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(American Journal of Pathology. 2006;169:1390-1401.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060005

Matrix Metalloproteinase 3 Is Present in the Cell Nucleus and Is Involved in Apoptosis

Karim Si-Tayeb*{dagger}, Arnaud Monvoisin*{dagger}, Claire Mazzocco*{dagger}, Sébastien Lepreux*{dagger}{ddagger}, Marion Decossas§{dagger}, Gaëlle Cubel*{dagger}, Danièle Taras*{dagger}, Jean-Frédéric Blanc*{dagger}, Derrick R. Robinson{ddagger}{dagger} and Jean Rosenbaum*{dagger}

From INSERM E362,* Bordeaux; Université Victor Segalen Bordeaux 2, Bordeaux; and IFR 66,{dagger} Bordeaux; CHU de Bordeaux,{ddagger} Hôpital Pellegrin, Service d’Anatomie Pathologique, Bordeaux; and CNRS,§ UMR 5162, Equipe ATIP: Interaction Mitochondrie-Cytosquelette chez les Trypanosomes Bordeaux, France

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.




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