RT Journal Article
SR Electronic
T1 Selective Down-Regulation of c-<em>jun</em> Gene Expression by Pentoxifylline and c-<em>jun</em> Antisense Interrupts Platelet-Derived Growth Factor Signaling: Pentoxifylline Inhibits Phosphorylation of c-Jun on Serine 73
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1476
OP 1488
DO 10.1124/mol.61.6.1476
VO 61
IS 6
A1 Theresa C. Peterson
A1 Marc R. Peterson
A1 Harold A. Robertson
A1 Matthew During
A1 Michael Dragunow
YR 2002
UL http://molpharm.aspetjournals.org/content/61/6/1476.abstract
AB Platelet-derived growth factor (PDGF) signals through several pathways, including mitogen-activated protein (MAP) kinase, Jun kinase, and C kinase, and stimulates proliferation of fibroblasts. Pentoxifylline inhibits PDGF-driven proliferation of fibroblasts. We have reported that pentoxifylline did not inhibit binding of PDGF to its specific cell-surface receptors or PDGF receptor phosphorylation. In this study, we investigated the effect of PDGF on the expression of c-fos and c-jun, because c-fos and c-jun form activator protein-1 complexes that stimulate genes involved in proliferation. We determined whether pentoxifylline would alter the expression of c-fos and c-jun. Our results indicate that PDGF induced the expression of both c-fos and c-jun. Pentoxifylline effectively reduced c-jun gene expression, which had been up-regulated by PDGF, but did not alter c-fos gene expression. The lack of effect on c-fos supports other studies from this laboratory, which indicate that pentoxifylline did not inhibit PDGF activation of MAP kinase. Treatment of fibroblasts with a phosphothioate c-jun antisense oligodeoxynucleotide reduced the levels of c-Jun protein and blocked PDGF-stimulated proliferation, suggesting a critical role for c-jun in PDGF-mediated proliferation. Combination of pentoxifylline and c-jun antisense suggested that they were likely inhibiting PDGF-stimulated proliferation at a single site in the PDGF signaling pathway. These results suggest that pentoxifylline inhibits PDGF-stimulated proliferation by selectively decreasing c-jun expression. To further define the mechanism of action of pentoxifylline, we assessed the effect of pentoxifylline on c-Jun and phosphorylated c-Jun immunoreactivity in cells treated with PDGF and cells that were transfected with wild-type c-jun plasmid using immunocytochemistry and Western blot analyses, and our results indicate that pentoxifylline inhibited phosphorylation of c-Jun on serine 73.