bromochloroacetic-acid and Radiodermatitis

The intermediate filament protein keratin 17 (Krt17) shows highly dynamic and inducible expression in skin physiology and pathology. Because Krt17 exerts physiologically important functions beyond providing structural stability to keratinocytes whereas abnormal Krt17 expression is a key feature of dermatoses such as psoriasis and pachyonychia congenita, the currently unclear regulation of Krt17 expression needs to be better understood. Using a rat model of radiation dermatitis, we report here that Krt17 expression initially is down-regulated but later is strongly up-regulated by ionizing radiation. The early down-regulation correlates with the activation of p53 signaling. Deletion of p53 abolishes the initial down-regulation but not its subsequent up-regulation, suggesting that p53 represses Krt17 transcription. Because previous work reported up-regulation of Krt17 by ultraviolet irradiation, which also activates p53 signaling, the effect of ultraviolet radiation was reexamined. This revealed that the initial down-regulation of Krt17 is conserved, but the up-regulation comes much faster. Chromatin immunoprecipitation analysis in vivo and electromobility shift assay in vitro identified two p53-binding sites in the promoter region of Krt17. Thus, p53 operates as a direct Krt17 repressor, which invites therapeutic targeting in dermatoses characterized by excessive Krt17 expression.

Topics: Animals; Disease Models, Animal; DNA Damage; Down-Regulation; Gene Expression Regulation; Immunohistochemistry; Keratins; Mice; Mice, Inbred C57BL; Polymerase Chain Reaction; Promoter Regions, Genetic; Protein Binding; Radiodermatitis; Random Allocation; Rats; Rats, Wistar; Sensitivity and Specificity; Tumor Suppressor Protein p53

Moderate hyperplasia of Merkel cells (MC) in chronic sun-damaged skin and hypertrophic actinic keratoses is well known. In the present study we investigated the number of MC in 24 samples of chronic radiation dermatitis and 19 cases of fibroepithelioma of Pinkus (FP), which is known to arise preferably in radiation-damaged skin. Using antibodies against the low molecular weight cytokeratins 8, 18, and 20 and chromogranin A to visualize MC, we found hyperplasia of MC in chronic radiation dermatitis. Additionally, in all FPs we could detect many MC, especially in areas with a pronounced fenestrated pattern. Recently, regulative functions of MC on the growth of follicular epithelium under various conditions were discussed. Thus, MC hyperplasia suggests a causal role also in the development of FP. In this context, hyperplasia of MC in chronic radiation dermatitis could explain the frequent occurrence of FP due to radiation exposure. As we recently found MC also in trichoblastomas but not in basal-cell carcinomas, the MC in FP may indicate its relationship to the benign trichoblastoma rather than to the basal-cell carcinoma. It is possible that regulative influences of the MC are important for the clinically rather benign course of FP.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Basal Cell; Chromogranin A; Chromogranins; Female; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratins; Male; Merkel Cells; Radiodermatitis; Skin Neoplasms

Topics: Adolescent; Erythema; Female; Humans; Keratins; Radiodermatitis; Skin; Ultraviolet Rays