Characterization Of Wilms Tumor Suppressor Gene Product

维尔姆斯肿瘤抑制基因产物的表征

• 批准号: 7153397
• 负责人: Sean B. Lee
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7153397
• 关键词: Wilms' tumor; chromatin immunoprecipitation; chromosome translocation; gene expression profiling; human tissue; microarray technology; neoplasm /cancer genetics; nephrogenesis; organ culture; pediatric neoplasm /cancer; polymerase chain reaction; transcription factor; tumor suppressor genes; tumor suppressor proteins

The Wilms tumor suppressor gene WT1, which is mutated in 10-15% of Wilms tumor -- a pediatric kidney cancer -- encodes a transcription factor with C2H2 zinc finger DNA binding domain. WT1 is proposed to regulate transcription of genes that are critical for the initiation and differentiation of kidney, gonad, spleen, and adrenal gland since wt1-null mouse embryos lack all of these organs. In addition to Wilms tumor, other human syndromes and diseases are also caused by mutations in the WT1 gene such as Danys-Drash and Frasier syndromes. Using microarray expression profiling, we have identified a number of WT1 target genes that appears to be important for kidney development. The target genes were independently verified using quantitative RT-PCR, chromatin-immunoprecipitation, promoter-reporter assay and expression in WT1-positive cells in the develping kidneys. To examine the physiological role of these targets during kidney development, we used in vitro kidney organ culture assay to determine their effects on kidney differentiation. Identification of the target genes and defining their role during development will provide further insights to the development of Wilms tumor and organogenesis in general.

Wilms肿瘤抑制基因WT 1在10-15%的Wilms肿瘤（一种儿科肾癌）中发生突变，编码一种具有C2 H2锌指DNA结合结构域的转录因子。WT 1被提议调节对于肾、性腺、脾和肾上腺的启动和分化至关重要的基因的转录，因为WT 1缺失的小鼠胚胎缺乏所有这些器官。除了肾母细胞瘤，其他人类综合征和疾病也是由WT 1基因突变引起的，如Danys-Drash综合征和Frasier综合征。使用微阵列表达谱，我们已经确定了一些WT 1的靶基因，似乎是重要的肾脏发育。使用定量RT-PCR、染色质免疫沉淀、启动子-报告基因分析和发育中肾脏WT 1阳性细胞中的表达独立地验证靶基因。为了研究这些靶点在肾脏发育过程中的生理作用，我们使用体外肾器官培养测定来确定它们对肾脏分化的影响。鉴定靶基因并确定其在发育过程中的作用将为肾母细胞瘤的发展和器官发生提供进一步的见解。