Differential Use of Transcription Activation Function 2 Domain of the Vitamin D Receptor by 1,25-Dihydroxyvitamin D3 and Its A Ring-Modified Analogs

Peleg, Sara; Nguyen, Cuong; Woodard, Benjamin T.; Lee, Jae-Kyoo; Posner, Gary H.

doi:10.1210/mend.12.4.0083

Cited by 42 publications

(29 citation statements)

References 23 publications

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“…Recently, deletion-mutation analysis revealed that an activation domain of VDR is required for the interaction between VDR and SRC-1 (32 this ligand-dependent interaction between SRC-1 and VDR was observed in Saos-2 cells, but not in HeLa cells in our system. In Saos-2 cells, the interaction between VDR and SRC-1 was reduced by TEI-9647, suggesting that the conformational change of VDR elicited by the ligand differs between 1␣,25(OH) 2 D 3 and TEI-9647 as suggested by studies using other vitamin D analogues (22,33,34).…”

Section: Tei-9647 Inhibited the Vdr And Rxr Heterodimer Formation Detmentioning

confidence: 91%

Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1α,25-Dihydroxyvitamin D3 Analogue toward Vitamin D Receptor Function

Ozono

Saito

Miura

et al. 1999

Journal of Biological Chemistry

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5). The effects exerted via the VDR are called genomic effects, in contrast to non-genomic effects, which means that 1␣,25(OH) 2 D 3 acts within a short period without transcription of target genes (6). The VDR-mediated effects of 1␣,25(OH) 2 D 3 in vivo are well known, since there is a human disease associated with the abnormality of the VDR gene, which is called vitamin D dependence type II (7). In addition, a mouse model of the disease was generated by targeting the VDR gene and has been used the analysis of the VDR function in vivo (8, 9).The VDR consists of several functional domains such as DNA-binding and ligand-binding domains (1, 2). Heterodimerization of the VDR with retinoid X receptor (RXR) is also important for the binding to a vitamin D-responsive element (VDRE) with high affinity (1, 2, 5, 10). Ligand-dependent activation of transcription requires the extreme C-terminal portion of the VDR, which is designated as the AF-2 core domain (1,11,12). The interaction of these domains is required for the VDR to regulate the transcription of target genes.A large number of 1␣,25(OH) 2 D 3 analogues have been synthesized in an attempt to dissociate various biological activities including hypercalcemic effects, bone-forming effects, and promotion of cell differentiation (for review, see Ref. . Although this differentiation is believed to be mediated by VDR, more direct evidence is needed to establish whether TEI-9647 is an antagonist of the genomic action of vitamin D. Antagonists, if obtained, would be useful for determining whether each of the effects of 1␣,25(OH) 2 D 3 is mediated by the VDR. In addition, a potentially promising way to achieve the differential effect of vitamin D is to use analogues that antagonize particular effects elicited by vitamin D.In contrast to the case of VDR, several antagonists have been reported for other members of the nuclear hormone receptor superfamily, and have contributed to the understanding of the

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Section: Tei-9647 Inhibited the Vdr And Rxr Heterodimer Formation Detmentioning

confidence: 91%

Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1α,25-Dihydroxyvitamin D3 Analogue toward Vitamin D Receptor Function

Ozono

Saito

Miura

et al. 1999

Journal of Biological Chemistry

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“…We (16) and others (30) have shown that the transactivation potency of an analog of 1,25D 3 may be determined by its ability to induce VDR to assume a protease-resistant conformation. To examine whether this aspect of ligand interaction with the receptor indeed was impaired by the H305Q mutation, we performed quantitative protease sensitivity assays.…”

Section: Synthetic Analogs Restore Defective Vitamin D Receptor Actionmentioning

confidence: 92%

Section: Hereditary Vitamin D-resistant Rickets (Hvdrr)mentioning

confidence: 99%

“…20E-1,25D 3 (MC 1288) was obtained from Dr. L. Binderup (Leo Pharmaceuticals, Bellrup, Denmark) (24). JK-1626-2 (1␤-hydroxymethyl-3-epi-26,27-bishomo-25-hydroxy-vitamin D 3 ) was synthesized in the laboratory of Dr. G. H. Posner (16).…”

Section: Hereditary Vitamin D-resistant Rickets (Hvdrr)mentioning

confidence: 99%

“…The proposed mechanism for this enhanced potency is that in which the analog changes the conformation of the VDR to provide a more effective interface for interaction with RXR and transcription coactivators. Second, even analogs that are less potent transcriptionally than 1,25D 3 may contact different amino acid residues in the ligand-binding pocket such that they have the potential to bind and activate VDRs with mutations at the usual contact points for the hormone (15,16).To determine whether analogs can bind and restore transcriptional activity of VDR in HVDRR patients, we selected three HVDRR mutations that were restricted to the LBD of the * This work was supported by National Institutes of Health Grants DK 42482 (to D. F.), CA 44530 (to G. H. P), and DK 50583 (to S. P.). The costs of publication of this article were defrayed in part by the payment of page charges.…”

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A Rationale for Treatment of Hereditary Vitamin D-resistant Rickets with Analogs of 1α,25-Dihydroxyvitamin D3

Gardezi¹,

Nguyen²,

Malloy³

et al. 2001

Journal of Biological Chemistry

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Hereditary vitamin D-resistant rickets (HVDRR) is caused by heterogeneous inactivating mutations in the vitamin D receptor (VDR). Treatment of HVDRR patientswith high doses of oral calcium and supraphysiologic doses of 1␣,25-dihydroxyvitamin D 3 (1,25D 3 ) has had limited success. In this study we explored the use of vitamin D analogs as a potential therapy for this disorder. The rationale for the use of vitamin D analogs is that they bind the VDR at different amino acid residues than 1,25D 3 , and their ability to modulate VDR functions differs from that of the natural hormone. In this report, we examined the VDR from three HVDRR patients with mutations in the ligand-binding domain of the VDR (histidine 305 to glutamine, arginine 274 to leucine, and phenylalanine 251 to cysteine) for their responses to two vitamin D analogs, 20-epi-1,25D 3 and 1␤-hydroxymethyl-3-epi-16-ene-26a,27a-bishomo-25D 3 (JK-1626-2). Our results reveal that vitamin D analogs partially or completely restore the responsiveness of the mutated VDR. Analog treatment seemed to be more successful when the mutation affects the amino acids directly involved in ligand binding rather than amino acids that contribute to a functional VDR interface with dimerization partners or coactivators of transcription. Hereditary vitamin D-resistant rickets (HVDRR)1 is an autosomal recessive disorder characterized by end-organ resistance to 1␣,25-dihydroxyvitamin D 3 (1,25D 3 ) (1, 2). Clinically, the syndrome is recognized by severe early onset rickets with bowing of the lower extremities, short stature, and often alopecia (2-5). Resistance to 1,25D 3 in HVDRR leads to impaired intestinal calcium absorption. This results in a series of metabolic abnormalities including frank hypocalcemia, secondary hyperparathyroidism, elevated alkaline phosphatase levels, hypophosphatemia, and markedly increased 1,25D 3 levels (2). Treatment of HVDRR patients with high doses of oral calcium and supraphysiologic doses of 1,25D 3 has had limited success. More aggressive therapy to bypass the defect in intestinal calcium absorption is long term intravenous infusion of calcium that restores the serum calcium levels to normal and reverses the rickets in some cases (2, 5-7). However, this approach has the usual complications associated with intravenous therapy, and its use has been limited because of its complexity.The resistance to 1,25D 3 in HVDRR is caused by heterogeneous mutations in the nuclear receptor for vitamin D (2, 8, 9). Therefore, this disease emphasizes the importance of vitamin D receptor (VDR)-mediated action of 1,25D 3 in skeletal development and bone mineralization as well as in the development of hair follicles. Like other members of the nuclear receptor superfamily, the VDR is activated by binding to its ligand (1,25D 3 ), and its action is mediated through distinct functional domains for DNA binding, ligand binding, and transcriptional activation (10, 11). HVDRR patients with mutations in the DNA binding domain of VDR do not respond to 1,25D 3 treatment mainly...

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The vitamin D receptor gene FokI polymorphism: Functional impact on the immune system

et al. 2007

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1a,25-Dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) has important effects on the growth and function of multiple cell types. These pleiotropic effects of 1,25(OH) 2 D 3 are mediated through binding to the vitamin D receptor (VDR). Several polymorphisms of the human VDR gene have been identified, with the FokI polymorphism resulting in VDR proteins with different structures, a long f-VDR or a shorter F-VDR. The aim of this study was to investigate the functional consequences of the FokI polymorphism in immune cells. In transfection experiments, the presence of the shorter F-VDR resulted in higher NF-jBand NFAT-driven transcription as well as higher IL-12p40 promoter-driven transcription. Marginal differences were observed for AP-1-driven transcription, and no differential effects were observed for transactivation of a classical vitamin D-responsive element. Concordantly, in human monocytes and dendritic cells with a homozygous short FF VDR genotype, expression of IL-12 (mRNA and protein) was higher than in cells with a long ff VDR genotype. Additionally, lymphocytes with a short FF VDR genotype proliferated more strongly in response to phytohemagglutinin. Together, these data provide the first evidence that the VDR FokI polymorphism affects immune cell behavior, with a more active immune system for the short F-VDR, thus possibly playing a role in immune-mediated diseases.

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Differential Use of Transcription Activation Function 2 Domain of the Vitamin D Receptor by 1,25-Dihydroxyvitamin D3 and Its A Ring-Modified Analogs

Cited by 42 publications

References 23 publications

Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1α,25-Dihydroxyvitamin D3 Analogue toward Vitamin D Receptor Function

Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1α,25-Dihydroxyvitamin D3 Analogue toward Vitamin D Receptor Function

A Rationale for Treatment of Hereditary Vitamin D-resistant Rickets with Analogs of 1α,25-Dihydroxyvitamin D3

The vitamin D receptor gene FokI polymorphism: Functional impact on the immune system

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