WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene

The Wilms' tumor suppressor gene, WT1, encodes a zinc finger transcription factor that has been demonstrated to negatively regulate several growth fac tor and cognate receptor genes. However, inconsistent with its tumor suppre ssor function, WT1 has also been demonstrated to be required to inhibit pro grammed cell death in vitro and in vivo. Moreover, anaplastic Wilms' tumors , which typically express wild-type WT1, display extreme resistance to chem otherapeutic agents that kill tumor cells through the induction of apoptosi s, Although p53 mutations in anaplastic Wilms' tumors have been associated with chemoresistance, this event is believed to occur late during tumor pro gression. Therefore, since dysregulated WT1 expression occurs relatively ea rly in Wilms' tumors, we hypothesized that WT1 was required to transcriptio nally upregulate genes that provide a cell survival advantage to tumor cell s. Here we demonstrate that sporadic Wilms' tumors coexpress WT1 and the an ti-apoptotic Bcl-2 protein. Using rhabdoid cell lines overexpressing WT1, w e show that WT1 activates the endogenous bcl-2 gene through a transcription al mechanism. Transient transfections and electromobility shift assays demo nstrate that WT1 positively stimulates the bcl-2 promoter through a direct interaction. Moreover, WT1 expressing cells displaying upregulated Bcl-2 we re found to be resistant to apoptosis induced by staurosporine, vincristine and doxorubicine. These data suggest that in certain cellular contexts, WT 1 exhibits oncogenic potential through the transcriptional upregulation of anti-apoptotic genes such as bcl-2.