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.
The Aims of this project are:
Aim 1. To identify WT1 target genes by using microarray expression profiling analysis, and to validate the result using independent methods.
Aim 2. Validated targets will be further tested for their role in kindey development. To this end, we will examine the expression patterns of the target genes by RNA in-situ or immunohistochemistry during kidney development. In addition, in vitro kidney organ culture system will be utilized to examine the functional role of the target genes. This will be accomplished by using the combination of siRNA or shRNA, and neutralizing antibodies.
Aim 3. The roles of WT1 target genes in Wilms tumor. The identified targets will be further examined for their role in tumorigenesis. This will be done by looking at expression levels and mutations in the tumor samples. Candidate targets will then be further tested in cell lines for possible transformation and growth-promoting properties. 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.
| Li, Hongjie; Watford, Wendy; Li, Cuiling et al. (2007) Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development. J Clin Invest 117:1314-23 |
| Kim, Ho-Shik; Kim, Myoung Shin; Hancock, Anne L et al. (2007) Identification of novel Wilms'tumor suppressor gene target genes implicated in kidney development. J Biol Chem 282:16278-87 |
| Srichai, Manakan B; Konieczkowski, Martha; Padiyar, Aparna et al. (2004) A WT1 co-regulator controls podocyte phenotype by shuttling between adhesion structures and nucleus. J Biol Chem 279:14398-408 |
