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  • Title: AP-1 transcription factor complex is a target of signals from both WnT-7a and N-cadherin-dependent cell-cell adhesion complex during the regulation of limb mesenchymal chondrogenesis.
    Author: Tufan AC, Daumer KM, DeLise AM, Tuan RS.
    Journal: Exp Cell Res; 2002 Feb 15; 273(2):197-203. PubMed ID: 11822875.
    Abstract:
    Wnt signaling has been implicated in the regulation of limb mesenchymal chondrogenesis. In this study, we have analyzed the molecular mechanism of Wnt-7a inhibition of chondrogenic differentiation by examining the involvement of mitogen-activated protein kinase (MAPK) pathways, i.e., Erk and p38. The combination of Wnt-7a misexpression and Erk inhibition partially recovers Wnt-7a inhibition of chondrogenic differentiation, whereas the combination of Wnt-7a misexpression and p38 inhibition acts in a synergistic chondro-inhibitory fashion. Although Wnt-7a misexpression has no direct effect on Erk signaling, it increases the activity of one of the ultimate targets of the MAPK pathway, c-jun, a major component of the activator protein-1 (AP-1) transcription factor complex. In addition, Wnt-7a misexpression enhances the activity of an AP-1 promoter-luciferase reporter construct by approximately 2.3-fold in vitro. Interestingly, misexpression of wild-type N-cadherin in these micromass cultures suppresses the activity of the same AP-1 promoter by approximately 40%, whereas misexpression of an extracellular 390-amino-acid N-terminal deletion mutant of N-cadherin has a stimulatory effect on the AP-1 promoter activity by approximately 2.6-fold. Thus, our results suggest that at least a part of the chondro-inhibitory effect of Wnt-7a misexpression may involve AP-1 transcription factor stimulation. Furthermore, a very tightly regulated level of AP-1 activity is necessary for the process of limb mesenchymal chondrogenesis, and signals from Wnt-ligands (e.g., Wnt-7a), cell adhesion molecules (e.g., N-cadherin), and MAPK pathways (e.g., Erk and p38) are interactively involved in this regulation.
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