The WT1 Wilms' tumor suppressor gene: a novel target for insulin-like growth factor-I action.
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.
Bentov
Itay
I
Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
LeRoith
Derek
D
Werner
Haim
H
D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015870:Gene Expression / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D016162:Genes, Wilms Tumor / Q000187:drug effects*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases