Abstract |
The results of our previous study showed that tumor invasion and metastasis are promoted in extracellular matrix (ECM) tenascin-X-deficient (TNX-/-) mice via increased expression of matrix metalloproteinases ( MMPs). However, little is known about the relationship between TNX deficiency and activation of MMP genes. In this study, we investigated the molecular mechanism by which TNX deficiency activates the MMP-2 gene. We examined the intracellular signaling pathways that regulate gene expression of the proteinase in isolated fibroblasts. Results of gelatin zymography showed that MMP-2 was induced to a greater extent in TNX-/- fibroblasts embedded in type I collagen than in wild-type fibroblasts. RT-PCR analysis revealed that the increased level of MMP-2 expression was caused at the transcription level. Conversely, stable overexpression of TNX in a fibroblast cell line reduced MMP-2 expression and suppressed MMP-2 promoter activity. In addition, treatment of TNX-/- fibroblasts with SP600125, a c-Jun N-terminal kinase (JNK) inhibitor, and genistein, a tyrosine kinase inhibitor, suppressed the increased level of proMMP-2 and increased MMP-2 promoter activity in TNX-/- fibroblasts. Furthermore, increased activation of JNK and tyrosine phosphorylation of certain proteins were observed in TNX-/- fibroblasts. These findings suggest that induction of MMP-2 by TNX deficiency is mediated, at least in part, through the JNK and protein tyrosine kinase phosphorylation pathway.
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Authors | Ken-Ichi Matsumoto, Takeharu Minamitani, Yasuko Orba, Mami Sato, Hirofumi Sawa, Hiroyoshi Ariga |
Journal | Experimental cell research
(Exp Cell Res)
Vol. 297
Issue 2
Pg. 404-14
(Jul 15 2004)
ISSN: 0014-4827 [Print] United States |
PMID | 15212943
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Androstadienes
- Anthracenes
- Enzyme Inhibitors
- Flavonoids
- Imidazoles
- Proto-Oncogene Proteins c-jun
- Pyridines
- Tenascin
- tenascin X
- pyrazolanthrone
- Genistein
- Protein-Tyrosine Kinases
- Matrix Metalloproteinase 2
- SB 203580
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
- Wortmannin
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Topics |
- Androstadienes
(pharmacology)
- Animals
- Animals, Newborn
- Anthracenes
(pharmacology)
- Cells, Cultured
- Enzyme Activation
- Enzyme Inhibitors
(pharmacology)
- Fibroblasts
(enzymology, metabolism)
- Flavonoids
(pharmacology)
- Genistein
(pharmacology)
- Imidazoles
(pharmacology)
- Male
- Matrix Metalloproteinase 2
(genetics, metabolism)
- Mice
- Mice, Knockout
- Phosphorylation
- Protein-Tyrosine Kinases
(drug effects, metabolism)
- Proto-Oncogene Proteins c-jun
(metabolism)
- Pyridines
(pharmacology)
- Skin
(ultrastructure)
- Tenascin
(deficiency)
- Wortmannin
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