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1.
Clin Exp Dermatol ; 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38747172

RESUMEN

Acne vulgaris (AV) is the eighth most common non-fatal disease globally. Previous work identified an association between AV and increased Filaggrin (FLG) expression in the follicular epidermis, but further work did not find a clear link between loss of function (LoF) Filaggrin gene (FLG) mutations and protection from AV. In this work we aimed to explore any association between AV and FLG LoF mutations using a cohort of genotyped Bangladeshi patients with atopic eczema (AE) in East London. Retrospective notes review was performed on 245 patients who had been genotyped for FLG LoF mutations and undergone clinical assessment. The Chi squared or Fisher's exact test was used to determine differences between groups. We found a significant reduction in history of AV in AE patients with FLG LoF mutations relative to AE patients without FLG mutations (p = 0.02). We showed a non-significant reduction in AV diagnosis in patients with impaired barrier function (measured by trans epidermal water loss) and palmar hyperlinearity. We found that patients with severe AE were less likely to have a history of AV only if they had an existing FLG LoF mutation (p = 0.02). In the context of AE, our work suggests that FLG LoF mutations protect patients from developing AV.

2.
Br J Dermatol ; 189(1): 91-102, 2023 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-36972303

RESUMEN

BACKGROUND: Ichthyosis defines a group of chronic conditions that manifest phenotypically as a thick layer of scales, often affecting the entire skin. While the gene mutations that lead to ichthyosis are well documented, the actual signalling mechanisms that lead to scaling are poorly characterized; however, recent publications suggest that common mechanisms are active in ichthyotic tissue and in analogous models of ichthyosis. OBJECTIVES: To determine common mechanisms of hyperkeratosis that may be easily targeted with small-molecule inhibitors. METHODS: We combined gene expression analysis of gene-specific short hairpin RNA (shRNA) knockdowns in rat epidermal keratinocytes (REKs) of two genes mutated in autosomal recessive congenital ichthyosis (ARCI), Tgm1 and Alox12b, and proteomic analysis of skin scale from patients with ARCI, as well as RNA sequencing data from rat epidermal keratinocytes treated with the Toll-like receptor 2 (TLR2) agonist Pam3CSK4. RESULTS: We identified common activation of the TLR2 pathway. Exogenous TLR2 activation led to increased expression of important cornified envelope genes and, in organotypic culture, caused hyperkeratosis. Conversely, blockade of TLR2 signalling in keratinocytes from patients with ichthyosis and our shRNA models reduced the expression of keratin 1, a structural protein overexpressed in ichthyosis scale. A time course of TLR2 activation in REKs revealed that although there was rapid initial activation of innate immune pathways, this was rapidly superseded by widespread upregulation of epidermal differentiation-related proteins. Both nuclear factor kappa B phosphorylation and GATA3 upregulation was associated with this switch, and GATA3 overexpression was sufficient to increase keratin 1 expression. CONCLUSIONS: Taken together, these data define a dual role for TLR2 activation during epidermal barrier repair that may be a useful therapeutic modality in treating diseases of epidermal barrier dysfunction.


Asunto(s)
Ictiosis , Receptor Toll-Like 2 , Animales , Ratas , Ictiosis/genética , Queratina-1/genética , Mutación , Fenotipo , Proteómica , ARN Interferente Pequeño , Receptor Toll-Like 2/genética
3.
Exp Dermatol ; 27(8): 892-900, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29845670

RESUMEN

Formation of a stratified epidermis is required for the performance of the essential functions of the skin; to act as an outside-in barrier against the access of microorganisms and other external factors, to prevent loss of water and solutes via inside-out barrier functions and to withstand mechanical stresses. Epidermal barrier function is initiated during embryonic development and is then maintained throughout life and restored after injury. A variety of interrelated processes are required for the formation of a stratified epidermis, and how these processes are both temporally and spatially regulated has long been an aspect of dermatological research. In this review, we describe the roles of multiple protein kinases in the regulation of processes required for epidermal barrier formation.


Asunto(s)
Epidermis/enzimología , Epidermis/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Diferenciación Celular , Células Epidérmicas/enzimología , Proteínas Filagrina , Perfilación de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Humanos , Inflamación , Proteínas de Filamentos Intermediarios/metabolismo , Queratinocitos/enzimología , Permeabilidad , Transducción de Señal , Fenómenos Fisiológicos de la Piel
5.
J Allergy Clin Immunol ; 139(4): 1228-1241, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27913303

RESUMEN

BACKGROUND: Filaggrin, which is encoded by the filaggrin gene (FLG), is an important component of the skin's barrier to the external environment, and genetic defects in FLG strongly associate with atopic dermatitis (AD). However, not all patients with AD have FLG mutations. OBJECTIVE: We hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and therefore we present novel therapeutic targets for this disease. RESULTS: We describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in patients with AD. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype. CONCLUSION: Our findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Catepsina H/metabolismo , Dermatitis Atópica/metabolismo , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Western Blotting , Catepsina H/deficiencia , Dermatitis Atópica/patología , Proteínas Filagrina , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Queratinocitos/metabolismo , Queratinocitos/patología , Masculino , Ratones , Ratones Noqueados , Microscopía Electrónica de Transmisión , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína Reguladora Asociada a mTOR , Piel/metabolismo , Piel/patología
6.
J Cell Sci ; 124(Pt 10): 1681-90, 2011 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-21511732

RESUMEN

The epidermal barrier varies over the body surface to accommodate regional environmental stresses. Regional skin barrier variation is produced by site-dependent epidermal differentiation from common keratinocyte precursors and often manifests as site-specific skin disease or irritation. There is strong evidence for body-site-dependent dermal programming of epidermal differentiation in which the epidermis responds by altering expression of key barrier proteins, but the underlying mechanisms have not been defined. The LCE multigene cluster encodes barrier proteins that are differentially expressed over the body surface, and perturbation of LCE cluster expression is linked to the common regional skin disease psoriasis. LCE subclusters comprise genes expressed variably in either external barrier-forming epithelia (e.g. skin) or in internal epithelia with less stringent barriers (e.g. tongue). We demonstrate here that a complex of TALE homeobox transcription factors PBX1, PBX2 and Pknox (homologues of Drosophila Extradenticle and Homothorax) preferentially regulate external rather than internal LCE gene expression, competitively binding with SP1 and SP3. Perturbation of TALE protein expression in stratified squamous epithelia in mice produces external but not internal barrier abnormalities. We conclude that epidermal barrier genes, such as the LCE multigene cluster, are regulated by TALE homeodomain transcription factors to produce regional epidermal barriers.


Asunto(s)
Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Proteínas Represoras/metabolismo , Fenómenos Fisiológicos de la Piel/genética , Animales , Secuencia de Bases , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Proteínas Ricas en Prolina del Estrato Córneo/genética , Células Epidérmicas , Epidermis/metabolismo , Humanos , Queratinocitos/metabolismo , Ratones , Ratones Transgénicos , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Piel/citología , Piel/metabolismo
7.
Exp Dermatol ; 22(11): 754-6, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24433183

RESUMEN

Epidermal barrier acquisition during late mammalian development is a prerequisite for terrestrial existence. Over a 24-h period, the epidermis goes from being a barrier-deficient, dye permeable epithelium to a barrier-competent epithelium. We have previously shown that Akt signalling is necessary for barrier acquisition in the mouse and that the protein phosphatase 2A regulatory subunit Ppp2r2a causes barrier acquisition by dephosphorylation of cJun. Here, we demonstrate that there is transient interaction between the gap junction protein Connexin 43 (Cx43) and Zonula occludins-1 (Zo-1) during epidermal barrier acquisition. Ppp2r2a knockdown prevented plasma membrane co-localisation and interaction between the two proteins. Ppp2r2a knockdown also increased phosphorylation at Serine 368 of Connexin 43. Cx43 phosphorlyation at Serine368 occurred just prior to the interaction between Connexin 43 and Zo-1. We therefore propose a model in which Ppp2r2a is required both for the initial interaction between Zo-1 and Cx43 and the consequent dephosphorylation of Connexin 43, preventing interaction of Zo-1 and allowing Zo-1 to initiate tight junction formation and barrier acquisition.


Asunto(s)
Conexina 43/química , Epidermis/patología , Regulación de la Expresión Génica , Proteína Fosfatasa 2/fisiología , Animales , Membrana Celular/metabolismo , Conexinas/metabolismo , Epidermis/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Queratinocitos/citología , Proteínas de la Membrana/metabolismo , Ratones , Fosforilación , Estructura Terciaria de Proteína , Ratas , Transducción de Señal , Proteína de la Zonula Occludens-1/metabolismo
8.
Hum Mol Genet ; 19(13): 2594-605, 2010 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-20385541

RESUMEN

The autosomal recessive congenital ichthyoses are a family of related diseases, causing a severe defect in the barrier function of the epidermis. Neonates are usually born as collodion babies, but later form scales characteristic of the disease, due to a combination of thickening of the cornified layer and an increase in the production of non-polar lipids. Current treatments of choice are exfoliative creams and moisturizing agents and the use of oral retinoids. The skin condition and treatment impact significantly on quality of life and, with oral retinoids, there are potential complications associated with long-term use. A greater understanding of the mechanisms that result in scaling should lead to better directed therapies, not only for the inherited ichthyoses, but also other hyperkeratotic disorders. Using siRNA knockdown of the principle gene mutated in lamellar ichthyosis (LI), transglutaminase-1, in rat keratinocytes, we created an in vitro organotypic culture model that closely mimics the disease. Interleukin-1 alpha (IL1A) expression was increased and there was a lack of loricrin cross-linking. All LI patients tested had an increased IL1A and treatment of wild-type organotypic cultures with IL1A was sufficient to induce hyperkeratosis. Treatment of disease mimic organotypic cultures with IL-1 receptor antagonist led to a dose-dependent decrease in hyperkeratosis without a reduction in non-polar lipids in the cornified layer, which has the potential to reduce scaling without the requirement to constantly apply emollients.


Asunto(s)
Ictiosis Lamelar/terapia , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Interleucina-1alfa/antagonistas & inhibidores , Adulto , Animales , Células Cultivadas , Niño , Preescolar , Femenino , Humanos , Ictiosis Lamelar/metabolismo , Recién Nacido , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Queratinocitos/enzimología , Masculino , Proteínas de la Membrana/biosíntesis , Técnicas de Cultivo de Órganos , Ratas , Piel/patología , Transglutaminasas/deficiencia
9.
Development ; 136(20): 3423-31, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19762425

RESUMEN

Acquisition of epidermal barrier function occurs late in mouse gestation. Several days before birth a wave of barrier acquisition sweeps across murine fetal skin, converging on dorsal and ventral midlines. We investigated the molecular pathways active during epidermal barrier formation. Akt signaling increased as the barrier wave crossed epidermis and Jun was transiently dephosphorylated. Inhibitor experiments on embryonic explants showed that the dephosphorylation of Jun was dependent on both Akt and protein phosphatase 2A (Pp2a). Inhibition of Pp2a and Akt signaling also caused defects in epidermal barrier formation. These data are compatible with a model for developmental barrier acquisition mediated by Pp2a regulation of Jun dephosphorylation, downstream of Akt signaling. Support for this model was provided by siRNA-mediated knockdown of Ppp2r2a (Pr55alpha or B55alpha), a regulatory subunit of Pp2a expressed in an Akt-dependent manner in epidermis during barrier formation. Ppp2r2a reduction caused significant increase in Jun phosphorylation and interfered with the acquisition of barrier function, with barrier acquisition being restored by inhibition of Jun phosphorylation. Our data provide strong evidence that Ppp2r2a is a regulatory subunit of Pp2a that targets this phosphatase to Jun, and that Pp2a action is necessary for barrier formation. We therefore describe a novel Akt-dependent Pp2a activity that acts at least partly through Jun to affect initial barrier formation during late embryonic epidermal development.


Asunto(s)
Epidermis/embriología , Epidermis/enzimología , Proteína Fosfatasa 2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Animales , Diferenciación Celular , Células Cultivadas , Células Epidérmicas , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Queratinocitos/enzimología , Ratones , Fosforilación , Proteína Fosfatasa 2/genética , ARN Interferente Pequeño/genética , Ratas , Técnicas de Cultivo de Tejidos
10.
Cell Death Differ ; 28(6): 1849-1864, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33462407

RESUMEN

Keratinocyte cornification and epidermal barrier formation are tightly controlled processes, which require complete degradation of intracellular organelles, including removal of keratinocyte nuclei. Keratinocyte nuclear destruction requires Akt1-dependent phosphorylation and degradation of the nuclear lamina protein, Lamin A/C, essential for nuclear integrity. However, the molecular mechanisms that result in complete nuclear removal and their regulation are not well defined. Post-confluent cultures of rat epidermal keratinocytes (REKs) undergo spontaneous and complete differentiation, allowing visualisation and perturbation of the differentiation process in vitro. We demonstrate that there is dispersal of phosphorylated Lamin A/C to structures throughout the cytoplasm in differentiating keratinocytes. We show that the dispersal of phosphorylated Lamin A/C is Akt1-dependent and these structures are specific for the removal of Lamin A/C from the nuclear lamina; nuclear contents and Lamin B were not present in these structures. Immunoprecipitation identified a group of functionally related Akt1 target proteins involved in Lamin A/C dispersal, including actin, which forms cytoskeletal microfilaments, Arp3, required for actin filament nucleation, and Myh9, a component of myosin IIa, a molecular motor that can translocate along actin filaments. Disruption of actin filament polymerisation, nucleation or myosin IIa activity prevented formation and dispersal of cytoplasmic Lamin A/C structures. Live imaging of keratinocytes expressing fluorescently tagged nuclear proteins showed a nuclear volume reduction step taking less than 40 min precedes final nuclear destruction. Preventing Akt1-dependent Lamin A/C phosphorylation and disrupting cytoskeletal Akt1-associated proteins prevented nuclear volume reduction. We propose keratinocyte nuclear destruction and differentiation requires myosin II activity and the actin cytoskeleton for two intermediate processes: Lamin A/C dispersal and rapid nuclear volume reduction.


Asunto(s)
Actomiosina/metabolismo , Lámina Nuclear/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Diferenciación Celular , Humanos
11.
J Dev Biol ; 8(4)2020 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-33291764

RESUMEN

The outer layer of the skin, the epidermis, is the principal barrier to the external environment: post-mitotic cells terminally differentiate to form a tough outer cornified layer of enucleate and flattened cells that confer the majority of skin barrier function. Nuclear degradation is required for correct cornified envelope formation. This process requires mRNA translation during the process of nuclear destruction. In this review and perspective, we address the biology of transcriptional bursting and the formation of ribonuclear particles in model organisms including mammals, and then examine the evidence that these phenomena occur as part of epidermal terminal differentiation.

12.
J Invest Dermatol ; 140(4): 774-784.e11, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31626786

RESUMEN

Varicella zoster virus (VZV) is a skin-tropic virus that infects epidermal keratinocytes and causes chickenpox. Although common, VZV infection can be life-threatening, particularly in the immunocompromized. Therefore, understanding VZV-keratinocyte interactions is important to find new treatments beyond vaccination and antiviral drugs. In VZV-infected skin, kallikrein 6 and the ubiquitin ligase MDM2 are upregulated concomitant with keratin 10 (KRT10) downregulation. MDM2 binds to KRT10, targeting it for degradation via the ubiquitin-proteasome pathway. Preventing KRT10 degradation reduced VZV propagation in culture and prevented epidermal disruption in skin explants. KRT10 knockdown induced expression of NR4A1 and enhanced viral propagation in culture. NR4A1 knockdown prevented viral propagation in culture, reduced LC3 levels, and increased LAMP2 expression. We therefore describe a drug-able pathway whereby MDM2 ubiquitinates and degrades KRT10, increasing NR4A1 expression and allowing VZV replication and propagation.


Asunto(s)
Regulación de la Expresión Génica , Herpes Zóster/genética , Herpes Zóster/metabolismo , Herpesvirus Humano 3/fisiología , Queratina-10/genética , Queratinocitos/patología , ARN/genética , Replicación Viral , Herpes Zóster/virología , Humanos , Queratina-10/biosíntesis , Queratinocitos/metabolismo , Queratinocitos/virología
13.
Cancer Res ; 67(17): 8207-15, 2007 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-17804734

RESUMEN

Epithelial tumorigenesis has been linked to AKT up-regulation. Human papillomaviruses (HPV) cause anogenital cancers and anogenital HPV infection up-regulates AKT activity. Mounting evidence points to a role for cutaneous HPVs as etiologic factors in skin tumorigenesis. High-risk cutaneous beta HPVs have been linked to carcinogenesis in immunosuppressed patients, and high-risk cutaneous HPV8 genes enhance tumorigenesis in transgenic mice. We find that, in contrast to anogenital HPVs, cutaneous HPV8 early genes down-regulate epidermal AKT activity by down-regulating AKT1 isoform levels. This down-regulation occurs before papilloma formation or tumorigenesis and leads to cutaneous differentiation changes that may weaken the epidermal squame for viral release. We find that, in viral warts (papillomas) and HPV gene-induced epidermal tumors, AKT activity can be activated focally by up-regulation and phosphorylation of the AKT2 isoform. In squamous cell carcinomas (SCC), AKT1 down-regulation is also common, consistent with a viral influence, whereas AKT2 up-regulation is widespread. Activation of up-regulated AKT2 by serine phosphorylation associates with high-grade tumors. Our data suggest that AKT2 up-regulation is characteristic of SCC and that coincident AKT2 activation through serine phosphorylation correlates with malignancy. These findings highlight differences between the effects of anogenital and cutaneous HPV on epithelial AKT activity and furthermore show that AKT isoforms can behave differently during epidermal tumorigenesis. These findings also suggest AKT2 as a possible therapeutic tumor target in SCC.


Asunto(s)
Carcinoma de Células Escamosas/genética , Proteínas Oncogénicas Virales/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Neoplasias Cutáneas/genética , Transactivadores/metabolismo , Alphapapillomavirus/genética , Animales , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/etiología , Células Cultivadas , Expresión Génica , Genes Virales , Humanos , Queratinocitos/citología , Queratinocitos/virología , Ratones , Técnicas de Cultivo de Órganos , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/etiología
14.
J Clin Invest ; 129(8): 3153-3170, 2019 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-31264977

RESUMEN

Hedgehog (Hh) proteins regulate development and tissue homeostasis, but their role in atopic dermatitis (AD) remains unknown. We found that on induction of mouse AD, Sonic Hedgehog (Shh) expression in skin, and Hh pathway action in skin T cells were increased. Shh signaling reduced AD pathology and the levels of Shh expression determined disease severity. Hh-mediated transcription in skin T cells in AD-induced mice increased Treg populations and their suppressive function through increased active transforming growth factor-ß (TGF-ß) in Tregs signaling to skin T effector populations to reduce disease progression and pathology. RNA sequencing of skin CD4+ T cells from AD-induced mice demonstrated that Hh signaling increased expression of immunoregulatory genes and reduced expression of inflammatory and chemokine genes. Addition of recombinant Shh to cultures of naive human CD4+ T cells in iTreg culture conditions increased FOXP3 expression. Our findings establish an important role for Shh upregulation in preventing AD, by increased Gli-driven Treg cell-mediated immune suppression, paving the way for a potential new therapeutic strategy.


Asunto(s)
Dermatitis Atópica/inmunología , Proteínas Hedgehog/inmunología , Transducción de Señal/inmunología , Piel/inmunología , Linfocitos T Reguladores/inmunología , Proteína Gli2 con Dedos de Zinc/inmunología , Animales , Dermatitis Atópica/genética , Dermatitis Atópica/patología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Regulación de la Expresión Génica/inmunología , Proteínas Hedgehog/genética , Ratones , Ratones Noqueados , Transducción de Señal/genética , Piel/patología , Linfocitos T Reguladores/patología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología , Proteína Gli2 con Dedos de Zinc/genética
15.
Nucleus ; 9(1): 56-64, 2018 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29205081

RESUMEN

Eukaryotic nuclei are essential organelles, storing the majority of the cellular DNA, comprising the site of most DNA and RNA synthesis, controlling gene expression and therefore regulating cellular function. The majority of mammalian cells retain their nucleus throughout their lifetime, however, in three mammalian tissues the nucleus is entirely removed and its removal is essential for cell function. Lens fibre cells, erythroblasts and epidermal keratinocytes all lose their nucleus in the terminal differentiation pathways of these cell types. However, relatively little is known about the pathways that lead to complete nuclear removal and about how these pathways are regulated. In this review, we aim to discuss the current understanding of nuclear removal mechanisms in these three cell types and expand upon how recent studies into nuclear degradation in keratinocytes, an easily accessible experimental model, could contribute to a wider understanding of these molecular mechanisms in both health and pathology.


Asunto(s)
Núcleo Celular/metabolismo , Queratinocitos/metabolismo , Animales , ADN/metabolismo , Humanos
16.
Cancers (Basel) ; 9(7)2017 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-28696382

RESUMEN

Cutaneous squamous cell carcinoma (cSCC) derives from keratinocytes in the epidermis and accounts for 15-20% of all cutaneous malignancies. Although it is usually curable by surgery, 5% of these tumours metastasise leading to poor prognosis mostly because of a lack of therapies and validated biomarkers. As the incidence rate is rising worldwide it has become increasingly important to better understand the mechanisms involved in cSCC development and progression in order to develop therapeutic strategies. Here we discuss some of the evidence indicating that activation of phosphoinositide 3-kinases (PI3Ks)-dependent signalling pathways (in particular the PI3Ks targets Akt and mTOR) has a key role in cSCC. We further discuss available data suggesting that inhibition of these pathways can be beneficial to counteract the disease. With the growing number of different inhibitors currently available, it would be important to further investigate the specific contribution of distinct components of the PI3Ks/Akt/mTOR pathways in order to identify the most promising molecular targets and the best strategy to inhibit cSCC.

17.
Front Immunol ; 8: 103, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28321213

RESUMEN

Human regulatory T cells (Treg) are important in immune regulation, but can also show plasticity in specific settings. CD161 is a lectin-like receptor and its expression identifies an effector-like Treg population. Here, we determined how CD161+ Treg relate to CD161+ conventional T cells (Tconv). Transcriptional profiling identified a shared transcriptional signature between CD161+ Tconv and CD161+ Treg, which is associated with T helper (Th)1 and Th17 cells, and tissue homing, including high expression of gut-homing receptors. Upon retinoic acid (RA) exposure, CD161+ T cells were more enriched for CCR9+ and integrin α4+ß7+ cells than CD161- T cells. In addition, CD161+ Tconv and CD161+ Treg were enriched at the inflamed site in autoimmune arthritis, and both CD161+ and CD161- Treg from the inflamed site were suppressive in vitro. CD161+ T cells from the site of autoimmune arthritis showed a diminished gut-homing phenotype and blunted response to RA suggesting prior imprinting by RA in the gut or at peripheral sites rather than during synovial inflammation. TCRß repertoires of CD161+ and CD161- Tconv and Treg from blood showed limited overlap whereas there was clear overlap between CD161+ and CD161- Tconv, and CD161+ and CD161- Treg from the inflamed site suggesting that the inflamed environment may alter CD161 levels, potentially contributing to disease pathogenesis.

18.
J Invest Dermatol ; 136(7): 1460-1470, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27021405

RESUMEN

Epidermal keratinocytes migrate through the epidermis up to the granular layer where, on terminal differentiation, they progressively lose organelles and convert into anucleate cells or corneocytes. Our report explores the role of autophagy in ensuring epidermal function providing the first comprehensive profile of autophagy marker expression in developing epidermis. We show that autophagy is constitutively active in the epidermal granular layer where by electron microscopy we identified double-membrane autophagosomes. We demonstrate that differentiating keratinocytes undergo a selective form of nucleophagy characterized by accumulation of microtubule-associated protein light chain 3/lysosomal-associated membrane protein 2/p62 positive autolysosomes. These perinuclear vesicles displayed positivity for histone interacting protein, heterochromatin protein 1α, and localize in proximity with Lamin A and B1 accumulation, whereas in newborn mice and adult human skin, we report LC3 puncta coincident with misshaped nuclei within the granular layer. This process relies on autophagy integrity as confirmed by lack of nucleophagy in differentiating keratinocytes depleted from WD repeat domain phosphoinositide interacting 1 or Unc-51 like autophagy activating kinase 1. Final validation into a skin disease model showed that impaired autophagy contributes to the pathogenesis of psoriasis. Lack of LC3 expression in psoriatic skin lesions correlates with parakeratosis and deregulated expression or location of most of the autophagic markers. Our findings may have implications and improve treatment options for patients with epidermal barrier defects.


Asunto(s)
Autofagia , Núcleo Celular/metabolismo , Epidermis/fisiología , Queratinocitos/citología , Proteínas Asociadas a Microtúbulos/metabolismo , Animales , Animales Recién Nacidos , Diferenciación Celular , Células Cultivadas , Epidermis/embriología , Humanos , Lamina Tipo A/metabolismo , Lamina Tipo B/metabolismo , Lisosomas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Complejos Multiproteicos/metabolismo , Fagosomas/metabolismo , Psoriasis/patología , Piel/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
19.
Int J Dev Biol ; 48(2-3): 171-9, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15272382

RESUMEN

The last ten years has revealed some of the key players in the development and differentiation of the hair follicle and the epidermis in general. In this review, we discuss how our current understanding of these processes has been made possible by the elucidation of the molecular basis of human inherited diseases and mouse mutants which display defects in the hair and epidermis. For examples, the study of ectodermal dysplasias and the basal cell carcinoma predisposition disease Gorlin syndrome have allowed the determination of signalling hierarchies critical in the formation of the hair follicle. Epidermolytic diseases and hyperkeratoses have focussed attention on the importance of the programs of keratin expression, while ichthyoses provide insight in the final stage of epidermal development, cornification. Finally, the increasing range of diseases and mouse models exhibiting alopecias are revealing the critical pathways in control of the hair follicle cycle.


Asunto(s)
Diferenciación Celular , Enfermedades de la Piel/genética , Piel/embriología , Piel/crecimiento & desarrollo , Alopecia/genética , Alopecia/patología , Animales , Síndrome del Nevo Basocelular/genética , Síndrome del Nevo Basocelular/patología , Epidermis/patología , Predicción , Predisposición Genética a la Enfermedad , Humanos , Queratinas/genética , Queratinas/metabolismo , Queratosis/genética , Queratosis/patología , Ratones , Ratones Transgénicos , Modelos Biológicos , Mutación , Piel/patología , Enfermedades de la Piel/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología
20.
J Invest Dermatol ; 135(2): 331-333, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25573043

RESUMEN

The epidermis is a relatively hypoxic tissue, despite being continually exposed to air. The role of hypoxia in epidermal differentiation and skin barrier function is incompletely understood. In this issue, Wong et al. show that hypoxia-inducible factors are central to the processes of epidermal differentiation and barrier formation, in particular by promoting the expression of the key skin barrier protein filaggrin.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Epidermis/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Proteínas de Filamentos Intermediarios/genética , Animales , Proteínas Filagrina
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