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

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 ) in skin physiology, we crossed mice harboring floxed with mice expressing K14-Cre-ER to generate mice in which tamoxifen induces the deletion of 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 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-ER 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.

Casein kinase 1α: biological mechanisms and theranostic potential

“…CK1α was recently reported that CK1α participates in p53-dependent paracrine factor secretion in skin hyperpigmentation [ 230 ]. Future studies will likely provide additional evidence of a role for CK1α in secretion.…”

FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning

“…Recently, lenalidomide-induced degradation of CK1a was shown to be effective in the treatment of pre-leukemic human myelodysplastic syndrome (MDS) (Stahl & Zeidan, 2017). Similarly, genetic ablation of CK1a has been shown to activate the tumour suppressor p53, suggesting CK1a could make an anti-cancer target (Chang, Kuo et al, 2017, Chen, Li et al, 2005. Yet, other studies have demonstrated that CK1 inhibitors stabilise b-catenin and activate Wnt signalling, which promotes cell proliferation (MacDonald, Tamai et al, 2009, Schittek & Sinnberg, 2014, Teo & Kahn, 2010.…”

Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia

“…Casein kinase 1α (CK1α), encoded by CSNK1A1 , is a classical negative regulator for the Wnt/β-catenin signaling pathway ( 14 ). In addition to Wnt/β-catenin signaling, CK1α also regulates p53, GLI transcription factors and other important signaling pathways ( 15 – 17 ). CK1α has been reported to be implicated in apoptosis, survival, senescence and other cellular physiological processes, thus regulating the occurrence and development of multiple tumors ( 17 , 18 ).…”