CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation

Chung Hsing Chang, Che Jung Kuo, Takamichi Ito, Yu Ya Su, Si Tse Jiang, Min Hsi Chiu, Yi Hsiung Lin, Andrea Nist, Marco Mernberger, Thorsten Stiewe, Shosuke Ito, Kazumasa Wakamatsu, Yi An Hsueh, Sheau Yann Shieh, Irit Snir-Alkalay, Yinon Ben-Neriah

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Abstract

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.

Original languageEnglish
Pages (from-to)E8035-E8044
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number38
DOIs
Publication statusPublished - Sep 19 2017

All Science Journal Classification (ASJC) codes

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    Chang, C. H., Kuo, C. J., Ito, T., Su, Y. Y., Jiang, S. T., Chiu, M. H., Lin, Y. H., Nist, A., Mernberger, M., Stiewe, T., Ito, S., Wakamatsu, K., Hsueh, Y. A., Shieh, S. Y., Snir-Alkalay, I., & Ben-Neriah, Y. (2017). CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation. Proceedings of the National Academy of Sciences of the United States of America, 114(38), E8035-E8044. https://doi.org/10.1073/pnas.1702763114