title: Regulation of vitamin D receptor expression by retinoic acid receptor alpha in acute myeloid leukemia cells.
abstract: Acute myeloid leukemia (AML) is the predominant acute leukemia among adults, characterized by an accumulation of malignant immature myeloid precursors. A very promising way to treat AML is differentiation therapy using either all-trans-retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D), or the use of both these differentiation-inducing agents. However, the effect of combination treatment varies in different AML cell lines, and this is due to ATRA either down- or up-regulating transcription of vitamin D receptor (VDR) in the cells examined. The mechanism of transcriptional regulation of VDR in response to ATRA has not been fully elucidated. Here, we show that the retinoic acid receptor α (RARα) is responsible for regulating VDR transcription in AML cells. We have shown that a VDR transcriptional variant, originating in exon 1a, is regulated by RARα agonists in AML cells. Moreover, in cells with a high basal level of RARα protein, the VDR gene is transcriptionally repressed as long as RARα agonist is absent. In these cells down-regulation of the level of RARα leads to increased expression of VDR. We consider that our findings provide a mechanistic background to explain the different outcomes from treating AML cell lines with a combination of ATRA and 1,25D.
authors.affiliation: Laboratory of Protein Biochemistry, Faculty of Biotechnology, University of Wrocław, Joliot-Curie 14a, 50-383 Wrocław, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Marchwicka
authors.affiliation: Laboratory of Molecular and Cellular Immunology, Department of Tumor Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Science, Weigla 12, 53-114 Wrocław, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Cebrat
authors.affiliation: Laboratory of Molecular and Cellular Immunology, Department of Tumor Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Science, Weigla 12, 53-114 Wrocław, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Łaszkiewicz
authors.affiliation: Laboratory of Molecular and Cellular Immunology, Department of Tumor Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Science, Weigla 12, 53-114 Wrocław, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Śnieżewski
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston B15 2TT, UK.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Brown
authors.affiliation: Laboratory of Protein Biochemistry, Faculty of Biotechnology, University of Wrocław, Joliot-Curie 14a, 50-383 Wrocław, Poland. Electronic address: ema@cs.uni.wroc.pl.
authors.forename: Ewa
authors.initials: E
authors.lastname: Marcinkowska
mesh_terms: D002117:Calcitriol / Q000494:pharmacology; D004790:Enzyme Induction; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: C000607071:RARA protein, human; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol
keywords: Differentiation; Expression; Retinoic acid receptor alpha; Target gene; Vitamin D receptor; mRNA