Cyclic AMP modulates the response of central nervous system glia to fibroblast growth factor-2 by redirecting signalling pathways.
Fibroblast growth factor-2 (FGF-2) acts as both a potent mitogen and differentiation factor for CNS glia. In the present study, we provide evidence that intracellular cAMP determines the proliferation-differentiation decision of astroglia to FGF-2 by either facilitating FGF-2 signalling to extracellular signal-related protein kinase (ERK) or cAMP response element binding protein (CREB). Pharmacologically increasing intracellular cAMP levels in cultured cortical astroglia by treatment with dbcAMP or forskolin attenuated FGF-2-induced ERK phosphorylation and glial cell proliferation. Similarly, FGF-2-induced glial proliferation was attenuated in the presence of the MEK inhibitor, PD98059, thus, confirming a direct correlation between FGF-2-induced ERK activation and glial cell proliferation. On the other hand, increases in intracellular cAMP levels in cortical astroglia prolonged FGF-2-induced CREB phosphorylation and subsequently potentiated the cAMP response element-dependent transcription of the immediate early gene, c-fos. Moreover, the effects of cAMP on the time-course of FGF-2-dependent CREB phosphorylation were mimicked by PD98059, suggesting that the cAMP-induced redirection of FGF-2-signalling is linked to the RAF-MEK-ERK signalling pathway.
Bayatti
N
N
Anatomie und Zellbiologie, Universität Ulm, Ulm, Germany.
Engele
J
J
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D003994:Bucladesine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016760:Proto-Oncogene Proteins c-fos; D016222:Fibroblast Growth Factor 2; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one