Characterization of the Wilms tumor gene product WT1

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We examined the function of WT1 in cellular proliferation and differentiation, and obtained the following results.1. Microinjection of the WT1 cDNA in NIH3T3 cells blocked serum-induced cell cycle progression into S phase. The inhibitory activity of WT1 was abrogated by the overexpression of cyclin E/CDK2 as well as cyclin D1/CDK4. Furthermore, both CDK4- and CDK2-associated kinase activities were downregulated in cells overexpressing WT1, whereas the levels of CDK4, CDK2 and cyclin D1 expression were unchanged. These findings suggest that inhibition of the activity of cyclin/CDK complexes may be involved in mediating the WT1-induced cell cycle block.2. The expression of WT1 decreased during retinoic acid-induced differentiation of embryonal carcinoma F9 cells. Cell lines constitutively expressing the exogenous WT1 failed to differentiate into primitive endoderm cells and underwent apoptotic death, suggesting that downregulation of WT1 expression is necessary for normal differentiation of F9 cells into parietal endoderm cells. We also found that WT1 is a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukeia.3. Using a yeast two-hybrid system, we obtained a novel cDNA clone which encodes a putative WT1-associated protein. Detailed characterization of this protein is underway in our laboratory.