| Autor: |
Kajanne, Risto, Miettinen, Päivi, Mehlem, Annika, Leivonen, Suvi-Katri, Birrer, Michael, Foschi, Marco, Kähäri, Veli-Matti, Leppä, Sirpa |
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| Zdroj: |
Journal of Cellular Physiology; Aug2007, Vol. 212 Issue 2, p489-497, 9p, 4 Black and White Photographs, 3 Graphs |
| Abstrakt: |
EGF-R regulates cell proliferation, migration, and invasion in fibroblasts. However, the connection of EGF-R with downstream signaling pathways mediating these responses has remained elusive. Here we provide genetic and biochemical evidence that EGF-R- and AP-1-mediated signals are required for MMP expression and collagen contraction in fibroblasts. In EGF-R (-/-) mouse embryonal fibroblasts, basal and inducible expression of several MMPs, including MMP-2, -3, and -14 is impaired in comparison to wild-type counterparts. The loss of MMP expression is associated with a suppression of EGF-induced Erk and Jnk activities, and AP-1 DNA-binding and transactivation capacities. While inhibition of Jnk mainly prevents EGF-induced phosphorylation of c-Jun, inhibition of Erk pathway suppresses both the expression and phosphorylation of c-Jun and c-Fos proteins. Moreover, the expression of MMP-3 and -14, and collagen contraction is partially prevented by Mek/Erk and Jnk inhibitors. However, Jnk inhibitor also suppresses cell growth independently of EGF-R activity. The central role of AP-1 as a mediator of EGF-R signaling in fibroblasts is emphasized by the finding that expression of a dominant negative c-Jun downregulates the expression of MMP-3. Conversely, expression of a constitutively active Mek1 can induce MMP-3 expression independently of upstream signals. The results indicate that ERK pathway and AP-1 are downstream effectors of the EGF-R-mediated MMP-3 expression and collagen contraction in fibroblasts. J. Cell. Physiol. 212: 489–497, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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