FIGURE 9.

Proposed model for nuclear import of VDR, RXR, and VDR/RXR interaction and DNA binding in non-transformed and Ras-transformed cells. In normal cells (A), the nuclear import of VDR and RXR is mediated by their respective ligands. Once in the nucleus, 1,25(OH)₂D₃ binding to VDR is critical for the VDR-RXR heterodimer interaction and binding to the hormone-response elements, recruitment of co-factors (CoAc), and effect on 1,25(OH)₂D₃ signaling. In the Ras-transformed keratinocyte (B), phosphorylation of RXR prevents the nuclear translocation of RXR and binding of the VDR-RXR complex to the hormone-response element. The recruitment of co-factors was impaired thus preventing 1,25(OH)₂D₃ signaling. Using either the MEK inhibitor UO126 or a non-phosphorylable RXR mutant, we can restore the cells nuclear import of RXR, VDR/RXR, as well as interaction with DNA and 1,25(OH)₂D₃ and VDR signaling.