title: Transcriptional and posttranscriptional regulation of type 1 plasminogen activator inhibitor and tissue-type plasminogen activator gene expression in HTC rat hepatoma cells by glucocorticoids and cyclic nucleotides.
abstract: We have reported previously that incubation of HTC rat hepatoma cells with the synthetic glucocorticoid dexamethasone causes a 90% decrease in tissue-type plasminogen activator (tPA) activity secondary to a 4-fold increase in plasminogen activator inhibitor-1 (PAI-1) mRNA accumulation. Dexamethasone also induces a modest and transient increase in tPA mRNA. The cyclic nucleotide analog 8-bromo-cAMP (cA) causes a greater than 50-fold increase in PA activity, the result of a 90% decrease in PAI-1 and a sustained 2-fold increase in tPA mRNA accumulation. Dexamethasone and cA in combination cause a 150-fold increase in PA activity, the result of an 80% decrease in PAI-1 and a synergistic 15-fold increase in tPA mRNA. To determine the mechanism of this complex hormonal regulation, we have examined rates of synthesis and decay of PAI-1 and tPA mRNAs. Here we report that dexamethasone induces a 5-fold increase in PAI-1 gene transcription and does not significantly alter PAI-1 message decay; PAI-1 mRNA has a half-life of about 4 h in both untreated and dexamethasone-treated cells. In contrast, cA regulates PAI-1 mRNA by both decreasing the rate of PAI-1 gene transcription by 60% and accelerating the rate of PAI-1 message decay. Regulation of tPA by cA, both alone and in combination with dexamethasone, occurs primarily at the level of transcription. Dexamethasone and cA-induced tPA mRNA has a half-life of 2.75 h; tPA mRNA degradation is significantly inhibited by either cycloheximide or actinomycin-D.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor 48109-0618.
authors.forename: J H
authors.initials: JH
authors.lastname: Heaton
authors.forename: S
authors.initials: S
authors.lastname: Kathju
authors.forename: T D
authors.initials: TD
authors.lastname: Gelehrter
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D005938:Glucocorticoids / Q000502:physiology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D009712:Nucleotides, Cyclic / Q000502:physiology*; D015849:Plasminogen Inactivators / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D005938:Glucocorticoids; D009712:Nucleotides, Cyclic; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003907:Dexamethasone; D010959:Tissue Plasminogen Activator