Regulation of the human plasminogen activator inhibitor type 2 gene: cooperation of an upstream silencer and transactivator

J Biol Chem. 2012 Mar 23;287(13):10579-10589. doi: 10.1074/jbc.M111.318758. Epub 2012 Feb 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogens / pharmacology
  • Enzyme Activators / pharmacology
  • HeLa Cells
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Macrophages / cytology
  • Macrophages / metabolism
  • Models, Biological*
  • Monocytes / cytology
  • Monocytes / metabolism
  • Plasminogen Activator Inhibitor 2 / biosynthesis*
  • Plasminogen Activator Inhibitor 2 / genetics
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • Response Elements / physiology*
  • Silencer Elements, Transcriptional / physiology*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology*
  • U937 Cells

Substances

  • Carcinogens
  • Enzyme Activators
  • FOSB protein, human
  • Plasminogen Activator Inhibitor 2
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Protein Kinase C
  • Tetradecanoylphorbol Acetate