Abstract
All-trans-retinoic acid (ATRA) and 1α,25-dihydroxyvitamin D (1,25D) are potent inducers of differentiation of myeloid leukemia cells. During myeloid differentiation specific transcription factors are expressed at crucial developmental stages. However, precise mechanism controlling the diversification of myeloid progenitors is largely unknown, CCAAT/enhancer-binding protein (C/EBP) transcription factors have been characterized as key regulators of the development and function of the myeloid system. Past data point at functional redundancy among C/EBP family members during myeloid differentiation. In this study, we show that in acute myeloid leukemia (AML) cells, high expression of vitamin D receptor gene (VDR) is needed for strong and sustained upregulation of CEBPB gene, while the moderate expression of VDR is sufficient for upregulation of CEBPD in response to 1,25D. The high expression level of the gene encoding for retinoic acid receptor α (RARA) allows for high and sustained expression of CEBPB, which becomes decreased along with a decrease of RARA expression. Expression of CEBPB induced by ATRA is accompanied by upregulated expression of CEBPE with similar kinetics. Our results suggest that CEBPB is the major VDR and RARA-responsive gene among the CEBP family, necessary for expression of genes connected with myeloid functions.
Highlights
CCAAT/enhancer-binding proteins (C/EBPs) are transcription factors that activate the expression of target genes through interaction with response elements within their promoters [1]
The first transcription factor in this family, C/EBPα, was isolated from the rat liver and it appeared to be important for adipocyte differentiation [3]
C/EBPs are modular proteins consisting of an activation domain, a DNA binding domain, and a leucine-rich dimerization domain that is responsible for forming dimers with other members of the family [4]
Summary
CCAAT/enhancer-binding proteins (C/EBPs) are transcription factors that activate the expression of target genes through interaction with response elements within their promoters [1]. There are six members of C/EBP family, and they regulate differentiation process in various tissues [2]. C/EBPs are modular proteins consisting of an activation domain, a DNA binding domain, and a leucine-rich dimerization domain that is responsible for forming dimers with other members of the family [4]. In order to activate transcription, the C/EBP dimers bind to the consensus sequence 5 -TT/GNNGNAAT/G-3 in promoter regions of target genes. For three out of six genes encoding C/EBP family members, alternative protein products are translated, due to a leaky ribosomal scanning mechanism. Some of them lack the N-terminal activation domains and exert inhibitory functions, presumably by a dominant negative mechanism [5]
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