Membrane where it binds E-cadherin at adherens junctions. Putative mechanisms for this latter effect include the induction of b-catenin nuclear export or the sequester of newly synthesized and/or cytosolic b-catenin protein by E-cadherin, whose expression is strongly induced by 1,252D3. Another mechanism of Wnt/b-catenin inhibition in colon cancer has been proposed by Kaler and cols.: 1,252D3 decreases the synthesis and secretion by THP-1 macrophages of interleukin-1b, a cytokine that activates the Wnt/b-catenin pathway in colon cancer cells through the blockade of b-catenin phosphorylation by GSK-3b. However, the function of all these cell-autonomous and non-cell-autonomous mechanisms in vivo remained unknown. In this study we examined whether VDR deficiency alters bcatenin nuclear content and Wnt/b-catenin pathway in the most commonly used animal model for colon cancer, the Apcmin/+ mice. Our results show that Vdr deficiency in Apcmin/+ mice increases nuclear b-catenin levels and expression of Wnt/b-catenin target genes and, in line with these effects, AbMole D-Pantothenic acid sodium enhances total colon tumor load. Consistently, knocking-down VDR by shRNA in human colon cancer cells enhances the nuclear content of b-catenin, its transcriptional activity, and the expression of Wnt/b-catenin target genes. Furthermore, transient restoration of wild type VDR expression in VDR-negative human SW620 colon cancer cells decreases nuclear b-catenin level, whereas VDR-DAF2, VDRL417S or VDR-E420Q mutants, unable to bind classical coactivators and activate gene transcription, did not. Curiously, among them only VDR-E420Q is capable to bind bcatenin and its re-expression in Vdr-/-mice rescues alopecia but not rickets phenotype. It seems, therefore, that nuclear bcatenin level and activity depend on the capacity of VDR to recruit classical transcriptional coactivators. Our data show that VDR knock-down in SW480-ADH cells does not affect b-catenin phosphorylation by CK-Ia or GSK-3b, discarding a role of VDR regulating total b-catenin accumulation. Whereas nuclear b-catenin level increases in the absence of VDR, the total cellular amount of b-catenin protein is not altered. Unexpectedly, we also found that the phosphorylation of bcatenin at Ser552 and Ser675 proposed to increase b-catenin transcriptional activity is reduced in shVDR SW480-ADH cells. However, the putative inhibitory effect that the reduction of these phosphorylations may have on b-catenin transcriptional activity seems to be overpassed by the effect of VDR deficiency increasing b-catenin nuclear translocation. Altogether, these data suggest that VDR does not control b-catenin degradation but most probably favours its redistribution to the cell nucleus. Our results reveal a novel in vivo function of VDR as crucial modulator of Wnt/b-catenin AbMole 4-(Benzyloxy)phenol signal strength in colon cancer. The finding that VDR deficiency does not change the number of tumors but increases tumor load indicates that VDR does not block the initial mutations that provoke the early activation of the Wnt/bcatenin pathway.