Matrix metalloproteinase-1 associates with intracellular organelles and confers resistance to lamin A/C degradation during apoptosis.
Since the first description of matrix metalloproteinase (MMP)-1 as an interstitial collagenase, great importance has been ascribed to this enzyme in extracellular matrix remodeling during tumoral, inflammatory, and angiogenic processes. As more evidence for the role of MMPs in targeting nonmatrix substrates emerges, casual observations that intracellular MMP-1 is found in vitro and in vivo prompt investigation of the role that MMP-1 may play on basic cell functions such as cell division and apoptosis. Here we show for the first time that MMP-1 not only has extracellular functions but that it is strongly associated with mitochondria and nuclei and accumulates within the cells during the mitotic phase of the cell cycle. On induction of apoptosis, MMP-1 co-localized with aggregated mitochondria and accumulated around fragmented nuclei. Inhibition of this enzyme by RNA interference or treatment with a broad MMP inhibitor caused faster degradation of lamin A, activation of caspases, and fragmentation of DNA when compared with untreated cells. These observations strongly suggest that intracellular association of MMP-1 to mitochondria and nuclei confers resistance to apoptosis and may explain the well-known association of this enzyme with tumor cell survival and spreading.
Limb
G Astrid
GA
Department of Pathology, Institute of Ophthalmology, University College London and Moorfields Eye Hospital, 11 Bath St., London EC1V 9EL. g.limb@ucl.ac.uk
Matter
Karl
K
Murphy
Gillian
G
Cambrey
Alison D
AD
Bishop
Paul N
PN
Morris
Glenn E
GE
Khaw
Peng T
PT
D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology; D020868:Gene Silencing; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D008928:Mitochondria / Q000201:enzymology; D008938:Mitosis; D015388:Organelles / Q000201:enzymology*; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000201:enzymology; D019311:Staurosporine / Q000494:pharmacology; D014018:Tissue Distribution
D034904:Lamin Type A; D061965:Matrix Metalloproteinase Inhibitors; C440308:lamin C; D020169:Caspases; D020781:Matrix Metalloproteinase 1; D019311:Staurosporine