ROLE OF TUMOR SUPPRESSOR GENE IN CHEMICALS CARCINOGENESI

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The objective of our laboratory is to understand the role of oncogenes and tumor suppressor genes in the inception, development and progression of neoplasia. Towards this goal, we are using chemically-induced rodent tumor model systems. Rat mammary and kidney tumors induced by neonatal exposure to N-nitroso N'methylurea (NMU) were found to contain point mutated H-and K-ras oncogenes. Two steps were defined 1) tumor initiation by ras activation in both mammary gland and kidney and 2) promotion of mammary tumorigenesis by hormones. In an effort to investigate additional genetic changes involved in tumorigenesis by NMU, we propose to study the role of the Wilms' tumor suppressor gene (WT1) in the development of kidney neoplasms. The rat kidney tumors resemble human Wilms' tumors, consisting of aggressive mesenchymal tumors and nephroblastomas that originate from the cells of the embryonal metanephric mesenchyme. The WT1 gene is often deleted or mutated in the human kidney tumors. To study whether similar molecular mechanisms are at play in the rat and human tumors, we cloned the full length rat WT1 cDNA. We have recently discovered that the peak of WT1 mRNA expression in the rat occurs at one week of age, coinciding with the time during which the rats are most susceptible to NMU-mediated development of kidney tumors. We found that mRNA levels of WT1 in the tumors are abnormally high in the kidney tumors compared to the adult kidney, suggesting a loss of gene regulation in the tumors. Thus, the kidney tumors show great promise as a model for studying the molecular and biological basis of Wilms' tumor development in human. Pursuing the leads offered by our preliminary results, we will 1) look for alterations by deletion and/or mutation in the WT1 gene as well as its 5' regulatory region, 2) determine whether the expression of WT1 protein is altered in the tumors, 3) study whether the normal WT1 gene has tumor suppressor functions and 4) determine whether WT1 contributes to neoplastic transformation of cells in vitro.