The Wilms' tumor gene product (WT1) modulates the response to 1,25-dihydroxyvitamin D-3 by induction of the vitamin D receptor

The Wilms' tumor gene (wt1) encodes a transcription factor involved in urog enital development, in particular in renal differentiation, and in hematopo ietic differentiation. Differentiation of a number of solid tumor and leuke mic cells lines can be mediated by 1,25-dihydroxyvitamin D-3. This is predo minantly mediated by the nuclear receptor for 1,25-dihydroxyvitamin D-3, th e vitamin D receptor (VDR). In initial experiments addressing a possible li nk between WT1 and VDR, we observed a correlated expression of WT1 and VDR mRNA in samples from renal tissues. HT29 colon carcinoma cells, stably tran sfected to express WT1, exhibited elevated endogenous VDR levels compared w ith control cells transfected with a control construct. Elevated VDR expres sion was found in wt1-transfected human embryonic kidney 293 cells, as well . In transient cotransfection experiments, we observed an activation of a v dr promoter reporter by WT1 through a WT1 recognition element, indicating t ranscriptional regulation of the vdr gene expression by WT1. The responsive sequence element was specifically bound by wild-type, but not by mutated W T1, in electrophoretic mobility shift assays. HT29 colon carcinoma cells, w hich respond to 1,25-dihydroxyvitamin D, with slow induction of growth arre st, were investigated for the influence of WT1 on 1,25-dihydroxyvitamin D-3 -mediated growth suppression. Although HT29 cells transfected with a contro l construct responded moderately to 1,25-dihydroxyvitamin Dar the response of HT29 cells expressing WT1 was strikingly enhanced, Stimulation with dihy droxyvitamin D, caused an up to 3-fold reduction in the growth rate of diff erent HT29 clones expressing WT1 as compared with control cells lacking WT1 expression. Thus, induction of VDR by WT1 leads to an enhanced response to 1,25-dihydroxyvitamin D-3. We conclude that the vitamin D receptor gene is a target for transcriptional activation by WT1, suggesting a possible phys iological role of this regulatory pathway.