title: Early growth response-1 induction by fibroblast growth factor-1 via increase of mitogen-activated protein kinase and inhibition of protein kinase B in hippocampal neurons.
abstract: OBJECTIVE
  The transcription factor early growth response-1 (Egr-1) and the acidic fibroblast growth factor (FGF-1) are involved in many regulatory processes, including hippocampus-associated learning and memory. However, the intracellular signalling mechanisms regulating Egr-1 in hippocampal cells are not entirely understood.
  
  
  METHODS
  We used primary mouse hippocampal neurons and the mouse hippocampal neuronal cell line HT22 to investigate how FGF-1 transiently induces Egr-1 protein. This was accomplished by a range of techniques including Western blotting, immunofluorescence, specific protein kinase inhibitors and transfectable constitutively active protein kinase constructs.
  
  
  RESULTS
  Protein kinase B (PKB) and mitogen-activated protein kinase (MAPK) were both initially phosphorylated and activated by FGF-1 treatment, but when phosphorylated MAPK reached maximal activation, phosphorylated PKB was at its lowest levels, suggesting an interaction between MAPK kinase (MEK-1/2) and phosphatidyl inositol-3-kinase (PI3K) during Egr-1 induction. Interestingly, pharmacological inhibition of MEK-1/2 resulted in a robust increase in the phosphorylation of PKB, which was repressed in the presence of increasing doses of a PI3K inhibitor. FGF-1-mediated Egr-1 induction was impaired by inhibition of MEK-1/2, but not of PI3K. However, elevated levels of PKB, induced by transfection of constitutively active PKB (myrAkt) into hippocampal neuronal HT22 cells, led to reduced levels of Egr-1 after FGF-1 application.
  
  
  CONCLUSIONS
  Our data indicate a contribution of inactive (dephosphorylated) PKB to FGF-1-mediated induction of Egr-1, and strongly suggest a functionally and pharmacologically interesting cross-talk between MEK-1/2 and PI3K signalling in hippocampal neurons after FGF-1 stimulation that may play a role in hippocampal synaptic plasticity.
authors.affiliation: Institut für Anatomie III, Dr Senckenbergische Anatomie, Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Benz
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shajari
authors.forename: Natalie
authors.initials: N
authors.lastname: Peruzki
authors.forename: Faramarz
authors.initials: F
authors.lastname: Dehghani
authors.forename: Erik
authors.initials: E
authors.lastname: Maronde
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis*; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008809:Mice, Inbred C3H; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D047428:Protein Kinase Inhibitors; D016220:Fibroblast Growth Factor 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases