Overexpression of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in metastatic MDCK cells transformed by v-src.
This article discusses the transformation of epithelial Madin-Durby canine kidney (MDCK) cells with v-src induced expression of membrane-type 1-matrix metalloproteinase (MT1-MMP) and metastatic growth in nude mice (Kadono Y et al., Cancer Res 1998; 58: 2240-44). To analyze genes associated with invasive phenotype of v-src MDCK cells, mRNA differential display was performed between control and the transformed cells. A clone 12', the expression of which was clearly up-regulated in the transformed cells, encoded a protein 81% homologous to human tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Northern hybridization showed that only MT1-MMP expression was enhanced and other matrix metalloproteinases (MMPs) were undetectable or rather repressed in the transformed cells. Proteolytic activity against type I gelatin was observed in v-src MDCK cells, which was inhibited only by TIMP-2 but not by TIMP-1. MDCK cells stably transfected with the MT1-MMP gene also degraded gelatin, which was selectively inhibited by TIMP-2. These results suggest that MT1-MMP, the expression of which is induced in v-src MDCK cells, degrades extracellullar matrix by itself rather than through the activation of progelatinase A, which in turn contributes to the metastasis of the transformed cells.
Noritake
H
H
Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Japan.
Miyamori
H
H
Goto
C
C
Seiki
M
M
Sato
H
H
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D017364:Collagenases / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism*; D005780:Gelatin / Q000378:metabolism; D016391:Genes, src / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D007680:Kidney Neoplasms / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018076:DNA, Complementary; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D005780:Gelatin; D017364:Collagenases; D020781:Matrix Metalloproteinase 1