Growth factors regulate beta-catenin-mediated TCF-dependent transcriptional activation in fibroblasts during the proliferative phase of wound healing.
Beta-catenin is a critical regulator of cell behavior during embryogenesis and neoplastic processes. It also plays a crucial role in repair by modulating dermal fibroblast activity during the proliferative phase of cutaneous wound healing. We hypothesize that growth factors liberated during the initial phase of wound healing convey signals to induce activation of beta-catenin-mediated TCF-dependent signaling during the proliferative phase. Dermal fibroblasts were isolated and cultured from mice containing a beta-galactosidase reporter responsive to beta-catenin-TCF transactivation (TCF-beta-gal). Cells were stimulated with growth factors present at the initial phase of wound healing. EGF and TGF-beta1 significantly increased beta-catenin protein levels and transcriptional activity, whereas beta-catenin mRNA expression was unaffected. This increase was attributed to inactivation of GSK-3beta, a kinase important for beta-catenin destabilization. Subcutaneous injection of EGF or TGF-beta1 before wounding of TCF-beta-gal mice resulted in larger scars and fibroblasts within these wounds that strongly stained for beta-galactosidase, indicating significant beta-catenin transcriptional activity in vivo. Thus, beta-catenin-mediated signaling is activated downstream of growth factors released during the initial phase of wound repair, and may act during the proliferative phase of wound healing to integrate signals from initial phase factors into the expression of genes important during the later, remodeling phase.
Cheon
Sophia S
SS
Program in Developmental Biology, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Nadesan
Puviindran
P
Poon
Raymond
R
Alman
Benjamin A
BA
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002921:Cicatrix / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020405:Dermis / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006133:Growth Substances / Q000378:metabolism* / Q000494:pharmacology; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics*; D051176:beta Catenin; D001616:beta-Galactosidase / Q000235:genetics
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D006133:Growth Substances; D051821:Lymphoid Enhancer-Binding Factor 1; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D004815:Epidermal Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D001616:beta-Galactosidase