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Matrix metalloproteinase 3 is present in the cell nucleus and is involved in apoptosis

Karim Si-Tayeb1, Arnaud Monvoisin, Claire Mazzocco

  • 1INSERM E362, Université Victor Segalen Bordeaux 2, 33076 Bordeaux, France.

The American Journal of Pathology
|September 28, 2006
PubMed

Insights

Matrix metalloproteinase (MMP)-3, a key enzyme in tissue remodeling, is found in the cell nucleus. Nuclear MMP-3 triggers apoptosis through its catalytic activity, offering new insights into cancer progression.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Oncology

Background:

  • Matrix metalloproteinase (MMP)-3 is implicated in cancer progression and tissue remodeling.
  • The intracellular localization of MMP-3, particularly in the nucleus, was previously uncharacterized.

Purpose of the Study:

  • To investigate the nuclear localization of MMP-3.
  • To determine the functional consequences of nuclear MMP-3.
  • To elucidate the mechanisms governing MMP-3 nuclear import.

Main Methods:

  • Immunofluorescence and immunoelectron microscopy to detect nuclear MMP-3.
  • Western blot analysis of nuclear extracts.
  • Transient transfection with enhanced green fluorescent protein (EGFP)-tagged MMP-3 constructs in Chinese hamster ovary (CHO) cells.
  • Site-directed mutagenesis to identify the nuclear localization signal (NLS) and catalytic activity.

Main Results:

  • MMP-3 was identified in the nucleus of cultured cells and human liver tissue.
  • Active MMP-3 (35-kd form) was detected in nuclear extracts and exhibited caseinolytic activity.
  • EGFP-tagged active MMP-3 (EGFP/aMMP-3) demonstrated nuclear translocation, mediated by a functional NLS.
  • Expression of nuclear-localized EGFP/aMMP-3 significantly increased apoptosis rates in CHO cells.
  • Apoptosis induction was dependent on MMP-3's catalytic activity, as it was blocked by catalytic site mutagenesis or MMP inhibitor GM6001.

Conclusions:

  • This study provides the first evidence for nuclear localization of MMP-3.
  • Nuclear MMP-3 can induce apoptosis through its catalytic activity.
  • The findings reveal novel mechanisms of MMP-3 intracellular transport and function, with implications for cancer therapy.

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