Cyclic AMP differentially regulates the expression of fibroblast growth factor and epidermal growth factor receptors in cultured cortical astroglia.
Fibroblast growth factor (FGF)-2 and transforming growth factor alpha (TGFalpha) promote astroglial proliferation during brain development and reactive processes. The mitogenic potential of both growth factors is attenuated by increasing intracellular cAMP levels, an effect currently assumed to depend on the inhibition of the mitogen-activated protein kinase cascade. In the present study, we sought to determine whether cAMP interferes with the mitogenic potential of FGF-2 and TGFalpha on astroglia by affecting the expression of respective growth factor receptors. Treatment of highly enriched cultures of cortical astrocytes with dibutyryl cAMP accelerated the TGFalpha-induced internalization and subsequent functional inactivation of epidermal growth factor (EGF) receptor by transiently inhibiting EGF receptor mRNA synthesis. In apparent contrast, both short- and long-term activation of cAMP-dependent signaling pathways robustly promoted the expression of FGF receptors 1 and 2, whereas expression levels of FGF receptor 3 remained unaffected. Moreover, elevation of intracellular cAMP levels did not prevent translocation of FGF receptor 1 to the cell nucleus, a mechanism thought to be essential for FGF-2-induced cell proliferation. We propose that cAMP controls the mitogenic effects of TGFalpha and FGF-2 on astroglial cells by distinctly different mechanisms. Whereas cAMP seems to interfere with the mitogenic effects of TGFalpha on astroglial cells by affecting both the expression level and signaling of the EGF receptor, the modulatory effects of cAMP on FGF-2-induced astroglial proliferation seem to solely result from an inhibition of FGF receptor-activated signaling pathways.
Anatomie und Zellbiologie, Universität Ulm, 89069 Ulm, Germany.
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Bayatti
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Engele
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D003994:Bucladesine / Q000494:pharmacology; D002451:Cell Compartmentation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D016211:Transforming Growth Factor alpha; D016222:Fibroblast Growth Factor 2; D003994:Bucladesine; D000242:Cyclic AMP; D066246:ErbB Receptors; C496350:Fgfr1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1