RESUMO
Mutations of the neurofibromatosis 2 (NF2) tumor suppressor gene have frequently been detected not only in schwannomas and other central nervous system tumors of NF2 patients but also in their sporadic counterparts and malignant tumors unrelated to the NF2 syndrome such as malignant mesothelioma, indicating a broader role for the NF2 gene in human tumorigenesis. However, the mechanisms by which the NF2 product, merlin or schwannomin, is regulated and controls cell proliferation remain elusive. Here, we identify a novel GTP-binding protein, dubbed NGB (referring to NF2-associated GTP binding protein), which binds to merlin. NGB is highly conserved between Saccharomyces cerevisiae, Caenorhabditis elegans, and human cells, and its GTP-binding region is very similar to those found in R-ras and Rap2. However, ectopic expression of NGB inhibits cell growth, cell aggregation, and tumorigenicity in tumorigenic schwanomma cells. Down-regulation and infrequent mutation of NGB were detected in human glioma cell lines and primary tumors. The interaction of NGB with merlin impairs the turnover of merlin, yet merlin does not affect the GTPase nor GTP-binding activity of NGB. Finally, the tumor suppressor functions of NGB require merlin and are linked to its ability to suppress cyclin D1 expression. Collectively, these findings indicate that NGB is a tumor suppressor that regulates and requires merlin to suppress cell proliferation.
Assuntos
Proteínas de Ligação ao GTP/metabolismo , Neurofibromina 2/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Adesão Celular , Movimento Celular , Proliferação de Células , Sequência Conservada , Ciclina D1/metabolismo , Regulação para Baixo , Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/isolamento & purificação , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Dados de Sequência Molecular , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neurofibromina 2/genética , Ligação Proteica , Ratos , Alinhamento de Sequência , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/isolamento & purificação , Técnicas do Sistema de Duplo-Híbrido , Ubiquitina/metabolismoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Fatores Etários , Algoritmos , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/patologia , Diagnóstico Diferencial , Nível de Saúde , Humanos , Linfoma/diagnóstico , Linfoma/patologia , Linfoma/terapia , Estadiamento de Neoplasias , Prognóstico , Medição de RiscoRESUMO
Isolated neurosarcoidosis involving the optic nerve meninges is extremely rare and is often indistinguishable from a meningioma in its anatomic site and MR imaging presentation. Characteristic findings include enhanced perineural encasement and thickening of the affected optic nerve on contrast-enhanced T1-weighted cranial MR imaging studies. We present the case report of a patient with isolated necrotizing neurosarcoidosis of the left optic nerve, with clinical and MR imaging findings strongly suggestive of a preoperative diagnosis of a meningioma.
