Regulation of PDGFR-alpha in rat pulmonary myofibroblasts by staurosporine.
Upregulation of the platelet-derived growth factor (PDGF) receptor-alpha (PDGFR-alpha) is a mechanism of myofibroblast hyperplasia during pulmonary fibrosis. We previously identified interleukin (IL)-1beta as a major inducer of the PDGFR-alpha in rat pulmonary myofibroblasts in vitro. In this study, we report that staurosporine, a broad-spectrum kinase inhibitor, upregulates PDGFR-alpha gene expression and protein. A variety of other kinase inhibitors did not induce PDGFR-alpha expression. Staurosporine did not act via an IL-1beta autocrine loop because the IL-1 receptor antagonist protein did not block staurosporine-induced PDGFR-alpha expression. Furthermore, staurosporine did not activate a variety of signaling molecules that were activated by IL-1beta, including nuclear factor-kappaB, extracellular signal-regulated kinase, and c-Jun NH2-terminal kinase. However, both staurosporine- and IL-1beta-induced phosphorylation of p38 mitogen-activated protein kinase and upregulation of PDGFR-alpha by these two agents was inhibited by the p38 inhibitor SB-203580. Finally, staurosporine inhibited basal and PDGF-stimulated mitogenesis over the same concentration range that induced PDGFR-alpha expression. Collectively, these data demonstrate that staurosporine is a useful tool for elucidating the signaling mechanisms that regulate PDGFR expression in lung connective tissue cells and possibly for evaluating the role of the PDGFR-alpha as a growth arrest-specific gene.
Lindroos
P M
PM
Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Wang
Y Z
YZ
Rice
A B
AB
Bonner
J C
JC
D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016328:NF-kappa B; D010982:Platelet-Derived Growth Factor; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019311:Staurosporine