RESUMEN
Casein kinase 1α (CK1α), a component of the ß-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 ß-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.
Asunto(s)
Quinasa de la Caseína I/metabolismo , Queratinocitos/metabolismo , Pigmentación de la Piel , Quemadura Solar/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Quinasa de la Caseína I/antagonistas & inhibidores , Quinasa de la Caseína I/genética , Epidermis/metabolismo , Epidermis/patología , Queratinocitos/patología , Melaninas/biosíntesis , Melaninas/genética , Melanocitos/metabolismo , Melanocitos/patología , Ratones , Ratones Noqueados , Quemadura Solar/genética , Quemadura Solar/patología , Proteína p53 Supresora de Tumor/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
The Jun dimerization protein 2 (Jdp2) is expressed predominantly in granule cell progenitors (GCPs) in the cerebellum, as was shown in Jdp2-promoter-Cre transgenic mice. Cerebellum of Jdp2-knockout (KO) mice contains lower number of Atoh-1 positive GCPs than WT. Primary cultures of GCPs from Jdp2-KO mice at postnatal day 5 were more resistant to apoptosis than GCPs from wild-type mice. In Jdp2-KO GCPs, the levels of both the glutamateâcystine exchanger Sc7a11 and glutathione were increased; by contrast, the activity of reactive oxygen species (ROS) was decreased; these changes confer resistance to ROS-mediated apoptosis. In the absence of Jdp2, a complex of the cyclin-dependent kinase inhibitor 1 (p21Cip1) and Nrf2 bound to antioxidant response elements of the Slc7a11 promoter and provide redox control to block ROS-mediated apoptosis. These findings suggest that an interplay between Jdp2, Nrf2, and p21Cip1 regulates the GCP apoptosis, which is one of critical events for normal development of the cerebellum.
RESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Two new hexadecanuclear lanthanide complexes employing the 1,5-bis(salicylidene)carbohydrazide (H2bsc) ligand are reported herein. These polynuclear aggregates crystallize in the R3[combining macron] space group, which is unprecedented in a family of lanthanide complexes with such high nuclearity. Magnetic susceptibility measurements reveal weak intramolecular interactions between the magnetic centres, and in the case of compound 2 (DyIII), single-molecule magnet properties are observed.
RESUMEN
A Dy6 complex composed of two Dy3 triangular units, [Dy6(µ3-OH)(CO3)3(bsc)3(MeOH)14(H2O)](Cl)5·(H2O)·(MeOH)2 (1), was isolated and found to exhibit slow relaxation of the magnetisation under zero applied dc field, resulting in a high energetic barrier to relaxation.
RESUMEN
Using the Schiff-base ligand 1,5-bis(2-hydroxy-3-methoxybenzylidene)carbonohydrazide (H2hmc), dinuclear and nonanuclear compounds, [Dy2(Hhmc)2(NO3)4]·THF·MeCN (1) and [Dy9(µ3-O)4(µ-OH)6(hmc)4(NO3)4(DMF)4](OH)·H2O·THF·DMF (2) are generated through the addition of different bases, respectively. Single-crystal X-ray diffraction analysis revealed a unique Dy9 core structure of complex 2, and the magnetic properties of both compounds are fully studied.