VDR/RXR heterodimer

Fig. 4.6. HRE structure of the RXR heterodimer. Shown is the consensus sequence of the HREs of the RXR heterodimers (see Fig. 4.7) and the different possible arrangements of the hexameric half-site sequences. The hexamers can be arranged palindromically as inverted repeats (a), as everted repeats (b), or as direct repeats (c). n indicates the number of base pairs that lie between the two hexamers. RXR receptor for 9-ds retinoic acid RAR receptor for all-trans retinoic acid T3R receptor for the T3 hormon PPAR peroxisome prohferator-activated receptor VDR receptor for vitamin D3.

Figure 10.12 Response elements for heterodimers of the nuclear receptor for ds-retinoic acid (RXR) with the receptors for vitamin D (VDR), thyroid hormone (TR) and trans-retinoic acid (RAR). The half-sites of these response elements have identical nucleotide sequences and are organized as direct repeats. They differ in the number of base pairs in the spacer region between the half-sites. This difference forms the basis for the ability of the heterodimers to discriminate between the different response elements.

Figure 29-6. Gene transcription is regulated by retinoic acid.Ah-Zrwm-retinoic acid and 9-cA-retinoic acid are ligands for retinoic acid receptors (RARs) and retinoid X receptors (RXRs), respectively. The RXRs can form heterodimers with RARs and with the thyroid hormone receptors (TRs), the vitamin D receptor (VDR), and the peroxisome proliferator-activated receptors (PPARs) and a number of other hormone- and nutrient-responsive transcription factors to moderate gene transcription. Because of the ability of RXR to form heterodimers with other nuclear receptors, vitamin A has abroad effect on many hormonally and nutrient-responsive genes.

Heterodimers of RAR and RXR with VDR may explain the synergistic or additive inhibition observed in prostate cancer cells when combinations of 1,25-D or its analogs and retinoids are administered (B8, C3, C15, P13, S7). Nevertheless, it cannot be excluded that either 1,25-D or retinoids could induce the synthesis of another protein that could enhance the response of the cell to either compound (B8). 

The vitamin D receptor (VDR/NR1I1) is a member of the superfamily of steroid hormone receptors. It regulates calcium homeostasis, cell proliferation, and differentiation, and exerts immunomodulatory and antimicrobial functions [119]. VDR binds to and mediates the calcemic effects of calcitriol (la,25-dihydroxy vitamin D3) after forming an heterodimer with RXR. la,25-dihydroxyvitamin D3 negatively regulates its own synthesis by repressing the 25-hydroxyvitamin D3 la-hydroxylase (CYP27B1) in a cell-type selective event that involves different combinations of multiple VDR response elements [120, 121]. 

Some nuclear-receptor response elements, such as those for the receptors that bind vitamin D3, thyroid hormone, and retinoic acid, are direct repeats of the same sequence recognized by the estrogen receptor, separated by three to five base pairs (Figure ll-42c-e). The specificity for responding to these different hormones by binding distinct receptors Is determined by the spacing between the repeats. The receptors that bind to such direct-repeat response elements do so as heterodimers with a common nuclear-receptor monomer called RXR. The vitamin D3 response element, for example, Is bound by the RXR-VDR heterodimer. 

The RXR-RAR, RXR-TR, and RXR-VDR heterodimers all require the cognate ligand for the nuclear receptor partner (retinoic acid, thyroid hormone, or vitamin D, respectively) in order to function as transcrip-... 

VDR requires RXR as a heterodimer partner to be fully active. Second, RXR-RXR homodimers could now regulate transcription from RXR target genes (response elements with a single nucleotide spacer). This dependence on RXR by RAR, TR, and VDR, coupled with the independent activity of RXR homodimers, allows for overlapping control of multiple gene networks in response to the relative ratios of the appropriate nuclear receptor ligands and 9-c/s-retinoic acid. 

Effect of 9-c/s-retinoic acid on nuclear receptor activity. (Top) When vitamin D levels are high, but 9-c/s-retinoic acid levels are low, vitamin D responsive genes would be activated preferentially by RXR-VDR heterodimers. (Bottom) When 9-c/.s-retinoic acid levels are high, ligand-bound RXR-RXR homodimers would form and preferentially activate 9-c/s-retinoic acid responsive genes, while at the same time causing a decrease in the expression of vitamin D responsive genes. 

Figure 6 A schematic representation of the mechanism of action of 1,25 OH)2D in various target cells resulting in a variety of biological responses. The free form of 1,25(OH)2D3 enters the target cell and interacts with its nuclear vitamin D receptor (VDR), which is phosphorylated (Pi). The 1,25(OH)2D-VDR complex combines with the retinoic acid X receptor (RXR) to form a heterodimer, which, in turn, interacts with the vitamin D responsive element (VDRE), causing an enhancement or inhibition of transcription of vitamin D-responsive genes including calcium-binding protein (CaBP), ECaC, 24-OHase, RANKL, alkaline phosphatase (alk Pase), prostate-specific antigen (PSA), and PTH.

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