Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Nucleic Acids Res ; 46(D1): D428-D434, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29136216

RESUMO

Short linear motifs (SLiMs) are protein binding modules that play major roles in almost all cellular processes. SLiMs are short, often highly degenerate, difficult to characterize and hard to detect. The eukaryotic linear motif (ELM) resource (elm.eu.org) is dedicated to SLiMs, consisting of a manually curated database of over 275 motif classes and over 3000 motif instances, and a pipeline to discover candidate SLiMs in protein sequences. For 15 years, ELM has been one of the major resources for motif research. In this database update, we present the latest additions to the database including 32 new motif classes, and new features including Uniprot and Reactome integration. Finally, to help provide cellular context, we present some biological insights about SLiMs in the cell cycle, as targets for bacterial pathogenicity and their functionality in the human kinome.


Assuntos
Bases de Dados de Proteínas , Células Eucarióticas/metabolismo , Interações Hospedeiro-Patógeno/genética , Anotação de Sequência Molecular , Proteínas/química , Software , Motivos de Aminoácidos , Animais , Bactérias/genética , Bactérias/metabolismo , Sítios de Ligação , Ciclo Celular/genética , Células Eucarióticas/citologia , Células Eucarióticas/microbiologia , Células Eucarióticas/virologia , Fungos/genética , Fungos/metabolismo , Humanos , Internet , Modelos Moleculares , Plantas/genética , Plantas/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas/genética , Proteínas/metabolismo , Vírus/genética , Vírus/metabolismo
2.
Cell Syst ; 5(6): 628-637.e6, 2017 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-29199022

RESUMO

The CCCTC-binding factor (CTCF) is known to establish long-range DNA contacts that alter the three-dimensional architecture of chromatin, but how the presence of CTCF influences nearby gene expression is still poorly understood. Here, we analyze CTCF chromatin immunoprecipitation sequencing, RNA sequencing, and Hi-C data, together with genotypes from a healthy human cohort, and measure statistical associations between inter-individual variability in CTCF binding and alternative exon usage. We demonstrate that CTCF-mediated chromatin loops between promoters and intragenic regions are prevalent and that when exons are in physical proximity with their promoters, CTCF binding correlates with exon inclusion in spliced mRNA. Genome-wide, CTCF-bound exons are enriched for genes involved in signaling and cellular stress-response pathways. Structural analysis of three specific examples, checkpoint kinase 2 (CHK2), CDC-like kinase 3 (CLK3), and euchromatic histone-lysine N-methyltransferase (EHMT1), suggests that CTCF-mediated exon inclusion is likely to downregulate enzyme activity by disrupting annotated protein domains. In total, our study suggests that alternative exon usage is regulated by CTCF-dependent chromatin structure.


Assuntos
Fator de Ligação a CCCTC/genética , Cromatina/metabolismo , Regulação da Expressão Gênica , Processamento Alternativo , Quinase do Ponto de Checagem 2/genética , Quinase do Ponto de Checagem 2/metabolismo , Cromatina/genética , Biologia Computacional , Éxons/genética , Genoma , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Variações Dependentes do Observador , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais/genética , Estresse Fisiológico/genética , Relação Estrutura-Atividade
3.
Cell Metab ; 13(4): 389-400, 2011 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-21459324

RESUMO

The aberrant accumulation of lipids in the liver ("fatty liver") is tightly associated with several components of the metabolic syndrome, including type 2 diabetes, coronary heart disease, and atherosclerosis. Here we show that the impaired hepatic expression of transcriptional cofactor transducin beta-like (TBL) 1 represents a common feature of mono- and multigenic fatty liver mouse models. Indeed, the liver-specific ablation of TBL1 gene expression in healthy mice promoted hypertriglyceridemia and hepatic steatosis under both normal and high-fat dietary conditions. TBL1 deficiency resulted in inhibition of fatty acid oxidation due to impaired functional cooperation with its heterodimerization partner TBL-related (TBLR) 1 and the nuclear receptor peroxisome proliferator-activated receptor (PPAR) α. As TBL1 expression levels were found to also inversely correlate with liver fat content in human patients, the lack of hepatic TBL1/TBLR1 cofactor activity may represent a molecular rationale for hepatic steatosis in subjects with obesity and the metabolic syndrome.


Assuntos
Fígado Gorduroso/etiologia , Hipertrigliceridemia/etiologia , Fígado/metabolismo , Transducina/metabolismo , Animais , Gorduras na Dieta/farmacologia , Dimerização , Modelos Animais de Doenças , Humanos , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , PPAR alfa/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Transducina/antagonistas & inibidores , Transducina/genética
4.
Diabetes ; 59(8): 1991-2000, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20522600

RESUMO

OBJECTIVE: Based on its role as an energy storage compartment and endocrine organ, white adipose tissue (WAT) fulfills a critical function in the maintenance of whole-body energy homeostasis. Indeed, WAT dysfunction is connected to obesity-related type 2 diabetes triggered at least partly by an inflammatory response in adipocytes. The pseudokinase tribbles (TRB) 3 has been identified by us and others as a critical regulator of hepatic glucose homeostasis in type 2 diabetes and WAT lipid homeostasis. Therefore, this study aimed to test the hypothesis that the TRB gene family fulfills broader functions in the integration of metabolic and inflammatory pathways in various tissues. RESEARCH DESIGN AND METHODS: To determine the role of TRB family members for WAT function, we profiled the expression patterns of TRB13 under healthy and metabolic stress conditions. The differentially expressed TRB1 was functionally characterized in loss-of-function animal and primary adipocyte models. RESULTS: Here, we show that the expression of TRB1 was specifically upregulated during acute and chronic inflammation in WAT of mice. Deficiency of TRB1 was found to impair cytokine gene expression in white adipocytes and to protect against high-fat diet-induced obesity. In adipocytes, TRB1 served as a nuclear transcriptional coactivator for the nuclear factor kappaB subunit RelA, thereby promoting the induction of proinflammatory cytokines in these cells. CONCLUSIONS: As inflammation is typically seen in sepsis, insulin resistance, and obesity-related type 2 diabetes, the dual role of TRB1 as both a target and a (co) activator of inflammatory signaling might provide a molecular rationale for the amplification of proinflammatory responses in WAT in these subjects.


Assuntos
Tecido Adiposo/fisiopatologia , Inflamação/fisiopatologia , Proteínas Serina-Treonina Quinases/genética , Adipócitos/fisiologia , Animais , Linhagem Celular , Cromatina/fisiologia , Primers do DNA , Humanos , Rim/embriologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/metabolismo , RNA/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA