Ligands of nuclear hormone receptors. Depicts schematically the molecular mechanisms of differentiation induction of nuclear hormone receptor agonists. (A) All-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL). The characteristic chromosomal translocation t(15;17)(q22;q21) in APL leads to the production of a fusion protein between the PML protein and the retinoic acid receptor alpha (RARα). This fusion product is able to form homodimers and disrupt normal RARα signaling. It binds to retinoic acid response elements (RAREs) of target genes and recruits corepressors (Co-Rs) such as histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), and sequesters retinoic X receptor (RXR) and the wild-type PML protein (PML), which finally leads to repression of genes necessary for granulocytic differentiation. Treatment with pharmacological concentrations of ATRA causes a conformational change of the PML-RARα fusion product leading to the release of the corepressors, recruitment of histone acetyl transferases (HATs), and relief of transcriptional repression. This causes the treated APL cells to undergo terminal granulocytic differentiation and finally apoptosis. (B) Biologically active vitamin D [1,25(OH)₂D₃] binds to the nuclear vitamin D receptor (VDR), which heterodimerizes with retinoic X receptor (RXR). This activated complex binds to vitamin D response elements (VDREs) in the promoter regions of genes inducing cell-cycle arrest, apoptosis, and differentiation in cancer cells. Furthermore, it leads to an up-regulation of the antimicrobial peptide cathelicidin (CAMP) in myeloid cells. (C) Thiazolidinediones (TZDs) bind to peroxisome proliferator activated receptor gamma (PPARγ). This activated complex acts as a transcription factor by heterodimerizing with (RXR) and binding to PPARγ-responsive elements in the promoter regions of target genes involved in cell-cycle arrest, apoptosis, growth inhibition, and differentiation of cancer cells.