Posttranscriptional regulation of plasminogen activator inhibitor-1 in human lung carcinoma cells in vitro.
Plasminogen activator inhibitor-1 (PAI-1), the major circulating inhibitor of urokinase [urokinase-type plasminogen activator (uPA)], has been linked to the pathogenesis of lung cancer. PAI-1 belongs to the serpin family of inhibitors and inhibits both free urokinase (uPA) and receptor-bound urokinase (uPA receptor). Although PAI-1 has been related to a poor prognosis in lung carcinoma, mechanisms that regulate its expression in human lung cancer cells are not well understood. We used cultured human small cell and non-small cell lung carcinoma cell lines as model systems to elucidate the regulatory mechanisms that control expression of PAI-1. Levels of PAI-1 protein were significantly increased in selected lung carcinoma cells compared with those in normal small-airway epithelial cells. Corresponding steady-state levels of PAI-1 mRNA were similarly increased in these cells. The half-life of PAI-1 mRNA was prolonged in these lung carcinoma cell lines after transcriptional or translational blockade. We identified a 60-kDa protein that binds the 3'-untranslated region of PAI-1, and complex formation of this binding protein with PAI-1 mRNA reciprocally correlates with mRNA stability. The findings demonstrate that expression of PAI-1 is regulated at the posttranscriptional level in small cell- and non-small cell-derived human lung carcinoma cell lines. Altered regulation of PAI-1 at the posttranscriptional level may contribute to relative overexpression by malignant lung epithelial cells. A newly identified regulatory protein that binds to the 3'-untranslated region of PAI-1 mRNA appears to be involved in the posttranscriptional regulation of PAI-1 gene expression by human lung carcinoma cells in vitro.
Shetty
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Department of Medical Specialties, The University of Texas Health Center at Tyler, Tyler, Texas 75708, USA.
Idell
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D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017395:Plasminogen Activator Inhibitor 1; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins