Glucocorticoid-modulated gene expression of tissue- and urinary-type plasminogen activator and plasminogen activator inhibitor 1 and 2

R. L. Medcalf, E. Van Den Berg, W. D. Schleuning

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Constitutive gene expression of four components of the plasminogen activating enzyme system, urinary and tissue-type plasminogen activator (u-PA and t-PA), plasminogen activator inhibitor 1 (PAI-1) and PAI-2 in HT-1080 human fibrosarcoma cells, was modulated by the synthetic glucocorticoid dexamethasone (Dex, 10-7 M). More than 90% of u-PA, t-PA and PAI-1 antigen was found in conditioned medium, whereas PAI-2 was mainly cell associated. In 48-h culture supernatants (expressed per 106 cells) PAI-1 antigen increased from 350 to 3,300 ng and t-PA from 19 to 38 ng. u-PA and PAI-2 in the same samples decreased from 380 to 46 ng and from 3.5 to 1.8 ng, respectively. Northern blot hybridization and nuclear 'Run-on' transcription assays demonstrated that the increase of t-PA and PAI-1 and the decrease of u-PA were associated with equivalent changes of gene template activity. Modulation of u-PA, t-PA, and PAI-1 gene expression by Dex was completely blocked by the glucocorticoid antagonist RU 38486, suggesting that all effects were mediated through the glucocorticoid receptor. Cycloheximide, an inhibitor of protein biosynthesis induced a rapid transient increase of t-PA, u-PA and PAI-1 mRNA and a sustained increase of PAI-2 mRNA, but blocked the more long term effects of Dex, suggesting that both constitutive and hormonally regulated maintenance of mRNA steady state levels required protein biosynthesis.

Original languageEnglish
Pages (from-to)971-978
Number of pages8
JournalJournal of Cell Biology
Issue number3
Publication statusPublished - 1 Jan 1988
Externally publishedYes

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