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1,25-Dihydroxyvitamin D₃ Transrepresses Retinoic Acid Transcriptional Activity via Vitamin D Receptor in Myeloid Cells

Laboratoire de Biologie Cellulaire Hématopoïétique, Institut National de la Santé et de la Recherche Médicale Equipe Mixte Inserm 00-03, Institut Universitaire d’Hématologie, Paris 7, Hôpital Saint-Louis, 75010 Paris, France

Address all correspondence and requests for reprints to: Christine Chomienne, M.D., Ph.D., Laboratoire de Biologie Cellulaire Hématopoïétique, INSERM Equipe Mixte Inserm 00–03, Institut Universitaire d’Hématologie, Paris 7, Hôpital Saint-Louis, 75010 Paris, France. E-mail: christine.chomienne{at}sls.ap-hop-paris.fr.

Granulocytes and monocytes originate from a common committed progenitor cell. Commitment to either granulocytic or monocytic lineage is triggered by specific extracellular signals involving cytokines or nuclear receptor ligands (all-trans-retinoic acid (RA) and 1,25-dihydroxyvitamin D₃). Here we show that the stimulatory effect of 1,25-dihydroxyvitamin D₃ on the production of monocytic colonies (CFU-M) is accompanied by a repression of granulocytic colony (CFU-G) production. We further demonstrate that in bipotent HL-60 myeloid cells as in purified human CD34+ myeloid progenitor cells, the 1,25-dihydroxyvitamin D₃-induced monocytic differentiation is concomitant with a direct inhibition of the RA-transcriptional activity. Indeed, a transrepression of the RARß RA-target gene promoter via formation of a nuclear complex involving VDR was identified in vitro and in vivo. The fact that binding of RXR-RAR on DR3 is not observed suggests that contrary to RA-induced granulocytic differentiation, 1,25-dihydroxyvitamin D₃-mediated monocytic differentiation requires positive and negative transcriptional controls both likely mediated by the RXR-VDR heterodimer. These novel findings implicate that 1,25-dihydroxyvitamin D₃ exerts a dominant negative effect on the RA-dependent granulocytic commitment of human bone marrow cells via repression of the RA-target gene promoters. Hence, the transcriptional response to RA and 1,25-dihydroxyvitamin D₃ in myeloid cells depends on a complex combinatory pattern of interaction among different nuclear receptors with DNA.

NURSA Molecule Pages Link:

Nuclear Receptors:   RARβ  |  VDR  |  RXRα

Coregulators:   SMRT

Ligands:   all-trans-Retinoic acid  |  Calcitriol

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