Brain-derived neurotrophic factor stimulates beta-amyloid gene promoter activity by a Ras-dependent/AP-1-independent mechanism in SH-SY5Y neuroblastoma cells.
The beta-amyloid peptide, the major component of Alzheimer-associated plaques, derives from a larger beta-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.
Ruiz-León
Y
Y
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Pascual
A
A
D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D004247:DNA / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000502:physiology; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D020813:Receptor, trkB; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D018808:Transcription Factor AP-1; D004247:DNA; D020813:Receptor, trkB; D011493:Protein Kinase C; D018631:ras Proteins