title: Matrix metalloproteinase 3 is present in the cell nucleus and is involved in apoptosis.
abstract: Matrix metalloproteinase (MMP)-3 is a protease involved in cancer progression and tissue remodeling. Using immunofluorescence and immunoelectron microscopy, we identified nuclear localization of MMP-3 in several cultured cell types and in human liver tissue sections. Western blot analysis of nuclear extracts revealed two immunoreactive forms of MMP-3 at 35 and 45 kd, with the 35-kd form exhibiting caseinolytic activity. By transient transfection, we expressed active MMP-3 fused to the enhanced green fluorescent protein (EGFP/aMMP-3) in Chinese hamster ovary cells. We showed that EGFP/aMMP-3 translocates into the nucleus. A functional nuclear localization signal was demonstrated by the loss of nuclear translocation after site-directed mutagenesis of a putative nuclear localization signal and by the ability of the MMP-3 nuclear localization signal to drive a heterologous protein into the nucleus. Finally, expression by Chinese hamster ovary cells of EGFP/aMMP-3 induced a twofold increase of apoptosis rate, compared with EGFP/pro-MMP-3, which does not translocate to the nucleus. Increased apoptosis was abolished by site-directed mutagenesis of the catalytic site of MMP-3 or by using the MMP inhibitor GM6001. This study elucidates for the first time the mechanisms of nuclear localization of a MMP and shows that nuclear MMP-3 can induce apoptosis via its catalytic activity.
authors.affiliation: INSERM E362, Université Victor Segalen Bordeaux 2, 33076 Bordeaux, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Si-Tayeb
authors.forename: Arnaud
authors.initials: A
authors.lastname: Monvoisin
authors.forename: Claire
authors.initials: C
authors.lastname: Mazzocco
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lepreux
authors.forename: Marion
authors.initials: M
authors.lastname: Decossas
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Cubel
authors.forename: Danièle
authors.initials: D
authors.lastname: Taras
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Blanc
authors.forename: Derrick R
authors.initials: DR
authors.lastname: Robinson
authors.forename: Jean
authors.initials: J
authors.lastname: Rosenbaum
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002467:Cell Nucleus / Q000201:enzymology*; D006224:Cricetinae; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D014407:Tumor Cells, Cultured
chemical_list: D019913:Nuclear Localization Signals; D019278:Matrix Metalloproteinase 3