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 ro dent carcinogen and suspected human carcinogen, are mediated by the Ah receptor, a ligand-activated transcription factor. Genes altered by T CDD at the transcriptional level in the transformed human keratinocyte cell line SCC-12 F include cytochrome P4501Al (CYP1A1), CYP1B1, trans forming growth factor-beta(2), and plasminogen activator inhibitor-2 ( PAI-2). Plasminogen activators are serine proteases involved in a numb er of cell processes, including migration, proliferation, growth facto r activation, and tumorigenesis. In this study we investigated the eff ect of TCDD on other members of the plasminogen activator family. We r eport that in addition to the transcriptional induction of PAI-2, trea tment 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 w as maximal by 12 hr and remained approximately twofold above control l evels for the 48-hr assay period. Transcription of u-PA was not altere d 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 foll owing TCDD treatment. Tissue-plasminogen activator and PAI-1 expressio n were not altered by TCDD. Thus, TCDD acts through different mechanis ms in SCC-12F cells to induce both a plasminogen activator and a speci fic inhibitor of plasminogen activation. These results, together with our earlier results showing an induction of TGF-alpha by TCDD as a res ult of a stabilization of the TGF-alpha mRNA, demonstrate the importan ce of both transcriptional and post-transcriptional events in the regu lation of gene expression by TCDD. (C) 1995 Academic Press, Inc.