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1.
Am J Pathol ; 185(9): 2354-63, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26212909

RESUMO

NF-κB signaling plays a crucial role in regulating proliferation and differentiation in the epidermis. Alterations in the NF-κB pathway can lead to skin pathologies with a significant burden to human health such as psoriasis and cutaneous squamous cell carcinoma (cSCC). Caspase recruitment domain (CARD)-containing scaffold proteins are key regulators of NF-κB signaling by providing a link between membrane receptors and NF-κB transcriptional subunits. Mutations in the CARD family member, CARD14, have been identified in patients with the inflammatory skin diseases psoriasis and pityriasis rubra pilaris. Here, we describe that the gene coding for another CARD scaffold protein, CARD11, is mutated in more than 38% of 111 cSCCs, and show that novel variants outside of the coiled-coil domain lead to constitutively activated NF-κB signaling. CARD11 protein expression was detectable in normal skin and increased in all cSCCs tested. CARD11 mRNA levels were comparable with CARD14 in normal skin and CARD11 mRNA was increased in cSCC. In addition, we identified CARD11 mutations in peritumoral and sun-exposed skin, suggesting that CARD11-mediated alterations in NF-κB signaling may be an early event in the development of cSCC.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença/genética , Guanilato Ciclase/genética , Mutação , NF-kappa B/metabolismo , Neoplasias de Células Escamosas/genética , Neoplasias Cutâneas/genética , Células Cultivadas , Epiderme/patologia , Humanos , Neoplasias Cutâneas/patologia
3.
J Invest Dermatol ; 134(10): 2630-2638, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24662767

RESUMO

Cutaneous SCC (cSCC) is the most frequently occuring skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here, we use massively parallel exome and targeted level sequencing of 132 sporadic cSCCs and of 39 squamoproliferative lesions and cSCCs arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples, to identify NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib-induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC, suggesting polyclonal origin. Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCCs, and regions of NOTCH1 loss or downregulation are frequently observed in normal-looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.


Assuntos
Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Mutação/genética , Receptor Notch1/genética , Transdução de Sinais/genética , Neoplasias Cutâneas/genética , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinogênese/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Humanos , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor Notch1/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais/fisiologia , Pele/metabolismo , Pele/patologia , Dermatopatias/tratamento farmacológico , Dermatopatias/metabolismo , Dermatopatias/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Sulfonamidas/uso terapêutico , Vemurafenib
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