Inhibition of casein kinase 1α in keratinocytes provides a potential UV protection strategy for melanocortin 1 receptor variants

Summary: Abstract Body: Variants in the melanocortin 1 receptor (MC1R) gene generating poor eumelanin formation have been documented with insufficient UV protection and increased risk of skin cancers. We have demonstrated that casein kinase (CK) 1α ablation in keratinocytes increases eumelanin production and melanocyte numbers by activating p53/KitL/c-Kit signaling pathway in wildtype mice. Since CK1α inhibition induced hyperpigmentation is independent of MC1R expression and UV sparing, we hypothesize CK1α inhibition in keratinocytes may serve as a rescue strategy for MC1R defective individuals. The aim of this translational research was to test this hypothesis. We first established the Mc1r-deficient mice Mc1r549del, and further established K14-CreERT2-CK1αfl/fl; Mc1r549del mice, in which CK1α can be selectively knockout in the keratinocytes of Mc1r549del by tamoxifen. The results showed CK1α inhibition in keratinocytes caused skin pigmentation in Mc1r549del mice with increased eumelanin formation, increased melanocyte numbers in epidermis, and decreased DNA damage during acute UVB exposure. Except skin, the hair color of Mc1r549del became darker with increased eumelanin in hair shafts. To tracing the melanocyte precursors’ behavior in hair follicle, we established Fusion Red-labelled-melanocyte reporter mice in Mc1r549del mice and examined the effects of topical CK inhibitor (CKI). Confocal microscopy showed increased numbers of melanocyte precursors in the hair germ and outer root sheath of hair follicle, and in the epidermis. RT-PCR and Western blotting showed up-regulation of p53/KitL/c-Kit/MITF/ tyrosinase signaling pathway in Mc1r549del mice. Treatment of CKI on human keratinocytes showed increased KitL expression; on human skin explants showed up-regulation of p53/KitL/c-Kit/MITF/tyrosinase signaling pathway, too. Thus, CK1 inhibition on skin provides a potential strategy to protect MC1R variants from UV damage. Chung-Hsing Chang^{2, 1}, Chao-Jung Chang¹ 1. Dermatology, Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan Province, Taiwan. 2. Dortoral Degree Program in Translational Medicine, Tzu Chi University, Hualien, Taiwan Province, Taiwan. UV Biology/Injury and Non-melanoma Cancers