Urokinase-mediated transactivation of the plasminogen activator inhibitor type 2 (PAI-2) gene promoter in HT-1080 cells utilises AP-1 binding sites and potentiates phorbol ester-mediated induction of endogenous PAI-2 mRNA.
Urokinase-type plasminogen activator (u-PA) bound to its receptor, u-PAR, initiates signal transduction pathways able to induce expression of the activator protein-1 (AP-1) family member c-fos [1]. Since transcription factors bound to AP-1 recognition sequences within the PAI-2 gene promoter play a role in basal and phorbol ester-mediated induction of PAI-2 gene expression, we hypothesised that u-PA/u-PAR-mediated modulation of AP-1 activity would in turn influence constitutive and inducible PAI-2 gene expression. Treatment of HT-1080 or U-937 cells with high molecular weight u-PA (HMW u-PA) resulted in induction of nuclear proteins binding to a functional AP-1 element in the proximal PAI-2 promoter. This increase in AP-1 activity correlated with a transactivation of the PAI-2 gene promoter in transiently transfected HT-1080 cells. We also demonstrate the u-PA treatment potentiated phorbol ester (PMA)-mediated induction of PAI-2 mRNA, indicating that u-PA binding produces a bone fide response in vivo.
Dear
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Department of Medicine, Monash University, Victoria, Australia.
Costa
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Medcalf
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RL
D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D016384:Consensus Sequence; D005354:Fibrosarcoma; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments / Q000494:pharmacology; D017396:Plasminogen Activator Inhibitor 2 / Q000096:biosynthesis* / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*
D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D017396:Plasminogen Activator Inhibitor 2; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D015500:Chloramphenicol O-Acetyltransferase; D014568:Urokinase-Type Plasminogen Activator; D013755:Tetradecanoylphorbol Acetate