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1.
PLoS Genet ; 8(12): e1003070, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23284286

RESUMEN

Bladder exstrophy epispadias complex (BEEC) is a severe congenital anomaly; however, the genetic and molecular mechanisms underlying the formation of BEEC remain unclear. TP63, a member of TP53 tumor suppressor gene family, is expressed in bladder urothelium and skin over the external genitalia during mammalian development. It plays a role in bladder development. We have previously shown that p63(-/-) mouse embryos developed a bladder exstrophy phenotype identical to human BEEC. We hypothesised that TP63 is involved in human BEEC pathogenesis. RNA was extracted from BEEC foreskin specimens and, as in mice, ΔNp63 was the predominant p63 isoform. ΔNp63 expression in the foreskin and bladder epithelium of BEEC patients was reduced. DNA was sequenced from 163 BEEC patients and 285 ethnicity-matched controls. No exon mutations were detected. Sequencing of the ΔNp63 promoter showed 7 single nucleotide polymorphisms and 4 insertion/deletion (indel) polymorphisms. Indel polymorphisms were associated with an increased risk of BEEC. Significantly the sites of indel polymorphisms differed between Caucasian and non-Caucasian populations. A 12-base-pair deletion was associated with an increased risk with only Caucasian patients (p = 0.0052 Odds Ratio (OR) = 18.33), whereas a 4-base-pair insertion was only associated with non-Caucasian patients (p = 0.0259 OR = 4.583). We found a consistent and statistically significant reduction in transcriptional efficiencies of the promoter sequences containing indel polymorphisms in luciferase assays. These findings suggest that indel polymorphisms of the ΔNp63 promoter lead to a reduction in p63 expression, which could lead to BEEC.


Asunto(s)
Extrofia de la Vejiga , Epispadias , Mutación INDEL/genética , Regiones Promotoras Genéticas , Factores de Transcripción , Proteínas Supresoras de Tumor , Animales , Extrofia de la Vejiga/genética , Extrofia de la Vejiga/patología , Epispadias/genética , Epispadias/patología , Femenino , Regulación de la Expresión Génica , Humanos , Ratones , Mutagénesis Insercional , Polimorfismo Genético , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
2.
J Virol ; 79(17): 11443-56, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16103195

RESUMEN

Retroviral tagging has been used extensively and successfully to identify genes implicated in cancer pathways. In order to find oncogenes implicated in T-cell leukemia, we used the highly leukemogenic radiation leukemia retrovirus VL3 (RadLV/VL3). We applied the inverted PCR technique to isolate and analyze sequences flanking proviral integrations in RadLV/VL3-induced T lymphomas. We found retroviral integrations in c-myc and Pim1 as already reported but we also identified for the first time Notch1 as a RadLV common integration site. More interestingly, we found a new RadLV common integration site that is situated on mouse chromosome X (XA4 region, bp 45091000). This site has also been reported as an SL3-3 and Moloney murine leukemia virus integration site, which strengthens its implication in murine leukemia virus-induced T lymphomas. This locus, named Kis2 (Kaplan Integration Site 2), was found rearranged in 11% of the tumors analyzed. In this article, we report not only the alteration of the Kis2 gene located nearby in response to RadLV integration but also the induction of the expression of Phf6, situated about 250 kbp from the integration site. The Kis2 gene encodes five different alternatively spliced noncoding RNAs and the Phf6 gene codes for a 365-amino-acid protein which contains two plant homology domain fingers, recently implicated in the Börjeson-Forssman-Lehmann syndrome in humans. With the recent release of the mouse genome sequence, high-throughput retroviral tagging emerges as a powerful tool in the quest for oncogenes. It also allows the analysis of large DNA regions surrounding the integration locus.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Nucleares/metabolismo , ARN no Traducido/metabolismo , ARN Viral/metabolismo , Virus de la Leucemia Inducida por Radiación/fisiología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Leucemia Experimental/virología , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/genética , Datos de Secuencia Molecular , Células 3T3 NIH , Proteínas Nucleares/genética , ARN Mensajero/genética , ARN Viral/genética , Receptor Notch1 , Receptores de Superficie Celular/genética , Infecciones por Retroviridae/virología , Alineación de Secuencia , Factores de Transcripción/genética , Infecciones Tumorales por Virus/virología , Integración Viral , Cromosoma X/genética , Región del Complejo T del Genoma
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