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Role of nucleolin in posttranscriptional control of MMP-9 expression

Michael Fähling1, Andreas Steege, Andrea Perlewitz

  • 1Charité, Universitätsmedizin Berlin, Institut für Vegetative Physiologie, 10117 Berlin, Germany. Michael.Faehling@charite.de

Biochimica Et Biophysica Acta
|September 13, 2005
PubMed

Insights

Iron chelator treatment rapidly increases Matrix-metalloproteinase-9 (MMP-9) protein levels by enhancing translation efficiency, not mRNA levels. This posttranscriptional regulation involves the 3' untranslated region of MMP-9 mRNA and nucleolin binding.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Matrix-metalloproteinases (MMPs) degrade extracellular matrix (ECM) components, playing key roles in physiological and pathophysiological processes.
  • MMP-9 is implicated in conditions such as cancer metastasis and fibrosis.
  • Hypoxia is known to influence MMP expression, but the underlying regulatory mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the effect of an iron chelator, mimicking hypoxia, on Matrix-metalloproteinase-9 (MMP-9) expression in HT1080 cells.
  • To elucidate the regulatory mechanisms, specifically at the posttranscriptional level, controlling MMP-9 expression.
  • To identify key mRNA elements and protein factors involved in MMP-9 translational regulation.

Main Methods:

  • Treatment of HT1080 fibrosarcoma cells with the iron chelator 2,2-Dipyridyl.
  • Quantification of MMP-9 protein and mRNA levels.
  • Reporter gene assays utilizing untranslated regions (UTRs) of MMP-9 mRNA.
  • RNA/protein interaction studies to identify binding partners.

Main Results:

  • 2,2-Dipyridyl treatment caused a rapid, 3-fold increase in MMP-9 protein levels within 3 hours, without altering mRNA concentration.
  • The observed increase in MMP-9 expression was attributed to enhanced translational efficiency.
  • Reporter gene assays indicated that the 3'UTR of MMP-9 mRNA is critical for this posttranscriptional regulation.
  • Elevated binding of nucleolin to the MMP-9 3'UTR was identified as a key factor in promoting MMP-9 translation.

Conclusions:

  • MMP-9 expression is regulated posttranscriptionally through modulation of translational efficiency.
  • The 3'UTR of MMP-9 mRNA plays a crucial role in this regulation.
  • Nucleolin binding to the 3'UTR is a significant mechanism for enhancing MMP-9 translation, particularly under conditions mimicking hypoxia.

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