Selection, p53, and pigmentation

Ögmundsdóttir, Margrét H.; Steingrímsson, Eiríkur

doi:10.1111/pcmr.12203

Cited by 1 publication

(2 citation statements)

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“…CK1α ablation resulted in the stabilization and up-regulation of β-catenin ( Fig. 1 E and F), which by itself may cause skin tumorigenesis (19)(20)(21)(22), but we observed no skin tumor formation for at least 9 mo. Skin samples were then harvested, and mRNAs and proteins were extracted from the epidermis for analysis by RT-PCR and Western blot, respectively.…”

Section: Ablation Of Ck1α In Keratinocytes Induces Skin Hyperpigmentamentioning

confidence: 59%

“…p53, a well-known tumor-suppressor protein, is a transcription factor that plays a pivotal role in cellular responses to genotoxic stress and DNA damage (18). In the skin, p53 also acts as a central player against UV damage via the p53/ proopiomelanocortin (POMC)/α-MSH/melanocortin 1 receptor (MC1R)/microphthalmia-associated transcription factor (MITF) skin-tanning pathway and through the DNA repair/cell-cycle arrest/apoptotic pathway (4,19). As CK1α ablation is a robust means of activating p53 in many tissues, the physiological role of CK1α in the skin remains to be elucidated.…”

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confidence: 99%

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

Chang

Kuo

Ito

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Ablation Of Ck1α In Keratinocytes Induces Skin Hyperpigmentamentioning

confidence: 59%

mentioning

confidence: 99%