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Effect of thrombin, the thrombin receptor activation peptide, and other
mitogens on vascular smooth muscle cell urokinase receptor mRNA levels
U Reuning, SP Little, EP Dixon and NU Bang
Lilly Research Laboratory, Indianapolis, IN.
Bovine vascular smooth muscle cells (SMC) express the urokinase-type
plasminogen activator receptor (u-PAR) claimed to be important in cell
invasion. Receptor numbers and affinity are regulated by thrombin and
several other mitogens involved in SMC proliferation. We investigated the
effects of these mitogens on u-PAR mRNA levels. On continuous thrombin
stimulation the u-PAR message in SMC was 10 +/- 2.3-fold elevated reaching
a maximum between 6 and 9 hours and declining to control values within 48
hours. Thrombin present for 30 minutes on the cell surface produced similar
effects. Stimulation with the thrombin receptor activation peptide
S-F-L-L-R-N representing the NH2-terminus of the tethered ligand also
increased u-PAR mRNA levels with an identical time course.
D-Phe-Pro-Arg-chloromethyl ketone (PPACK) active site blocked thrombin and
the catalytically inactive thrombin mutant S205A did not affect u-PAR mRNA
levels. Thrombin stimulation also resulted in a 2 +/- 0.2-fold transient
increase in thrombin receptor mRNA preceding the rise in u-PAR message.
Transforming growth factor beta 1 (TGF beta 1) and platelet-derived growth
factor (PDGF) showed similar time courses for the elevation of u-PAR mRNA
levels with a maximal 5.5 +/- 0.9 and 12 +/- 2.5-fold increase,
respectively. Basic fibroblast growth factor (bFGF) and phorbol myristate
acetate (PMA) showed a more prolonged effect increasing u-PAR mRNA levels 8
+/- 2.0- fold and 12.3 +/- 2.5-fold, respectively, within 6 hours but
remaining 5 to 10-fold elevated at 48 hours. In order to decide if the
u-PAR mRNA increase was due to message stabilization or a consequence of
transcriptional activation we used the RNA polymerase II inhibitor 5,6-
dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB) during the stimulation
experiments. u-PAR mRNA levels on TGF beta 1 stimulation of SMC decayed
after the addition of DRB indicating that enhancement of transcriptional
activity was involved in the induction. In contrast, the time course of
u-PAR mRNA elevation on thrombin, bFGF, and PMA stimulation was not
significantly altered in the presence of DRB suggesting that in these
latter cases u-PAR mRNA message accumulation was at least in part due to
mRNA stabilization. Increased transcriptional activity, mRNA stabilization
and expression of u-PAR protein on the SMC surface in response to growth
factors may facilitate enhanced cell surface protease activity, cell
migration, and development of atheromatous lesions.
Volume 84,
Issue 11,
pp. 3700-3708,
12/01/1994
Copyright © 1994 by The American Society of Hematology
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