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.
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.
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: A Cevik
authors.initials: AC
authors.lastname: Tufan
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Daumer
authors.forename: Anthony M
authors.initials: AM
authors.lastname: DeLise
authors.forename: Rocky S
authors.initials: RS
authors.lastname: Tuan
mesh_terms: D000818:Animals; D030161:Avian Proteins; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002642:Chick Embryo; D020219:Chondrogenesis / Q000502:physiology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D008648:Mesoderm / Q000166:cytology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics*; D051153:Wnt Proteins; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D030161:Avian Proteins; D015820:Cadherins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; C490509:WNT7A protein, Gallus gallus; D051153:Wnt Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases