WILMS-TUMOR 1-KTS ISOFORMS INDUCE P53-INDEPENDENT APOPTOSIS THAT CAN BE PARTIALLY RESCUED BY EXPRESSION OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR OR THE INSULIN-RECEPTOR

The Wilms' tumor 1 gene (WT1) encodes a transcription factor of the zi nc-finger family, As a result of alternative RNA splicing, the gene ca n be expressed as four polypeptides that differ in the presence or abs ence of a stretch of 17 amino acids just NH2 terminal of the four zinc fingers and a stretch of three amino acids (+/-KTS) between zinc fing ers 3 and 4, In this study, cDNA constructs encoding the four human Wi lms' tumor 1 splice variants were transiently transfected into the p53 -negative Hep3B and the p53-positive HepG2 hepatoma cell lines, Morpho logical assessment of the WT1-expressing cells showed that the WT1(-KT S) splice variants induced apoptosis in both cell lines, whereas the W T1(+KTS) isoforms did not, The induction of apoptosis by the WT1(-KTS) isoforms appears to be p53 independent in the hepatoma cell lines, Fu rthermore, it was found that the WT1(-KTS)-induced apoptosis could not be suppressed by coexpression of either the M(r) 21,000 E1B, the Bcl- 2, or the BAG-1 protein, Coexpression of either the epidermal growth f actor receptor or the insulin receptor, however, partially rescued the cells from apoptosis.