title: NGF upregulates the plasminogen activation inhibitor-1 in neurons via the calcineurin/NFAT pathway and the Down syndrome-related proteins DYRK1A and RCAN1 attenuate this effect.
abstract: BACKGROUND
  Plasminogen activator inhibitor 1 (PAI-1) is a key regulator of the plasminogen activation system. Although several lines of evidence support a significant role of PAI-1 in the brain, the regulation of its expression in neurons is poorly understood. In the present study we tested the hypothesis that NGF induces the upregulation of PAI-1 via the calcineurin/nuclear factor of activated T cells (NFAT) pathway and analysed whether the overexpression of the Down syndrome-related proteins DYRK1A and RCAN1 modulated the effect of NGF on PAI-1 expression.
  
  
  RESULTS
  NGF upregulated PAI-1 mRNA levels in primary mouse hippocampal neurons cultured for 3 days in vitro and in the rat pheochromocytoma cell line PC12. Reporter gene assays revealed that NGF activated the calcineurin/NFAT pathway in PC12 cells. Induction of PAI-1 by NGF was sensitive to the calcineurin inhibitor FK506 and the specific inhibition of NFAT activation by the cell permeable VIVIT peptide. Activation of calcineurin/NFAT signalling through other stimuli resulted in a much weaker induction of PAI-1 expression, suggesting that other NGF-induced pathways are involved in PAI-1 upregulation. Overexpression of either DYRK1A or RCAN1 negatively regulated NFAT-dependent transcriptional activity and reduced the upregulation of PAI-1 levels by NGF.
  
  
  CONCLUSIONS
  The present results show that the calcineurin/NFAT pathway mediates the upregulation of PAI-1 by NGF. The negative effect of DYRK1A and RCAN1 overexpression on NGF signal transduction in neural cells may contribute to the altered neurodevelopment and brain function in Down syndrome.
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty of the RWTH Aachen University, Aachen, Germany. stegi121@yahoo.gr
authors.forename: Georgios C
authors.initials: GC
authors.lastname: Stefos
authors.forename: Ulf
authors.initials: U
authors.lastname: Soppa
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
authors.forename: Walter
authors.initials: W
authors.lastname: Becker
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004314:Down Syndrome / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D000097603:Dyrk Kinases
chemical_list: D019703:Calcineurin; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; D020932:Nerve Growth Factor; D017395:Plasminogen Activator Inhibitor 1; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C548050:RCAN1 protein, rat