Convergence of vitamin D and retinoic acid signalling at a common hormone response element

Although 1,25-dihydroxyvitamin D-3 (1,25D(3)) and retinoic acid ( RA) have distinct developmental and physiological roles, both regulate the cell cycle. We provide molecular and genomic evidence that their cognate nuclear receptors regulate common genes through everted repeat TGA(C/T) TPyN8PuG(G/T) TCA (ER8) response elements. ER8 motifs were found in the promoters of several target genes of 1,25D3 and/or RA. Notably, an element was characterized in the cyclin-dependent kinase (CDK) inhibitor p19(ink4d) gene, and 1,25D(3)- or RA-induced p19(INK4D) expression. P19(ink4d) knockdown together with depletion of p27(kip1), another CDK inhibitor regulated by 1,25D3 and RA, rendered cells resistant to ligand-induced growth arrest. Remarkably, p19(INK4D)-deficient cells showed increased autophagic cell death, which was markedly enhanced by 1,25D3, but not RA, and attenuated by loss of p27(KIP1). These results show a limited crosstalk between 1,25D3 and RA signalling by means of overlapping nuclear receptor DNA binding specificities, and uncover a role for p19(INK4D) in control of cell survival.