Promise of vitamin D analogues in the treatment of hyperproliferative conditions

Model of the transcriptional mechanism of action of 1α,25-(OH)₂D₃ enters the picture at 1 o'clock interacting with the unliganded VDR-retinoid X receptor basal complex and locating the vitamin D–responsive element–containing vitamin D–dependent gene. The initial steps in activation involving conformational changes in the VDR and recruitment of coactivators are shown in the 3 o'clock complex. At this point, a SWI/SWF chromatin remodeling complex affects changes in chromatin allowing recruitment of the transcription initiation complex, including attraction of DRIPs shown at 6 o'clock. Active transcription of the vitamin D–dependent gene occurs. The complex at 9 o'clock is involved in turning over the VDR and recycling the rest of the transcriptional machinery. Note that the ligand 1α,25-(OH)₂D₃ is also subject to degradation by CYP24A1, an inducible cytochrome P450 found in the target cell. Reproduced from ref. 20; Figure 9 in Chapter 13 in “Vitamin D 2nd Edition” published by Elsevier, New York. With kind permission from G. Kerr Whitfield and Mark R. Haussler and Elsevier.