Platelet-derived growth factor-mediated signal transduction underlying astrocyte proliferation: site of ethanol action.
Platelet-derived growth factor (PDGF) is a critical regulator of cell proliferation. Because ethanol inhibits cell proliferation in vivo and in vitro, we hypothesize that ethanol-induced inhibition results from differential interference with signal transduction pathways activated by PDGF. Cultured cortical astrocytes were used to examine the effects of ethanol on PDGF-mediated signal transduction, on the expression of two PDGF monomers (A- and B-chains), and on the expression of two PDGF receptor subunits (PDGFalphar and PDGFbetar). PDGF-B chain homodimer (PDGF-BB), and to a lesser extent PDGF-A chain homodimer (PDGF-AA), stimulated the proliferation of astrocytes raised in a serum-free medium. Ethanol attenuated these actions in a concentration-dependent manner. Ethanol inhibited both PDGF-AA- and PDGF-BB-mediated phosphorylation of PDGFalphar, but it had little effect on PDGFbetar autophosphorylation. Likewise, ethanol abolished the association of PDGFalphar to Ras GTPase-activating protein (Ras-GAP), but it did not affect the binding of Ras-GAP to PDGFbetar. PDGF stimulated the activities of mitogen-activated protein kinase (MAPK) in protein kinase C (PKC) independent and dependent manners. Ethanol inhibited the PKC-independent, acute activation of MAPK; however, it stimulated the PKC-dependent, sustained activation of MAPK. The expression of neither ligand was altered by exposure to ethanol for 3 d. Moreover, such treatment specifically upregulated PDGFalphar expression in a concentration-dependent manner. It did not, however, affect the binding affinity of either receptor. Thus, the signal transduction pathways initiated by PDGF-AA and PDGF-BB were differentially affected by ethanol. This differential vulnerability resulted from the preferential effects of ethanol on PDGFalphar autophosphorylation. Hence, ethanol-induced alterations are transduced through specific receptors of mitogenic growth factors.
Luo
J
J
Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa 52242-1000, USA.
Miller
M W
MW
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D000077214:Becaplermin; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008959:Models, Neurological; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000493:pharmacokinetics / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D000431:Ethanol; D017479:Receptors, Platelet-Derived Growth Factor; D011493:Protein Kinase C