Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 575
Filtrar
1.
Nat Commun ; 11(1): 2711, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483135

RESUMO

p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.


Assuntos
Transformação Celular Neoplásica/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Epiderme/metabolismo , Via de Sinalização Wnt/genética , Animais , Proliferação de Células/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Queratinócitos/metabolismo , Ceratose/genética , Ceratose/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Papiloma/genética , Papiloma/metabolismo , Papiloma/patologia
2.
Am J Hum Genet ; 107(1): 34-45, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32497488

RESUMO

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.


Assuntos
Artrogripose/genética , Mutação/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica/genética , Humanos , Ceratose/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto Jovem
3.
PLoS One ; 15(3): e0222619, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32150577

RESUMO

Ion channels have recently attracted attention as potential mediators of skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca2+-activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. Doxycycline-treated mice harboring the KCa3.1+-transgene under the control of the reverse tetracycline-sensitive transactivator (rtTA) showed 800-fold channel overexpression above basal levels in the skin and solid KCa3.1-currents in keratinocytes. This overexpression resulted in epidermal spongiosis, progressive epidermal hyperplasia and hyperkeratosis, itch and ulcers. The condition was accompanied by production of the pro-proliferative and pro-inflammatory cytokines, IL-ß1 (60-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. Treatment of mice with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis and hyperplasia, as well as induction of IL-ß1 (-88%) and IL-6 (-90%). In conclusion, KCa3.1-induction in the epidermis caused expression of pro-proliferative cytokines leading to spongiosis, hyperplasia and hyperkeratosis. This skin condition resembles pathological features of eczematous dermatitis and identifies KCa3.1 as a regulator of epidermal homeostasis and spongiosis, and as a potential therapeutic target.


Assuntos
Eczema/genética , Epiderme/patologia , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Ceratose/genética , Pele/metabolismo , Transgenes , Acetamidas/farmacologia , Animais , Citocinas/metabolismo , Doxiciclina/farmacologia , Eczema/tratamento farmacológico , Feminino , Homeostase/genética , Hiperplasia/tratamento farmacológico , Hiperplasia/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/antagonistas & inibidores , Queratinócitos/metabolismo , Ceratose/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transativadores/metabolismo , Compostos de Tritil/farmacologia
4.
Lab Invest ; 100(5): 751-761, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31925326

RESUMO

The skin plays a critical role in maintenance of water homeostasis. Dysfunction of the skin barrier causes not only delayed wound healing and hypertrophic scarring, but it also contributes to the development of various skin diseases. Dermatitis is a chronic inflammatory skin disorder that has several different subtypes. Skin of contact dermatitis and atopic dermatitis (AD) show epidermal barrier dysfunction. Nax is a sodium channel that regulates inflammatory gene expression in response to perturbation of barrier function of the skin. We found that in vivo knockdown of Nax using RNAi reduced hyperkeratosis and keratinocyte hyperproliferation in rabbit ear dermatitic skin. Increased infiltration of inflammatory cells (mast cells, eosinophils, T cells, and macrophages), a characteristic of dermatitis, was reduced by Nax knockdown. Upregulation of PAR-2 and thymic stromal lymphopoietin (TSLP), which induce Th2-mediated allergic responses, was inhibited by Nax knockdown. In addition, expression of COX-2, IL-1ß, IL-8, and S100A9, which are downstream genes of Nax and are involved in dermatitis pathogenesis, were also decreased by Nax knockdown. Our data show that knockdown of Nax relieved dermatitis symptoms in vivo and indicate that Nax is a novel therapeutic target for dermatitis, which currently has limited therapeutic options.


Assuntos
Dermatite Atópica , Pele , Canais de Sódio Disparados por Voltagem , Animais , Proliferação de Células/genética , Dermatite Atópica/genética , Dermatite Atópica/patologia , Dermatite Atópica/fisiopatologia , Regulação para Baixo/genética , Eosinófilos/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Queratinócitos/metabolismo , Ceratose/genética , Ceratose/patologia , Ceratose/fisiopatologia , Mastócitos/metabolismo , Coelhos , Pele/citologia , Pele/patologia , Pele/fisiopatologia , Canais de Sódio Disparados por Voltagem/genética , Canais de Sódio Disparados por Voltagem/metabolismo
6.
J Dtsch Dermatol Ges ; 17(12): 1227-1238, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31846220

RESUMO

Loricrin downregulation has been associated with age-related changes as well as inherited and inflammatory skin diseases. We hypothesize that changes in loricrin could be more related to altered barrier function and consequently disorders that affect epithelial cells, such as psoriasis, atopic dermatitis (AD), erythrokeratoderma, loricrin keratoderma (LK) and periodontitis. The aim of this review is to summarize what is known about the association between loricrin downregulation and epithelial-related disorders (ERDs). A search was performed on the following databases: Medline, Cochrane Library, PubMed, EMBASE, Lilacs, Scopus and Google Scholar, resulting in 16 included articles. Loricrin keratoderma was the ERD most frequently associated with loricrin mutations (730insG, 709insC and 578insG; 5/7 cases - 71.44 %). Atopic dermatitis was the ERD most frequently associated with loricrin downregulation (2/7 cases - 28.6 %). Mutilating palmoplantar keratoderma, progressive symmetrical erythrokeratoderma and a new type of erythrokeratoderma were not associated with any mutations. At the gene level, periodontitis patients showed the highest decrease (-6.89x), followed by AD (-6.5x) and psoriasis patients (-0.5x). In summary, loricrin mutation and downregulation were associated with several ERDs. The diversity in disease presentation is likely related to whether there is a total loss of loricrin, mislocalization and/or if the mutant form of loricrin causes dysfunction of other proteins and/or changes in cornification.


Assuntos
Proteínas de Membrana/metabolismo , Mutação , Dermatopatias/metabolismo , Análise Mutacional de DNA , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Ceratose/genética , Ceratose/metabolismo , Masculino , Proteínas de Membrana/genética , Membrana Mucosa/metabolismo , Psoríase/genética , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Dermatopatias/genética
7.
Oral Dis ; 25(7): 1715-1723, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31295760

RESUMO

OBJECTIVE: The molecular mechanisms underlying the development of dysplasia in leukoplakia are unknown. We used RNA sequencing to examine the molecular and biological pathway differences in oral leukoplakia with and without oral epithelial dysplasia. MATERIALS AND METHODS: Excisional biopsy specimens (25) were taken from 24 patients with oral leukoplakia diagnosed histopathologically as either oral epithelial dysplasia (13) or epithelial hyperplasia and keratosis without dysplasia (12). Transcriptome analysis used RNA sequencing, differential expression and hierarchical clustering. Biological signalling was examined by gene ontology, pathway and protein-protein interaction analysis. RESULTS: Differential expression analysis showed distinction between the two groups identifying 47 genes as altered in leukoplakia with dysplasia, including SAA1, SAA2, KRT31, KRT37, KRT76, ROBO2, DNAJB5 and DNAJA4. Using hierarchical clustering, dysplastic leukoplakia readily segregated from leukoplakia without dysplasia. Pathway and ontology enrichment analysis provided evidence that downregulation of extracellular matrix (ECM) pathways was a feature of dysplastic lesions. CONCLUSION: Our results suggest that there are detectable changes in the molecular profile of oral leukoplakia exhibiting dysplasia including downregulated ECM as a distinguishing feature of dysplastic lesions. This suggests that reactive changes in stroma may be an early manifestation of dysplastic development. Our study also demonstrates the feasibility of detecting such molecular changes in oral leukoplakia, providing avenues for further investigation of molecular mechanisms of oral dysplasia.


Assuntos
Carcinoma in Situ/patologia , Hiperplasia/patologia , Ceratose/patologia , Leucoplasia Oral/patologia , Neoplasias Bucais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma in Situ/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Hiperplasia/genética , Ceratose/genética , Leucoplasia Oral/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Análise de Sequência de RNA
8.
Hautarzt ; 70(7): 497-505, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31087125

RESUMO

Approximately 9000 different phenotypes are known in medicine. The definition phenotype includes both manifest diseases as well as features without any disease value and the pure genetic disposition to develop a disease (e.g. tumors or complex diseases); however, most phenotypes are rare monogenic hereditary diseases. Approximately 6400 of these phenotypes have so far been elucidated by molecular genetics and are caused by mutations in 4064 different genes. Of all genetic diseases, an estimated one third are associated with skin symptoms. Genodermatoses are the phenotypes predominantly related to the skin, of which approximately 600 are familiar to dermatologists. The syndromes with scaling and keratosis include cornification disorders where the symptoms are not limited to the skin. They are associated with skin symptoms such as ichthyosis, erythroderma and palmoplantar keratoderma but show additional symptoms from other organ groups. The typical combination of symptoms may be unique to a syndrome and therefore seminal for the diagnosis.


Assuntos
Neoplasias Ósseas , Condromatose , Ictiose , Ceratodermia Palmar e Plantar , Ceratose , Mutação/genética , Síndromes Neoplásicas Hereditárias , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Condromatose/genética , Condromatose/patologia , Humanos , Ictiose/genética , Ictiose/patologia , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Ceratose/genética , Ceratose/patologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Pele , Síndrome
20.
Circ Res ; 121(12): 1346-1359, 2017 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-29018034

RESUMO

RATIONALE: Arrhythmogenic cardiomyopathy is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (junction protein plakoglobin) mutations are responsible for a subset of patients with arrhythmogenic cardiomyopathy who exhibit cardiac arrhythmias and dysfunction, palmoplanter keratosis, and hair abnormalities (cardiocutaneous syndromes). OBJECTIVE: To determine phenotypic consequences of deletion of Dsp in a subset of cells common to the heart and skin. METHODS AND RESULTS: Expression of CSPG4 (chondroitin sulfate proteoglycan 4) was detected in epidermal keratinocytes and the cardiac conduction system. CSPG4pos cells constituted ≈5.6±3.3% of the nonmyocyte cells in the mouse heart. Inducible postnatal deletion of Dsp under the transcriptional control of the Cspg4 locus led to ventricular arrhythmias, atrial fibrillation, atrioventricular conduction defects, and death by 4 months of age. Cardiac arrhythmias occurred early and in the absence of cardiac dysfunction and excess cardiac fibroadipocytes, as in human arrhythmogenic cardiomyopathy. The mice exhibited palmoplantar keratosis and progressive alopecia, leading to alopecia totalis, associated with accelerated proliferation and impaired terminal differentiation of keratinocytes. The phenotype is similar to human cardiocutaneous syndromes caused by homozygous mutations in DSP. CONCLUSIONS: Deletion of Dsp under the transcriptional regulation of the CSPG4 locus led to lethal cardiac arrhythmias in the absence of cardiac dysfunction or fibroadiposis, palmoplantar keratosis, and alopecia, resembling the human cardiocutaneous syndromes. The findings offer a cellular basis for early cardiac arrhythmias in patients with arrhythmogenic cardiomyopathy and cardiocutaneous syndromes.


Assuntos
Displasia Arritmogênica Ventricular Direita/metabolismo , Desmoplaquinas/metabolismo , Ceratose/metabolismo , Fenótipo , Animais , Antígenos/genética , Displasia Arritmogênica Ventricular Direita/genética , Células Cultivadas , Desmoplaquinas/genética , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Ceratose/genética , Camundongos , Mutação , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteoglicanas/genética , Síndrome
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA