PubMed · 11403003
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R Chilton. 2000. Web alert.. https://pubmed.ncbi.nlm.nih.gov/11403003/
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Emerging data suggest that urokinase-type plasminogen activator (UPA), beyond its role in pericellular proteolysis, may also act as a mitogen. We investigated the function of endogenous UPA in mediating the mitogenic effects of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) on human vascular smooth muscle cells (SMC). Growth-arrested SMC constitutively expressed UPA, but UPA expression and secretion increased several times upon stimulation with either PDGF or bFGF. Inhibition of endogenous UPA with a polyclonal antibody significantly reduced DNA synthesis and proliferation of PDGF or bFGF stimulated SMC, this effect already being evident when the cells entered S-phase. The proliferative activity of endogenous UPA was dependent on a functional catalytic domain as demonstrated by inhibition experiments with a specific monoclonal antibody (394OA) and p-aminobenzamidine, respectively. In contrast, neither plasmin generation nor binding of UPA to its receptor (CD87) were required for UPA-mediated mitogenic effects. The results demonstrate that endogenous UPA is not only overexpressed in SMC upon stimulation with PDGF/bFGF, but also mediates the mitogenic activity of the growth factors in a catalytic-domain-dependent manner. Specific inhibition of this UPA domain may represent an attractive target for pharmacological interventions in atherogenesis and restenosis after angioplasty.
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The FasL/Fas system has been implicated in smooth muscle cell apoptosis and atherosclerotic plaque instability, a process that can lead to plaque rupture, precipitating myocardial infarction and sudden death. The transcriptional mechanisms regulating FasL gene expression in vascular smooth muscle cells are poorly understood. We recently described a novel mechanism mediating inducible FasL gene expression in smooth muscle cells involving the zinc finger transcription factor Sp1 (Kavurma, M. M., Santiago, F. S., Bofocco, E., and Khachigian, L. M. (2001) J. Biol. Chem. 276, 4964-4971). We now show that FasL gene expression is governed by cooperative activation between Sp1 and the Ets family of transcription factors. The overexpression of Ets-1 was sufficient to induce FasL promoter-dependent expression and protein synthesis. Ets-1 activation of the promoter was abrogated either by deletion or mutation of the Sp1 binding site. The overexpression of Ets-1 together with Sp1 produced cooperative activation of the FasL promoter. Sp1 induction of the FasL promoter was abrogated by an Ets-1 mutant lacking the activation domain. Conversely, Ets-1 activation of the promoter was blocked by an Sp1 mutant bearing the DNA-binding domain. The mutation of the (-365)GGAA(-362) element in the FasL promoter abolished Ets-1 activation and attenuated Sp1-inducible gene expression. Immunoprecipitation and supershift experiments revealed that endogenous Ets-1 and Sp1 physically interact and co-occupy this site. Thus, FasL gene expression in vascular smooth muscle cells is mediated by cooperativity between Ets-1 and Sp1.