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

Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E8035-E8044. doi: 10.1073/pnas.1702763114. Epub 2017 Sep 6.


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.

Keywords: Kit ligand; casein kinase 1α; melanocyte; p53; sunburn.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Casein Kinase I / antagonists & inhibitors
  • Casein Kinase I / genetics
  • Casein Kinase I / metabolism*
  • Epidermis / metabolism
  • Epidermis / pathology
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • Melanins / biosynthesis
  • Melanins / genetics
  • Melanocytes / metabolism
  • Melanocytes / pathology
  • Mice
  • Mice, Knockout
  • Skin Pigmentation*
  • Sunburn / genetics
  • Sunburn / metabolism*
  • Sunburn / pathology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Melanins
  • Tumor Suppressor Protein p53
  • beta Catenin
  • eumelanin
  • Casein Kinase I