NF-kappaB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death.
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.
Thyss
Raphaël
R
INSERM U634 Biologie et Physiopathologie Cutanée, UFR de Médecine, Nice, France.
Virolle
Virginie
V
Imbert
Véronique
V
Peyron
Jean-François
JF
Aberdam
Daniel
D
Virolle
Thierry
T
D000818:Animals; D016923:Cell Death / Q000502:physiology* / Q000528:radiation effects; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology / Q000528:radiation effects; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology / Q000528:radiation effects*; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D000097642:GADD45 Proteins
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011506:Proteins; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000097642:GADD45 Proteins; C497325:EGR1 protein, human