WT1 influences apoptosis through transcriptional regulation of Bcl-2 family members

WT1 is a zinc finger transcriptional regulatory protein that has been implicated in both normal development and in the generation of a variety of malignancies. Alternative splicing of the WT1 mRNA results in the expression of four major protein isoforms. There is increasing evidence that one of the functions of WT1 is the regulation of apoptosis, but there are conflicting reports about whether WT1 is pro- or anti-apoptotic. Careful review of the literature suggests that these apparent contradictions probably reflect cell lineage and isoform-specific differences in WT1 function. Expression of WT1 prevents programmed cell death in some cell types but promotes it in others, and different WT1 isoforms exert distinct effects as well. Investigation into the mechanisms by which WT1 regulates apoptosis has revealed that several bcl-2 family members are either direct or indirect WT1 target genes, including bcl-2 itself, the pro-apoptotic family members Bak and Bax, and the anti-apoptotic family member Bfl-1/A1. The specific bcl-2 family members regulated by WT1 expression vary by cell type and by isoform. Thus, a complete understanding of the role of WT1 in apoptosis will have to account for lineage- and isoform-specific effects of WT1 at both the cellular and molecular levels.