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The WT1 Wilms’ Tumor Suppressor Gene: A Novel Target for Insulin-Like Growth Factor-I Action

Department of Clinical Biochemistry (I.B., H.W.), Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and Diabetes Branch, National Institute of Diabetes, Digestive, and Kidney Diseases (D.L.), National Institutes of Health, Bethesda, Maryland 20892-1758

Address all correspondence and requests for reprints to: Haim Werner, Ph.D., Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: hwerner{at}post.tau.ac.il.

Abstract

IGF-I stimulates cell division in numerous cell types after activation of the IGF-I receptor, a transmembrane heterotetramer linked to the ras-raf-MAPK and phosphatidylinositol 3-kinase signaling pathways. The WT1 Wilms’ tumor suppressor is a zinc finger-containing transcription factor that is involved in a number of developmental processes, as well as in the etiology of certain neoplasias. In the present study, we demonstrated that IGF-I reduced WT1 expression in osteosarcoma-derived Saos-2 cells in a time- and dose-dependent manner. This effect was mediated through the MAPK signaling pathway, as shown by the ability of the specific inhibitor UO126 to abrogate IGF-I action. Furthermore, the effect of IGF-I involved repression of transcription from the WT1 gene promoter, as demonstrated using transient transfection assays. Taken together, our results suggest that the WT1 gene is a novel downstream target for IGF-I action. Reduced levels of WT1 may facilitate IGF-I-stimulated cell cycle progression. Most importantly, inhibition of WT1 gene expression by IGF-I may have significant implications in terms of cancer initiation and/or progression.