Regulation of PDGFR-a in rat pulmonary myofibroblasts by staurosporine.
Lindroos, Pamela M., Yi-Zhe Wang, Annette B. Rice, and James C. Bonner.
Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health
Sciences, National Institutes of Health, Research Triangle Park, North Carolina
27709
APStracts 7:0247L, 2000.
Upregulation of the platelet-derived growth factor receptor-a (PDGFR-a) is a mechanism
of myofibroblast hyperplasia during pulmonary fibrosis. We previously identified
interleukin (IL)-1ß as a major inducer of the PDGFR-a in rat pulmonary myofibroblasts
in vitro. In this study, we report that staurosporine, a broad-spectrum kinase inhibitor,
upregulates PDGFR-a gene expression and protein. A variety of other kinase inhibitors
did not induce PDGFR-a expression. Staurosporine did not act via an IL-1ß autocrine
loop because the IL-1 receptor antagonist protein did not block staurosporine-induced
PDGFR-a expression. Furthermore, staurosporine did not activate a variety of signaling
molecules that were activated by IL-1ß, including nuclear factor-?B, extracellular signal-
regulated kinase, and c-Jun NH2-terminal kinase. However, both staurosporine- and IL-
1ß-induced phosphorylation of p38 mitogen-activated protein kinase and upregulation of
PDGFR-a 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-a 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-a as a growth arrest-specific gene.
Received 3 February 2000; accepted in final form 14 August 2000
APS Manuscript Number L0041-0.
Article publication pending Am J Physiol Lung Cell Mol Physiol
ISSN 1080-4757 Copyright 2000 The American Physiological Society.
Published in APStracts on 7 November 2000