Casein kinase 1α (CK1α), a component of the β-catenin destruction complex, is a critical regulator of Wnt signaling; its ablation induces both Wnt and p53 activation. To characterize the role of CK1α (encoded by Csnk1a1) in skin physiology, we crossed mice harboring floxed Csnk1a1 with mice expressing K14–Cre–ERT2 to generate mice in which tamoxifen induces the deletion of Csnk1a1 exclusively in keratinocytes [single-knockout (SKO) mice]. As expected, CK1α loss was accompanied by β-catenin and p53 stabilization, with the preferential induction of p53 target genes, but phenotypically most striking was hyperpigmentation of the skin, importantly without tumorigenesis, for at least 9 mo after Csnk1a1 ablation. The number of epidermal melanocytes and eumelanin levels were dramatically increased in SKO mice. To clarify the putative role of p53 in epidermal hyperpigmentation, we established K14–Cre–ERT2 CK1α/p53 double-knockout (DKO) mice and found that coablation failed to induce epidermal hyperpigmentation, demonstrating that it was p53-dependent. Transcriptome analysis of the epidermis revealed p53-dependent up-regulation of Kit ligand (KitL). SKO mice treated with ACK2 (a Kit-neutralizing antibody) or imatinib (a Kit inhibitor) abrogated the CK1α ablation-induced hyperpigmentation, demonstrating that it requires the KitL/Kit pathway. Pro-opiomelanocortin (POMC), a precursor of α-melanocyte–stimulating hormone (α-MSH), was not activated in the CK1α ablation-induced hyperpigmentation, which is in contrast to the mechanism of p53-dependent UV tanning. Nevertheless, acute sunburn effects were successfully prevented in the hyperpigmented skin of SKO mice. CK1α inhibition induces skin-protective eumelanin but no carcinogenic pheomelanin and may therefore constitute an effective strategy for safely increasing eumelanin via UV-independent pathways, protecting against acute sunburn.
|Proceedings of the National Academy of Sciences of the United States of America
|Published - 19 Sep 2017
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank Dr. Che-Hung Shen for his helpful discussion and assistance with Supporting Information preparation. This work was supported by Taiwan Ministry of Science and Technology Grants103-2314-B-037-065 and 104-2314-B-037-011-MY3; Taiwan National Health Research Institute Grant EX104-105-10402BI; Taiwan Academia Sinica Institute of Biomedical Sciences Grant CRC105-P04; the Israel Science Foundation Centers of Excellence; European Research Council Within the Seventh Framework Programme Grant 294390 PICHO; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Israel Cancer Research Fund; and Japan Society for the Promotion of Science Grants 26461705 and 15K09794.
© 2017, National Academy of Sciences. All rights reserved.
- Casein kinase 1α
- Kit ligand