POSTTRANSCRIPTIONAL STABILIZATION OF UROKINASE PLASMINOGEN-ACTIVATOR MESSENGER-RNA BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN IN A HUMAN KERATINOCYTE CELL-LINE

The actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent rodent carcinogen and suspected human carcinogen, are mediated by the Ah receptor, a ligand-activated transcription factor. Genes altered by TCDD at the transcriptional level in the transformed human keratinocyte cell line SCC-12 F include cytochrome P4501Al (CYP1A1), CYP1B1, transforming growth factor-beta(2), and plasminogen activator inhibitor-2 (PAI-2). Plasminogen activators are serine proteases involved in a number of cell processes, including migration, proliferation, growth factor activation, and tumorigenesis. In this study we investigated the effect of TCDD on other members of the plasminogen activator family. We report that in addition to the transcriptional induction of PAI-2, treatment of SCC-12F cells with 10 nM TCDD also resulted in an increase in urokinase-plasminogen activator (u-PA) mRNA. Induction of u-PA mRNA was maximal by 12 hr and remained approximately twofold above control levels for the 48-hr assay period. Transcription of u-PA was not altered by TCDD as determined by nuclear runoff analysis. Instead, induction of u-PA occurred as a result of a stabilization of the u-PA mRNA following TCDD treatment. Tissue-plasminogen activator and PAI-1 expression were not altered by TCDD. Thus, TCDD acts through different mechanisms in SCC-12F cells to induce both a plasminogen activator and a specific inhibitor of plasminogen activation. These results, together with our earlier results showing an induction of TGF-alpha by TCDD as a result of a stabilization of the TGF-alpha mRNA, demonstrate the importance of both transcriptional and post-transcriptional events in the regulation of gene expression by TCDD. (C) 1995 Academic Press, Inc.