Convergence of vitamin D and retinoic acid signalling at a common hormone response element.
Although 1,25-dihydroxyvitamin D3 (1,25D3) 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 p19ink4d gene, and 1,25D3- or RA-induced p19INK4D) expression. P19ink4d knockdown together with depletion of p27kip1, another CDK inhibitor regulated by 1,25D3 and RA, rendered cells resistant to ligand-induced growth arrest. Remarkably, p19INK4D-deficient cells showed increased autophagic cell death, which was markedly enhanced by 1,25D3, but not RA, and attenuated by loss of p27KIP1. 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 p19INK4D in control of cell survival.
Tavera-Mendoza
Luz
L
Department of Medicine, McGill University, 3655 Drummond St, Montreal, Quebec, Canada H3G 1Y6.
Wang
Tian-Tian
TT
Lallemant
Benjamin
B
Zhang
Rui
R
Nagai
Yoshihiko
Y
Bourdeau
Véronique
V
Ramirez-Calderon
Mario
M
Desbarats
Julie
J
Mader
Sylvie
S
White
John H
JH
D001343:Autophagy; D015153:Blotting, Western; D002117:Calcitriol / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006651:Histocytochemistry; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D018613:Microscopy, Confocal; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000494:pharmacology; D020239:Receptor Cross-Talk; D018167:Receptors, Calcitriol / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D030181:Vitamin D Response Element; D001616:beta-Galactosidase / Q000378:metabolism
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D001616:beta-Galactosidase; D002117:Calcitriol