cuesta A, Zambrano A, Royo M, Pascual A
The expression of the beta-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 p53 regulates the expression of the APP gene in neuroblastoma cells. Transient expression of ectopic p53, as well as the activation of endogenous p53 by the DNA-damaging drug camptothecin or MDM2 depletion, decrease intracellular levels of APP in N2abeta neuroblastoma cells. This effect was also observed in primary cultures of rat neurons as well as in SH-SY5Y cells, a human neuroblastoma cell line. Transient transfection studies using plasmids which contain progressive deletions of the 5' region of the gene, demonstrate that p53 represses APP promoter activity through a mechanism that is mediated by DNA sequences located downstream of the transcription start site (+55/+101). Accordingly, expression of a dominant negative p53 mutant significantly increases the transcriptional activity of the APP promoter. In addition, data obtained in gel mobility shift assays show that p53 does not bind to the +55/+101 APP region, although reduces binding of the transcription factor Sp1. Reduction of Sp1 binding after activation of p53 with camptothecin was also observed in chromatin immunoprecipitation assays. All together our results strongly suggest a mechanism by which p53 precludes binding of Sp1 to DNA, and therefore the stimulation of the APP promoter by this transcription factor.
PMID: 19049493 [PubMed - as supplied by publisher]