Identification of a Novel Suppressive Vitamin D Response Sequence in the 5′-Flanking Region of the Murine Id1 Gene

Abstract

1 is not only a major calcitrophic hormone that controls systemic calcium metabolism but also a potent modulator of differentiation in several types of cells including osteoblasts (2, 3). Many studies have revealed that the molecular mechanisms of vitamin D actions, including its promotion of cell differentiation, could be explained mainly by its genomic actions via the vitamin D receptor (VDR) as a ligand-dependent transcription factor (4 -7). VDR binds to vitamin D response elements (VDREs) within the promoter regions of the target genes to activate or suppress their expression. Several types of differentiation-related genes are regulated through this type of vitamin D action during cell differentiation. In addition, recent studies also showed the involvement of the nongenomic action of vitamin D in regulation of cell differentiation (9 -11). For instance, monocyte differentiation was reported to be mediated by vitamin D without requiring binding to VDR (9), and keratinocyte differentiationrelated genes were shown to be stimulated by 1,25(OH) 2 D 3 without the presence of VDRE (6, 10, 11). Therefore, vitamin D could promote cell differentiation via both genomic and nongenomic actions (3, 6).We have been interested in the molecular mechanism of the differentiation of osteoblasts as one of the target cells of 1,25(OH) 2 D 3 (3). Similarly to other types of cells, expression of various phenotype-related genes is enhanced by 1,25(OH) 2 D 3 in osteoblasts (11)(12)(13)(14). In parallel to its direct control of the genes encoding phenotype-related proteins in osteoblasts, we hypothesized that vitamin D may regulate higher order regulatory genes to modulate osteoblastic differentiation. We have shown that Id1, a dominant negative regulator of helix-loophelix-type transcription factors (15), is expressed in osteoblasts and that its level is transcriptionally suppressed by 1,25(OH) 2 D 3 (1). Because Id1 has been shown to be a negative modulator of positive regulatory transcription factor(s) that modulate cell differentiation, 1,25(OH) 2 D 3 could exert its effects on osteoblasts by suppressing expression of Id1. In the previous study, we have also shown that the suppression was specific to 1,25(OH) 2 D 3 and was mediated at the level of gene transcription without requiring new protein synthesis (1). However, the mechanism with which 1,25(OH) 2 D 3 suppresses Id1 gene transcription was still unknown.Ligand-dependent or -independent repression by nuclear hormone receptor superfamilies has been investigated (8, 16 -23). However, the molecular mechanisms of transcriptional repression appear to be more complicated than those of transcriptional activation (22,23), and the mechanisms for steroidal or nonsteroidal ligand-dependent repression have also been found to be variable. In some cases, to suppress expression of the target genes, hormones utilize the same or similar response elements as those used for transactivation (18), whereas in other cases, sequences different from the classical hormone response elements are utiliz...

Global gene expression analysis in time series following N-acetyl L-cysteine induced epithelial differentiation of human normal and cancer cells in vitro

“…The cell cycle blockade and differentiation caused by such a drug, trichostatin A, caused decreased levels of ID-1 consistent with cell cycle senescence and differentiation of A2780 ovarian cancer cells [17]. Vitamin D is also known to promote differentiation and was shown by others to down-regulate ID-1 through a suppressive vitamin D response sequence in the 5'of the gene [18]. The ID-1 expression is regulated by a protein complex containing the immediate-early response gene EGR1 [19].…”

Vitamin D Signaling in Myogenesis: Potential for Treatment of Sarcopenia

“…To elucidate the possible role of Notch signaling in Foxo1-mediated inhibition of myoblast differentiation, by combining coculture system, transfection assay, chromatin immunoprecipitation assay, and short interfering RNA (siRNA) technology, authors showed that Foxo1 physically and functionally interacted with Notch by promoting corepressor clearance from DNA binding protein, CSL [CBF1/RBPjk/Su(H)/Lag-1], leading to inhibition of myoblast differentiation through activation of Notch target genes [47]. Another gene, Id (inhibitor of differentiation) gene, is also known target of 1 α ,25(OH) 2 D 3 [49]. Id mRNA was constitutively expressed in rat osteoblastic osteosarcoma ROS17/2.8 cells and its level was transcriptionally suppressed by 1 α ,25(OH) 2 D 3 [50].…”

1α,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells

“…Although transient overexpression of Id1 failed to alter either the kinetics of E-cadherin induction or the morphological changes associated with hormone treatment, it remains possible that Id1 regulation is necessary for the effects of 1a,25(OH) 2 D 3 on cell growth and differentiation. The regulation of Id1 by 1a,25(OH) 2 D 3 is apparently tissue specific, because in osteoblastic cells this hormone represses Id1 promoter activity, causing osteoblastic differentiation (Ezura et al, 1997). Additional research is needed to identify Id1 role among the plethora of processes and targets affected by 1a,25(OH) 2 D 3 in SW480-ADH cells.…”