title: Regulation of the human plasminogen activator inhibitor type 2 gene: cooperation of an upstream silencer and transactivator.
abstract: Transcriptional up-regulation of the plasminogen activator inhibitor type-2 (PAI-2) gene is a major response to cellular stress. The expression of PAI-2 is induced by a variety of cytokines and growth factors that act in a cell type- and differentiation stage-dependent manner. We previously reported that the human SERPINB2 gene promoter is controlled by three major transcription regulatory domains: an inducible proximal promoter, an upstream silencer (PAUSE-1), and a distal transactivator region between -5100 and -3300, which appears to overcome inhibition mediated by the silencer. The distal transactivator region is inducible by the phorbol ester PMA, a potent activator of the protein kinase C (PKC) pathway that is a powerful inducer of PAI-2 gene expression in monocytes, macrophages, and myelomonocytic cells as well as in epidermal keratinocytes. Here we show that a 21-bp region (-4952/-4932), containing an AP-1 element, is both necessary and sufficient for PMA-induced transactivator activity in PAI-2-expressing U937 cells. This site specifically binds FosB in PAI-2-expressing U937 cells but not in HeLa cells that do not express PAI-2, and overexpression of FosB, c-Fos, or c-Jun in HeLa cells is sufficient to cause derepression of transcription from the SERPINB2 promoter. Although FosB is likely to be involved in transactivator-mediated derepression of PAI-2 transcription in macrophage-like cells, as exemplified by the U937 cell line, c-Jun may be functional in other cell types. These data suggest a model for the transcriptional control of the human PAI-2 gene and further our understanding of the molecular basis for its tissue-specific expression.
authors.affiliation: University of Queensland and Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.
authors.forename: Brett
authors.initials: B
authors.lastname: Stringer
authors.affiliation: Center for Vascular and Inflammatory Diseases and Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201 and.
authors.forename: Ekemini A
authors.initials: EA
authors.lastname: Udofa
authors.affiliation: Center for Vascular and Inflammatory Diseases and Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201 and. Electronic address: tantalis@som.umaryland.edu.
authors.forename: Toni M
authors.initials: TM
authors.lastname: Antalis
mesh_terms: D002273:Carcinogens / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D017396:Plasminogen Activator Inhibitor 2 / Q000096:biosynthesis* / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology*; D037941:Silencer Elements, Transcriptional / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D020298:U937 Cells
chemical_list: D002273:Carcinogens; D020536:Enzyme Activators; C064269:FOSB protein, human; D017396:Plasminogen Activator Inhibitor 2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate