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.
Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Japan.
H
H
Noritake
H
H
Miyamori
C
C
Goto
M
M
Seiki
H
H
Sato
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