NF-κB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death

• DOI: 10.1038/sj.emboj.7600501
• Publication Date: 2004-12-23T12:24:09Z
• Authors: Raphaël Thyss; Virginie Virolle; Véronique Imbert; Jean-François Peyron; Daniel Aberdam; Thierry Virolle
• Keywords: Mice, Knockout; 0303 health sciences; Cell Death; DNA Repair; Cell Survival; Intracellular Signaling Peptides and Proteins; NF-kappa B; Epithelial Cells; Immediate-Early Proteins; DNA-Binding Proteins; Mice; 03 medical and health sciences; Epidermal Cells; Gene Expression Regulation; Animals; Humans; Epidermis; Promoter Regions, Genetic; Cells, Cultured; DNA Damage; Early Growth Response Protein 1; Protein Binding

Chronic sun exposure can lead to severe skin disorders such as carcinogenesis. The cell death process triggered by ultraviolet B (UVB) irradiation is crucial because it protects the surrounding tissue from the emergence and the accumulation of cells that bear the risk of becoming transformed. Here, we show that repression of NF-kappaB and Egr-1 expression drastically inhibits UVB-mediated cell death. Furthermore, we demonstrate that Egr-1 is induced upon UVB irradiation through NF-kappaB activation and the binding of p65/RelA within the Egr-1 promoter. We show that Egr-1 contributes to the regulation of the Gadd45a and Gadd45b genes, which are involved in the control of cell cycle, DNA repair and apoptosis, by direct binding to their promoter. Our study demonstrates for the first time a signaling cascade involving sequential activation of NF-kappaB, Egr-1 and Gadd45 to induce UVB-mediated cell death. Failure in the induction of each protagonist of this pathway alters the UVB-mediated cell death process. Therefore, impairment of the cascade could be at the onset of skin carcinogenesis mediated by genotoxic stress.