title: Stress Signals, Mediated by Membranous Glucocorticoid Receptor, Activate PLC/PKC/GSK-3β/β-catenin Pathway to Inhibit Wound Closure.
abstract: Glucocorticoids (GCs), key mediators of stress signals, are also potent wound healing inhibitors. To understand how stress signals inhibit wound healing, we investigated the role of membranous glucocorticoid receptor (mbGR) by using cell-impermeable BSA-conjugated dexamethasone. We found that mbGR inhibits keratinocyte migration and wound closure by activating a Wnt-like phospholipase (PLC)/ protein kinase C (PKC) signaling cascade. Rapid activation of mbGR/PLC/PKC further leads to activation of known biomarkers of nonhealing found in patients, β-catenin and c-myc. Conversely, a selective inhibitor of PKC, calphostin C, blocks mbGR/PKC pathway, and rescues GC-mediated inhibition of keratinocyte migration in vitro and accelerates wound epithelialization of human wounds ex vivo. This novel signaling mechanism may have a major impact on understanding how stress response via GC signaling regulates homeostasis and its role in development and treatments of skin diseases, including wound healing. To test tissue specificity of this nongenomic signaling mechanism, we tested retinal and bronchial human epithelial cells and fibroblasts. We found that mbGR/PLC/PKC signaling cascade exists in all cell types tested, suggesting a more general role. The discovery of this nongenomic signaling pathway, in which glucocorticoids activate Wnt pathway via mbGR, provides new insights into how stress-mediated signals may activate growth signals in various epithelial and mesenchymal tissues.
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Jozic
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia, USA.
authors.forename: Sasa
authors.initials: S
authors.lastname: Vukelic
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA; Immunology, Infection and Inflammation Graduate Program, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Olivera
authors.initials: O
authors.lastname: Stojadinovic
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA; Human Genomics and Genetics Graduate Program in Biomedical Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Horacio A
authors.initials: HA
authors.lastname: Ramirez
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Irena
authors.initials: I
authors.lastname: Pastar
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA; Human Genomics and Genetics Graduate Program in Biomedical Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA; Cellular and Molecular Pharmacology Graduate Program in Biomedical Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA. Electronic address: mtcanic@med.miami.edu.
authors.forename: Marjana
authors.initials: M
authors.lastname: Tomic Canic
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D011493:Protein Kinase C; D010738:Type C Phospholipases