CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation
CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation
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DOI：
10.1073/pnas.1702763114
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发表时间：
2017-09-19
影响因子：
11.1
通讯作者：
Ben-Neriah, Yinon
中科院分区：
文献类型：
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作者：
Chang, Chung-Hsing;Kuo, Che-Jung;Ben-Neriah, Yinon
酪蛋白激酶1α(CK1α)是β-连环素破坏复合体的一个组成部分，是Wnt信号的关键调节因子；它的消融可以诱导Wnt和P53的激活。为了研究Csnk1α基因在皮肤生理学中的作用，我们将含有Csnk1α1基因的小鼠与表达K14-Cre-ERT2基因的小鼠杂交，产生了他莫昔芬只在角质形成细胞中诱导Csnk1α1基因缺失的小鼠[单基因敲除(SKO)小鼠]。正如预期的那样，CK1α缺失伴随着β-连环素和P53的稳定，优先诱导P53靶基因，但最显著的是皮肤色素沉着，重要的是没有肿瘤形成，在Csnk1α1消融后至少9个月。SKO小鼠的表皮黑素细胞数量和真黑素水平显著增加。为了阐明P53在表皮色素沉着中的可能作用，我们建立了K14-Cre-ERT2 CK1α/P53双基因敲除(DKO)小鼠，发现消融不能诱导表皮色素沉着，表明它是P53依赖的。表皮转录组分析显示P53依赖的Kit配体(KitL)表达上调。用ACK2(试剂盒中和抗体)或伊马替尼(试剂盒抑制剂)处理的SKO小鼠消除了CK1α消融诱导的色素沉着，表明它需要KitL/Kit途径。前阿片黑素皮质素(POMC)是α-黑素细胞刺激素(α-MSH)的前体，在CK1α消融诱导的色素沉着中不被激活，这与依赖于P53的紫外线晒黑的机制相反。然而，在SKO小鼠的色素沉着的皮肤中，急性晒伤效应被成功地预防。抑制CK1α可诱导皮肤保护性真黑素，但不产生致癌真黑素，因此可能成为通过紫外线不依赖途径安全增加真黑素的有效策略，从而防止急性晒伤。
Casein kinase 1 alpha (CK1 alpha), a component of the beta-catenin destruction complex, is a critical regulator of Wnt signaling; its ablation induces both Wnt and p53 activation. To characterize the role of CK1 alpha (encoded by Csnk1 alpha 1) in skin physiology, we crossed mice harboring floxed Csnk1 alpha 1 with mice expressing K14-Cre-ERT2 to generate mice in which tamoxifen induces the deletion of Csnk1 alpha 1 exclusively in keratinocytes [single-knockout (SKO) mice]. As expected, CK1 alpha loss was accompanied by beta-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 Csnk1 alpha 1 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 CK1 alpha/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 CK1 alpha ablation-induced hyperpigmentation, demonstrating that it requires the KitL/Kit pathway. Pro-opiomelanocortin (POMC), a precursor of alpha-melanocyte-stimulating hormone (alpha-MSH), was not activated in the CK1 alpha 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. CK1 alpha 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.