Characterization Of Wilms Tumor Suppressor Gene Product

Wilms肿瘤抑制基因WT1在10-15%的Wilms肿瘤(一种儿童肾癌)中发生突变，它编码一种带有C2H2锌指DNA结合域的转录因子。WT1被认为是调节对肾脏、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WT1缺失的小鼠胚胎缺乏所有这些器官。除了Wilms瘤，其他人类综合征和疾病也是由WT1基因突变引起的，例如Danys-Drash和Frasier综合征。特别是，促结缔组织增生性小圆细胞肿瘤(DSRCT)是一种罕见但极具侵袭性的癌症，发生于腹部的青少年。在迄今检查的所有DSRCT病例中，由于染色体易位，在尤文斯肉瘤基因(EWS)和WT1之间产生了一种新的融合基因产物。我们的实验室致力于了解WT1和EWS/WT1基因产物的功能以及它们与各自的癌症生物学的关系。利用微阵列表达谱，我们已经确定了一些WT1靶基因，这些基因似乎对肾脏发育很重要。通过实时定量-聚合酶链式反应、染色质免疫沉淀、启动子-报告基因分析和WT1阳性细胞在发育肾脏中的表达，对目的基因进行了独立的验证。识别靶基因并确定它们在发育过程中的作用将为肾母细胞瘤的发生和器官发生提供更深入的认识。至于EWS/WT1项目，我们目前正在开发一种动物模型，以更好地了解DSRCT的病因和发展，并开发可能的治疗方法，因为DSRCT尚无有效的治疗方法。

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. In particular, Desmoplastic small round cell tumor (DSRCT) is a rare but extremely aggressive cancer arising in young adolescents in the abdominal area. In all cases of DSRCT examined to date, a novel fusion gene product between the Ewings Sarcoma gene (EWS) and the WT1 is created as a result of chromosomal translocation. Our laboratory is focused on understanding the functions of WT1 and EWS/WT1 gene products and how they are related to their respective cancer biology. 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 realtime-PCR, chromatin-immunoprecipitation, promoter-reporter assay and expression in WT1-positive cells in the develping kidneys. 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. As for the EWS/WT1 project, we are currently developing an animal model to better understand the etiology and the development of DSRCT and to develop possible therapeutics since there is no effective treatment for DSRCT.