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1.
Hum Mol Genet ; 15(18): 2709-20, 2006 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-16893906

RESUMEN

The molecular etiology of obesity predisposition is largely unknown. Here, we present evidence that genetic variation in TBC1D1 confers risk for severe obesity in females. We identified a coding variant (R125W) in TBC1D1 that segregated with the disease in 4p15-14-linked obesity pedigrees. In cases derived from pedigrees with the strongest linkage evidence, the variant was significantly associated with obesity (P=0.000007) and chromosomes carrying R125W accounted for the majority of the evidence that originally linked 4p15-14 with the disease. In addition, by selecting families that segregated R125W with obesity, we were able to generate highly significant linkage evidence for an obesity predisposition locus at 4q34-35. This result provides additional and confirming evidence that R125W affects obesity susceptibility, delimits the location of an obesity gene at 4q34-35 and identifies a gene/gene interaction that influences the risk for obesity predisposition. Finally, although the function of TBC1D1 is unknown, the protein is structurally similar to a known regulator of insulin-mediated Glut4 translocation.


Asunto(s)
Endopeptidasas/genética , Obesidad/genética , Proteínas Oncogénicas/genética , Cromosomas Humanos Par 4/genética , Femenino , Expresión Génica , Variación Genética , Haplotipos , Humanos , Desequilibrio de Ligamiento , Escala de Lod , Masculino , Obesidad/etiología , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Distribución Tisular , Ubiquitina Tiolesterasa
2.
Cancer Cell ; 9(5): 405-16, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16697960

RESUMEN

Our understanding of Ewing's sarcoma development mediated by the EWS/FLI fusion protein has been limited by a lack of knowledge regarding the tumor cell of origin. To circumvent this, we analyzed the function of EWS/FLI in Ewing's sarcoma itself. By combining retroviral-mediated RNA interference with reexpression studies, we show that ongoing EWS/FLI expression is required for the tumorigenic phenotype of Ewing's sarcoma. We used this system to define the full complement of EWS/FLI-regulated genes in Ewing's sarcoma. Functional analysis revealed that NKX2.2 is an EWS/FLI-regulated gene that is necessary for oncogenic transformation in this tumor. Thus, we developed a highly validated transcriptional profile for the EWS/FLI fusion protein and identified a critical target gene in Ewing's sarcoma development.


Asunto(s)
Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Genes Relacionados con las Neoplasias/genética , Proteínas de Homeodominio/genética , Proteínas de Fusión Oncogénica/genética , Sarcoma de Ewing/genética , Factores de Transcripción/genética , Animales , Transformación Celular Neoplásica , Proteína Homeobox Nkx-2.2 , Humanos , Ratones , Ratones Desnudos , Análisis por Micromatrices , Proteínas Nucleares , Proteína Proto-Oncogénica c-fli-1 , Interferencia de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína EWS de Unión a ARN , Retroviridae/genética , Transcripción Genética , Proteínas de Pez Cebra
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