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The transcription factor Wilms tumor 1 regulates matrix metalloproteinase-9 through a nitric oxide-mediated pathway

Marcelo Marcet-Palacios1, Marina Ulanova, Florentina Duta

  • 1Glaxo-Heritage Asthma Research Laboraotries, Heritage Medical Research Center, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Journal of Immunology (Baltimore, Md. : 1950)
|June 21, 2007
PubMed

Insights

Wilms tumor 1 (WT1) acts as a repressor of matrix metalloproteinase-9 (MMP-9) in human lung cells. This regulation is mediated by a nitric oxide (NO)-dependent pathway, impacting MMP-9 expression in lung diseases.

Area of Science:

  • Molecular Biology
  • Pulmonary Medicine
  • Cellular Signaling

Background:

  • Matrix metalloproteinase-9 (MMP-9) expression in human lung epithelial cells (LEC) is linked to respiratory diseases like asthma and COPD.
  • While MMP-9 production is known to be modulated by NO/soluble guanylate cyclase pathways, its transcriptional regulation remains unclear.
  • Wilms tumor 1 (WT1) is a transcription factor with a conserved binding site in the MMP-9 gene's 5' flanking region.

Purpose of the Study:

  • To investigate the role of Wilms tumor 1 (WT1) in the transcriptional regulation of matrix metalloproteinase-9 (MMP-9) in human lung epithelial cells (LEC).
  • To elucidate the involvement of the NO/soluble guanylate cyclase pathway in the regulation of WT1's activity concerning MMP-9 expression.

Main Methods:

  • Phylogenetic analysis to identify conserved sequences in the MMP-9 gene promoter.
  • Detection of WT1 in LEC and assessment of its subcellular localization upon stimulation with TNF or LPS/PMA/IFN-gamma.
  • WT1 knockdown using siRNA and assessment of MMP-9 expression.
  • Inhibition of the NO/soluble guanylate cyclase pathway.
  • WT1 pulldown assays and chromatin immunoprecipitation (ChIP) to confirm WT1 binding to the MMP-9 promoter.

Main Results:

  • WT1 was confirmed to be present in human LEC and its translocation from the nucleus to the cytosol was observed upon stimulation.
  • This WT1 translocation correlated with increased MMP-9 expression and could be inhibited by NO/soluble guanylate cyclase pathway inhibitors.
  • WT1 knockdown led to increased MMP-9 expression, and WT1 was confirmed to bind to the MMP-9 promoter, indicating a repressor role.

Conclusions:

  • WT1 functions as a repressor of MMP-9 expression in human LEC, regulated by a NO-mediated pathway.
  • This study is the first to report WT1's regulation of MMP-9.
  • Further research is warranted to explore the potential role of reduced WT1 levels or activity in diseases characterized by tissue remodeling, such as asthma and COPD.

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