title: Beta-catenin is a mediator of the response of fibroblasts to irradiation.
abstract: Radiation causes soft tissue complications that include fibrosis and deficient wound healing. beta-Catenin, a key component in the canonical Wnt-signaling pathway, is activated in fibrotic processes and wound repair and, as such, could play a role in mediating cellular responses to irradiation. beta-Catenin can form a transcriptionally active complex with members of the Tcf family. A reporter mouse model, in addition to human cell cultures, was used to demonstrate that ionizing radiation activates beta-catenin-mediated, Tcf-dependent transcription both in vitro and in vivo. Furthermore, radiation activates beta-catenin via a Wnt-mediated mechanism, as in the presence of dickkopf-1, an inhibitor of Wnt receptor activation, beta-catenin levels did not increase after irradiation. Fibroblast cell cultures were derived from mice expressing either null or stabilized beta-catenin alleles. Cells expressing stabilized beta-catenin alleles had a higher proliferation rate and formed more colony-forming units than wild-type or null cells after irradiation. Wound healing was studied in these same mice after irradiation. There was a positive correlation between the tensile strength of the wound, the expression levels of type 1 collagen in the skin, and beta-catenin levels. Mice treated with lithium showed increased beta-catenin levels and increased wound strength. beta-Catenin mediates the effects of ionizing radiation in fibroblasts, and its modulation has the potential to decrease the severity of radiation-induced soft tissue complications.
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
authors.forename: Ananta
authors.initials: A
authors.lastname: Gurung
authors.forename: Faisal
authors.initials: F
authors.lastname: Uddin
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
authors.forename: Peter C
authors.initials: PC
authors.lastname: Ferguson
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000528:radiation effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects*; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051820:TCF Transcription Factors / Q000378:metabolism; D013718:Tensile Strength / Q000528:radiation effects; D014158:Transcription, Genetic / Q000528:radiation effects; D051153:Wnt Proteins / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology / Q000528:radiation effects; D051176:beta Catenin / Q000378:metabolism / Q000528:radiation effects*
chemical_list: D024042:Collagen Type I; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin