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Brain‐derived neurotrophic factor stimulates β‐amyloid gene promoter activity by a Ras‐dependent/AP‐1‐independent mechanism in SH‐SY5Y neuroblastoma cells
Author(s) -
RuizLeón Yolanda,
Pascual Angel
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00547.x
Subject(s) - tropomyosin receptor kinase b , protein kinase c , neurotrophic factors , sh sy5y , bisindolylmaleimide , biology , amyloid precursor protein , microbiology and biotechnology , creb , brain derived neurotrophic factor , signal transduction , transcription factor , receptor , medicine , neuroblastoma , alzheimer's disease , cell culture , biochemistry , gene , genetics , disease
The β‐amyloid peptide, the major component of Alzheimer‐associated plaques, derives from a larger β‐amyloid precursor protein (APP), that is expressed in both neural and non‐neural cells. Overexpression of APP actively contributes to the development of senile plaques and is considered a risk factor for the disease. APP expression is regulated by a variety of cellular mediators, among them ligands of tyrosine kinase receptors. In this study, we present evidence that brain‐derived neurotrophic factor (BDNF) modulates, in a dose‐ and time‐dependent fashion, APP promoter activity in SH‐SY5Y neuroblastoma cells transiently expressing the receptor TrkB. The APP promoter contains two potential AP‐1 sites, and we examined whether or not protein kinase C (PKC) and the AP‐1 sites of the promoter mediate the BDNF‐induced stimulation of APP. Stimulation of APP promoter activity by BDNF was not affected by the PKC inhibitor bisindolylmaleimide, or by dominant negative mutants of the AP‐1 components Fos and Jun, which, however, blocked the response to phorbol esters. These results suggest that activation of the APP promoter by BDNF is largely independent of PKC and AP‐1. In contrast, activated Ras increased APP promoter activity in SH‐SY5Y cells, and a dominant negative mutant of Ras abolished BDNF‐mediated promoter stimulation. Taken together, our results suggest a mechanism that involves activation of the Ras/MAP kinase signaling pathway, and phosphorylation of as yet unidentified effectors which in turn can activate response elements within the APP promoter.