title: Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates the expression and the release of tissue plasminogen activator (tPA) in neuronal cells: involvement of tPA in the neuroprotective effect of PACAP.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) and tissue plasminogen activator (tPA) play important roles in neuronal migration and survival. However, a direct link between the neurotrophic effects of PACAP and tPA has never been investigated. In this study, we show that, in PC12 cells, PACAP induced a 9.85-fold increase in tPA gene expression through activation of the protein kinase A- and protein kinase C-dependent signaling pathways. In immature cerebellar granule neurons (CGN), PACAP stimulated tPA mRNA expression and release of proteolytically active tPA. Immunocytochemical labeling revealed the presence of tPA in the cytoplasm and processes of cultured CGN. The inhibitory effect of PACAP on CGN motility was not affected by the tPA substrate plasminogen or the tPA inhibitor plasminogen activator inhibitor-1. In contrast, plasminogen activator inhibitor-1 significantly reduced the stimulatory effect of PACAP on CGN survival. Altogether, these data indicate that tPA gene expression is activated by PACAP in both tumoral and normal neuronal cells. The present study also demonstrates that PACAP stimulates the release of tPA which promotes CGN survival by a mechanism dependent of its proteolytic activity.
authors.affiliation: INSERM U982, DC2N, Mont-Saint-Aignan, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Raoult
authors.forename: Benoît Denis
authors.initials: BD
authors.lastname: Roussel
authors.forename: Magalie
authors.initials: M
authors.lastname: Bénard
authors.forename: Thomas
authors.initials: T
authors.lastname: Lefebvre
authors.forename: Aurélia
authors.initials: A
authors.lastname: Ravni
authors.forename: Carine
authors.initials: C
authors.lastname: Ali
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Komuro
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.forename: David
authors.initials: D
authors.lastname: Vaudry
authors.forename: Ludovic
authors.initials: L
authors.lastname: Galas
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002531:Cerebellum / Q000166:cytology* / Q000502:physiology; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D008297:Male; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D010959:Tissue Plasminogen Activator