Elsevier

Experimental Cell Research

Volume 273, Issue 2, 15 February 2002, Pages 197-203
Experimental Cell Research

Regular Article
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

https://doi.org/10.1006/excr.2001.5448Get rights and content

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 ∼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 ∼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 ∼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.

References (30)

  • M Madhavan et al.

    Cadherins as predictive markers of nodal metastasis in breast cancer

    Mod. Pathol.

    (2001)
  • C.B Knudson et al.

    The chondrocyte pericellular matrix: A model for hyaluronan-mediated cell-matrix interactions

    Biochem. Soc. Trans.

    (1999)
  • A.C Tufan et al.

    Wnt regulation of Limb mesenchymal chondrogenesis is accompanied by altered N-cadherin-related functions

    FASEB J.

    (2001)
  • S.R Siddhanti et al.

    Molecular to pharmacologic control of osteoblast proliferation and differentiation

    J. Cell. Biochem.

    (1994)
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    To whom correspondence and reprint requests should be addressed at Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 13, 3W17, MSC 5755, Bethesda, MD 20892-5755. Fax: (301) 480-4315. E-mail: [email protected].

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