Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Int J Mol Sci ; 21(11)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32492816

RESUMO

Switch/sucrose non-fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin (SMARC) subfamily B member 1 (SMARCB1) is a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, one of the adenosine triphosphate (ATP)-dependent chromatin remodeler complexes. The unique role of SMARCB1 has been reported in various cellular contexts. Here, we focused on the general role of the ubiquitous expression of SMARCB1 in a normal cell state. We selected ARPE19 (human primary retinal pigment epithelium) and IMR90 (from human fetal lung fibroblasts) cell lines as they have completely different contexts. Furthermore, although these cell lines have been immortalized, they are relatively close to normal human cells. The loss of SMARCB1 in ARPE19 and IMR90 cells reduced cell cycle progression via the upregulation of P21. Transcriptome analysis followed by SMARCB1 knockdown in both cell lines revealed that SMARCB1 was not only involved in cell maintenance but also conferred immunomodulation. Of note, SMARCB1 bound to interleukin (IL) 6 promoter in a steady state and dissociated in an active immune response state, suggesting that SMARCB1 was a direct repressor of IL6, which was further confirmed via loss- and gain-of-function studies. Taken together, we demonstrated that SMARCB1 is a critical gatekeeper molecule of the cell cycle and immune response.


Assuntos
Regulação da Expressão Gênica , Epitélio Pigmentado da Retina/metabolismo , Proteína SMARCB1/fisiologia , Trifosfato de Adenosina/metabolismo , Ciclo Celular , Linhagem Celular , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Humanos , Imunidade , Interleucina-6/metabolismo , Transcriptoma
2.
Bull Cancer ; 107(1): 41-47, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31916995

RESUMO

A growing number of studies suggest a tumor suppressor role for the SWI/SNF complex involved in the remodeling of chromatin. Alterations of this complex have been found in many tumors of different origins, with topographic, morphologic and phenotypic diversity. Notably, they define 2 types of thoracic tumors: SMARCA4-deficient non-small cell lung carcinoma and SMARCA4-deficient sarcoma. Some clinical features appear to be common to both, such as intrathoracic localization, smoking exposure, male predominance and poor prognosis. However, the histological distinction between these two entities is sometimes difficult and it is not excluded that these entities belong to the same tumor spectrum with different degrees of differentiation. The therapy of these tumors is not yet codified. These tumors do not seem associated with oncogenic driver mutations allowing the prescription of targeted therapy, but immunotherapy has been shown to be effective in rare reported cases. More specific treatments using EZH2 inhibitors also seem promising in SMARCA4 deficient sarcomas.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Montagem e Desmontagem da Cromatina , DNA Helicases/deficiência , Proteínas de Neoplasias/deficiência , Proteínas Nucleares/deficiência , Sarcoma/genética , Neoplasias Torácicas/genética , Fatores de Transcrição/deficiência , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/fisiologia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , DNA Helicases/fisiologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/terapia , Terapia de Alvo Molecular , Complexos Multiproteicos/efeitos dos fármacos , Complexos Multiproteicos/fisiologia , Invasividade Neoplásica , Proteínas de Neoplasias/fisiologia , Proteínas Nucleares/fisiologia , Proteína SMARCB1/fisiologia , Sarcoma/patologia , Sarcoma/terapia , Neoplasias Torácicas/patologia , Neoplasias Torácicas/terapia , Fatores de Transcrição/fisiologia
3.
Genet Med ; 21(3): 572-579, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29907796

RESUMO

PURPOSE: SMARCB1 encodes a subunit of the SWI/SNF complex involved in chromatin remodeling. Pathogenic variants (PV) in this gene can give rise to three conditions. Heterozygous loss-of-function germline PV cause rhabdoid tumor predisposition syndrome and schwannomatosis. Missense PV and small in-frame deletions in exons 8 and 9 result in Coffin-Siris syndrome, which is characterized by intellectual disability (ID), coarse facial features, and fifth digit anomalies. METHODS: By a gene matching approach, individuals with a similar SMARCB1 PV were identified. Informed consent was obtained and patient data were collected to further establish genotype-phenotype relationship. RESULTS: A recurrent de novo missense PV (c.110G>A;p.Arg37His) in exon 2 of SMARCB1, encoding the DNA-binding domain, was identified in four individuals from different genetic centers. They shared a distinct phenotype consisting of profound ID and hydrocephalus due to choroid plexus hyperplasia. Other shared features include severe neonatal feeding difficulties; congenital heart, kidney, and eye anomalies; obstructive sleep apnea; and anemia. CONCLUSION: The p.Arg37His PV in the DNA-binding domain of SMARCB1 causes a distinctive syndrome, likely through a gain-of-function or dominant-negative effect, which is characterized by severe ID and hydrocephalus resulting from choroid plexus hyperplasia. This report broadens the phenotypic spectrum associated with PV in SMARCB1.


Assuntos
Hidrocefalia/genética , Deficiência Intelectual/genética , Proteína SMARCB1/genética , Adolescente , Criança , Pré-Escolar , Plexo Corióideo/fisiopatologia , Montagem e Desmontagem da Cromatina/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Exoma , Fácies , Feminino , Estudos de Associação Genética , Humanos , Hiperplasia/genética , Lactente , Masculino , Proteínas Nucleares/genética , Fenótipo , Proteína SMARCB1/fisiologia , Fatores de Transcrição/genética
4.
Anticancer Res ; 38(12): 6865-6868, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30504402

RESUMO

BACKGROUND/AIM: Switch/sucrose non-fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), also named integrase interactor 1, is one of the core subunit proteins in the SWI/SNF ATP-dependent chromatin remodeling complex encoded at chromosomal position 22q11.2. Complete loss of SMARCB1 expression has been reported in various malignant tumors. Immunohistochemistry has demonstrated that SMARCB1 mutation/inactivation correlates well with loss of nuclear SMARCB1 expression. This study investigated SMARCB1 expression in hepatocellular carcinomas (HCCs) and α-fetoprotein (AFP)-producing gastric carcinomas by immunohistochemistry. For comparison, SMARCB1 immunostaining in intrahepatic cholangiocarcinoma (ICC) was also performed. MATERIALS AND METHODS: Thirty classical HCCs, 30 ICCs and 10 AFP-producing gastric carcinomas were analyzed. RESULTS: Only one case of HCC had focal labeling of SMARCB1 in the nuclei. Twelve cases of ICC were immunopositive for SMARCB1, with either focal or diffuse reactivity. All AFP-producing gastric carcinomas were immunopositive for SMARCB1 in the nuclei, and the reactivity was consistently diffuse. CONCLUSION: SMARCB1 is a potential marker for distinguishing metastatic AFP-producing gastric carcinoma from HCC.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Carcinoma Hepatocelular/diagnóstico , Colangiocarcinoma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Proteína SMARCB1/metabolismo , Neoplasias Gástricas/diagnóstico , alfa-Fetoproteínas/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Diagnóstico Diferencial , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metástase Neoplásica , Valor Preditivo dos Testes , Proteína SMARCB1/fisiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
5.
Am J Pathol ; 188(7): 1510-1516, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29684361

RESUMO

The new paradigm of mutations in chromatin-modifying genes as driver events in the development of cancers has proved challenging to resolve the complex influences over disease phenotypes. In particular, impaired activities of members of the SWI/SNF chromatin remodeling complex have appeared in an increasing variety of tumors. Mutations in SNF5, a member of this ubiquitously expressed complex, arise in almost all cases of malignant rhabdoid tumor in the absence of additional genetic alterations. Therefore, we studied how activation of additional oncogenic pathways might shift the phenotype of disease driven by SNF5 loss. With the use of a genetically engineered mouse model, we examined the effects of a hypomorphic Vhl2B allele on disease phenotype, with a modest up-regulation of the hypoxia response pathway. Snf5+/-;Vhl2B/+ mice did not demonstrate a substantial difference in overall survival or a change in malignant rhabdoid tumor development. However, a high percentage of female mice showed complex hemorrhagic ovarian cysts, a phenotype rarely found in either parental mouse strain. These lesions also showed mosaic expression of SNF5 by immunohistochemistry. Therefore, our studies implicate that modest changes in angiogenic regulation interact with perturbations of SWI/SNF complex activity to modulate disease phenotypes.


Assuntos
Hemorragia/patologia , Mutação , Cistos Ovarianos/patologia , Proteína SMARCB1/fisiologia , Proteína Supressora de Tumor Von Hippel-Lindau/fisiologia , Animais , Feminino , Hemorragia/etiologia , Hemorragia/metabolismo , Camundongos , Camundongos Knockout , Cistos Ovarianos/etiologia , Cistos Ovarianos/metabolismo , Fenótipo
6.
Cancer Res ; 77(4): 862-873, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27923836

RESUMO

Components of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in various human cancers, yet only SMARCB1/hSNF5, a core member of the SWI/SNF complex, is mutated in malignant rhabdoid tumors (MRT). How SMARCB1/hSNF5 functions differently from other members of the SWI/SNF complex remains unclear. Here, we use Drosophila imaginal epithelial tissues to demonstrate that Snr1, the conserved homolog of human SMARCB1/hSNF5, prevents tumorigenesis by maintaining normal endosomal trafficking-mediated signaling cascades. Removal of Snr1 resulted in neoplastic tumorigenic overgrowth in imaginal epithelial tissues, whereas depletion of any other members of the SWI/SNF complex did not induce similar phenotypes. Unlike other components of the SWI/SNF complex that were detected only in the nucleus, Snr1 was observed in both the nucleus and the cytoplasm. Aberrant regulation of multiple signaling pathways, including Notch, JNK, and JAK/STAT, was responsible for tumor progression upon snr1-depletion. Our results suggest that the cytoplasmic Snr1 may play a tumor suppressive role in Drosophila imaginal tissues, offering a foundation for understanding the pivotal role of SMARCB1/hSNF5 in suppressing MRT during early childhood. Cancer Res; 77(4); 862-73. ©2017 AACR.


Assuntos
Proteínas de Drosophila/fisiologia , Discos Imaginais/fisiologia , Fatores de Transcrição/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Proteínas de Drosophila/análise , Drosophila melanogaster , Endossomos/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Receptores Notch/fisiologia , Proteína SMARCB1/fisiologia , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/análise
7.
Cancer Res ; 76(19): 5810-5821, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27503929

RESUMO

Anthracyclines are among the most effective yet most toxic drugs used in the oncology clinic. The nucleosome-remodeling SWI/SNF complex, a potent tumor suppressor, is thought to promote sensitivity to anthracyclines by recruiting topoisomerase IIa (TOP2A) to DNA and increasing double-strand breaks. In this study, we discovered a novel mechanism through which SWI/SNF influences resistance to the widely used anthracycline doxorubicin based on the use of a forward genetic screen in haploid human cells, followed by a rigorous single and double-mutant epistasis analysis using CRISPR/Cas9-mediated engineering. Doxorubicin resistance conferred by loss of the SMARCB1 subunit of the SWI/SNF complex was caused by transcriptional upregulation of a single gene, encoding the multidrug resistance pump ABCB1. Remarkably, both ABCB1 upregulation and doxorubicin resistance caused by SMARCB1 loss were dependent on the function of SMARCA4, a catalytic subunit of the SWI/SNF complex. We propose that residual SWI/SNF complexes lacking SMARCB1 are vital determinants of drug sensitivity, not just to TOP2A-targeted agents, but to the much broader range of cancer drugs effluxed by ABCB1. Cancer Res; 76(19); 5810-21. ©2016 AACR.


Assuntos
Montagem e Desmontagem da Cromatina , DNA Helicases/fisiologia , Proteínas Nucleares/fisiologia , Proteína SMARCB1/fisiologia , Fatores de Transcrição/fisiologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Haploidia , Humanos , Transcrição Gênica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...