Urokinase-type and tissue-type plasminogen activators as growth factors of human fibroblasts.
In this study we have verified the mitogenic effect of urokinase-type (u-PA) and tissue-type plasminogen activators (t-PA) on human normal fibroblasts. We report that both PAs can induce DNA replication and cell division in serum-deprived cultured human skin fibroblasts. The activity of u-PA and t-PA is, respectively, three- and twofold more potent than that exerted by epidermal growth factor (EGF) with an activity slightly lower (50-60%) than that induced by basic fibroblast growth factor (bFGF). The u-PA and t-PA, but not plasmin, induced DNA synthesis, which could be neutralized by anti-u-PA and anti-t-PA antibodies, respectively, but was insensitive to aprotinin treatment. The addition of anti-u-PA-receptor (u-PAR) monoclonal antibodies to the assays selectively suppressed the mitogenic effect exerted by u-PA, but not that of t-PA, and the amino-terminal fragment of u-PA, containing the EGF-like domain and the kringle module, did not elicit any mitogenic activity. Anti-bFGF antibodies completely suppressed the mitogenic activity of bFGF, but did not have any effect on that of u-PA and t-PA; the activity of both PAs was inhibited by anti-fibronectin IgG concentrations ineffective on bFGF. These results indicate that PAs may be considered growth factors of human fibroblasts.
Department of Biomedical Sciences and Biotechnologies, University of Brescia, Italy.
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G
De Petro
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A
Copeta
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Barlati
D000328:Adult; D000906:Antibodies / Q000494:pharmacology; D001345:Autoradiography; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004247:DNA / Q000032:analysis / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008934:Mitogens / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000276:immunology / Q000494:pharmacology*; D014316:Tritium; D014568:Urokinase-Type Plasminogen Activator / Q000276:immunology / Q000494:pharmacology*
D000906:Antibodies; D016895:Culture Media, Serum-Free; D005353:Fibronectins; D007074:Immunoglobulin G; D008934:Mitogens; D014316:Tritium; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D004247:DNA; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D013936:Thymidine