In this study, we analyzed the proximal region of the promoter including the VDRE, 5'UTR, TATA box and exon 1 of the GH-1 gene.
The SNPs tend to be clustered in the vitamin D response elements (VDRE) and near the transcription start site (Filion et al., 2006).
The main pathology is the overexpression of heterogeneous nuclear ribonucleoproteins (hnRNPs) C1 and C2 proteins, members of the hnRNP family, that prevent VDR-RXR heterodimer binding to VDRE (52,53).
The second step occurs mainly in the kidney where 25(OH)D is further hydroxylated by 1 [alpha]-hydroxylase to become the biologically active hormone 1,25(OH)2D (calcitriol), which binds to its nuclear receptor vitamin D responsive (VDR) to regulate gene transcription through heterodimerization with one of three retinoid X receptor (RXR) isoforms (RXR[alpha], RXR[beta], RXR[gamma]) and binds to cognate VDR elements (VDREs) in the promoter region of target genes (14,15).
)###33 Percent###Wagner eta!., 2005; Giordano, 2006; Horan et al., Decrease
Such an interaction is mechanistically consistent with the presence of vitamin D-responsive elements (VDREs
) across the PTPN2 locus and the observation that PTPN2 expression in lymphoblastoid cell lines is upregulated when exposed to the VDR ligand calcitriol .
Mutations in the DBD prevent the VDR from binding to vitamin D response elements (VDREs
) in target genes causing absolute resistance to 1,25(OH)2D resulting in a more severe clinical phenotype.
To identify genes directly regulated by the VDR, we searched for genes containing vitamin D response elements (VDREs
Summarizing, upon ligand-nuclear VDR interaction, vitamin D forms heterodimers with the retinoid X receptor (RXR) and its ligand (9 cis-retinoic acid); these dimers subsequently occupy specific binding sites on DNA, the vitamin D response elements (VDREs).
In T cells, vitamin D inhibits not only proliferation but also IL-2 and IFN[gamma] gene and protein expressions [43-46], likely through VDR-RXR complex interaction with VDREs in the promoter of the genes [47, 48]; it inhibits IL-17 and IL-2 expressions in [CD4.sup.+] T cells and decreases [CD8.sup.+] T cell-mediated cytotoxicity , with an overall effect towards a block of Th1-mediated response.
Importantly, several functional vitamin D response elements (VDREs
) upstream from the transcription start site of the murine and human RANKL gene have been recently identified, which potentially make 1,25[(OH).sub.2][D.sub.3] one of the most potent stimulators of RANKL expression [12,13].
The biological active form of vitamin D, 1[alpha],25[(OH).sub.2][D.sub.3], mediates most of its actions through the intracellular vitamin D receptor (VDR), which binds to vitamin D responsive dements (VDREs
) in the promoter region of responsive genes and regulates transcription.