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The direct p53 target gene, FLJ11259/DRAM, is a member of a novel family of transmembrane proteins

机译:直接的p53靶基因FLJ11259 / DRAM是新型跨膜蛋白家族的成员

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The tumor suppressor p53 regulates diverse biological processes primarily via activation of downstream target genes. Even though many p53 target genes have been described, the precise mechanisms of p53 biological actions are uncertain. In previous work we identified by inicroarray analysis a candidate p53 target gene, FLJI 1259/DRAM. In this report we have identified three uncharacterized human proteins with sequence homology to FLJ11259, suggesting that FLJ11259 is a member of a novel family of proteins with six transmembrane domains. Several lines of investigation confirm FLJI 1259 is a direct p53 target gene. p53 siRNA prevented cisplatin-mediated upregulation of FLJ11259 in NT2/D1 cells. Likewise in HCT116 p53+/+ cells and MCF10A cells, FLJ11259 is induced by cisplatin treatment but to a much lesser extent in isogenic p53-suppressed cells. A functional p53 response element was identified 22.3 kb upstream of the first coding exon of FLJ11259 and is shown to be active in reporter assays. In addition, chromatin immunoprecipitation assays indicate that p53 binds directly to this element in vivo and that binding is enhanced following cisplatin treatment. Confocal microscopy showed that an FLJ-GFP fusion protein localizes mainly in a punctate pattern in the cytoplasm. Overexpression studies in Cos-7, Saos2, and NT2/D1 cells suggest that FLJ11259 is associated with increased clonal survival. In summary, we have identified FLJ11259/DRAM as a p53-inducible member of a novel family of transmembrane proteins. FLJ11259/DRAM may be an important modulator of p53 responses in diverse tumor types. (C) 2007 Elsevier B.V. All rights reserved.
机译:肿瘤抑制因子p53主要通过激活下游靶基因来调节多种生物学过程。尽管已经描述了许多p53靶基因,但p53生物学作用的确切机制尚不确定。在先前的工作中,我们通过微阵列分析鉴定了候选的p53靶基因FLJI 1259 / DRAM。在本报告中,我们鉴定了三种与FLJ11259具有序列同源性的未表征的人类蛋白质,这表明FLJ11259是具有六个跨膜结构域的新型蛋白质家族的成员。多项研究证实,FLJI 1259是直接的p53靶基因。 p53 siRNA阻止了顺铂介导的NT2 / D1细胞中FLJ11259的上调。同样在HCT116 p53 + / +细胞和MCF10A细胞中,通过顺铂处理诱导FLJ11259,但在同基因的p53抑制的细胞中程度较小。在FLJ11259的第一个编码外显子上游22.3 kb处鉴定到功能性p53反应元件,并在报告基因分析中显示有活性。此外,染色质免疫沉淀试验表明p53在体内直接与该元件结合,顺铂处理后结合增强。共聚焦显微镜显示,FLJ-GFP融合蛋白主要定位在细胞质中呈点状。在Cos-7,Saos2和NT2 / D1细胞中的过表达研究表明,FLJ11259与克隆存活率提高有关。总而言之,我们已经鉴定出FLJ11259 / DRAM是新型跨膜蛋白家族的p53诱导成员。 FLJ11259 / DRAM可能是多种肿瘤类型中p53反应的重要调节剂。 (C)2007 Elsevier B.V.保留所有权利。

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