Characterization Of Wilms Tumor Suppressor Gene Product

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。特别是促纤维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。在迄今为止检查的所有DSRCT病例中，由于染色体易位，产生了尤文氏肉瘤基因（EWS）和WT 1之间的新型融合基因产物。我们的实验室专注于了解WT 1和EWS/WT 1基因产物的功能，以及它们如何与各自的癌症生物学相关。使用微阵列表达谱分析方法，我们正在确定启动和协调器官发生的WT 1靶基因。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。至于EWS/WT 1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没有有效的治疗方法。

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 method, we are in the process of identifying WT1 target genes that initiate and coordinate organogenesis. 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.