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.
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)
Heaton
J H
JH
Department of Human Genetics, University of Michigan Medical School, Ann Arbor 48109-0618.
Kathju
S
S
Gelehrter
T D
TD
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
D005938:Glucocorticoids; D009712:Nucleotides, Cyclic; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003907:Dexamethasone; D010959:Tissue Plasminogen Activator