Vitamin D Analogue-Specific Recruitment of Vitamin D Receptor Coactivators

Issa, Laura L.; Leong, Gary M.; Sutherland, Robert L.; Eisman, John A.

doi:10.1359/jbmr.2002.17.5.879

Cited by 51 publications

(24 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These findings led to the hypothesis that the specific profile of these analogs might be explained at the next level of transcriptional regulation by 1,25-(OH) 2 D 3 : the recruitment of coactivator molecules. Recent studies describe the effect of different analogs of 1,25-(OH) 2 D 3 on the interaction of VDR with coactivators (Takeyama et al, 1999;Issa et al, 2002). The present study investigates the 14-epi-analogs TX522 and TX527 and their influence on VDR-mediated recruitment of the coactivators TIF2, SRC-1, and DRIP205.…”

Section: Discussionmentioning

confidence: 95%

Superagonistic Action of 14-epi-Analogs of 1,25-Dihydroxyvitamin D Explained by Vitamin D Receptor-Coactivator Interaction

Eelen¹,

Verlinden²,

Rochel³

et al. 2005

Mol Pharmacol

View full text Add to dashboard Cite

Two 14-epi-analogs of 1,25-dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 ], 19-nor-14-epi-23-yne-1,25-(OH) 2 D 3 (TX522) and 19-nor-14,20-bisepi-23-yne-1,25-(OH) 2 D 3 (TX527), show enhanced antiproliferative (at least 10-fold) and markedly lower calcemic effects both in vitro and in vivo, compared with 1,25-(OH) 2 D 3 . This study aimed to evaluate their superagonistic effect at the level of interaction between the Vitamin D receptor (VDR) and coactivators. Mammalian two-hybrid assays with VP16-fused VDR and GAL4-DNA-binding-domain-fused steroid receptor coactivator 1 (SRC-1), transcriptional intermediary factor 2 (Tif2), or DRIP205 showed the 14-epi-analogs to be more potent inducers of VDR-coactivator interactions than 1,25-(OH) 2 D 3 (up to 16-and 20-fold stronger induction of VDR-SRC-1 interaction for TX522 and TX527 at 10 Ϫ10 M). Similar assays in which metabolism of 1,25-(OH) 2 D 3 was blocked with VID400, a selective inhibitor of the 1,25-(OH) 2 D 3 -metabolizing enzyme CYP24, showed that the enhanced potency of these analogs in establishing VDR-coactivator interactions can only partially be accounted for by their increased resistance to metabolic degradation. Crystallization of TX522 complexed to the ligand binding domain of the human VDR demonstrated that the epi-configuration of C14 caused the CD ring of the ligand to shift by 0.5 Å, thereby bringing the C12 atom into closer contact with Val300. Moreover, C22 of TX522 made an additional contact with the CD1 atom of Ile268 because of the rigidity of the triple bond-containing side chain. The position and conformation of the activation helix H12 of VDR was strictly maintained. In conclusion, this study provides deeper insight into the docking of TX522 in the LBP and shows that stronger VDR-coactivator interactions underlie the superagonistic activity of the two 14-epi-analogs.1,25-Dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 ], the biologically active form of vitamin D, plays a major role in bone metabolism and in calcium and phosphate homeostasis. In addition to this classic effect, 1,25-(OH) 2 D 3 also has an antiproliferative and prodifferentiating effect on various normal as well as malignant cells (Bouillon et al., 1995

show abstract

Section: Discussionmentioning

confidence: 95%

Superagonistic Action of 14-epi-Analogs of 1,25-Dihydroxyvitamin D Explained by Vitamin D Receptor-Coactivator Interaction

Eelen¹,

Verlinden²,

Rochel³

et al. 2005

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…This may prolong the half-life of the activated receptor, affect the DNA binding properties or promoter selectivity of the activated VDR and influence receptor interactions with tissue-specific co-factors. These factors determine the tissue-selectivity of vitamin D metabolites and may also explain how different vitamin D metabolites can induce differential gene expression profiles in the same cell [57,58].…”

Section: The Molecular Basis For Differential Actions Of Vitamin D Mementioning

confidence: 99%

The virtues of vitamin D—but how much is too much?

2010

View full text Add to dashboard Cite

Vitamin D deficiency is common in healthy adults and children as well as in the chronic kidney disease (CKD) population. What was once a disease of malnourished children in the developing world has re-emerged and reached pandemic proportions. In parallel with this development, there is a growing awareness that vitamin D is not simply a 'calcaemic hormone' but plays an important role in the prevention of cardiovascular disease, infectious and auto-immune conditions, renoprotection, glycaemic control and prevention of some common cancers. Most tissues in the body have a vitamin D receptor and the enzymatic machinery to convert 'nutritional' 25-hydroxyvitamin D to the active form 1,25-dihydroxyvitamin D; it is estimated that 3% of the human genome is regulated by the vitamin D endocrine system. Although there are few well-conducted studies on the benefits of vitamin D therapy, an exuberant use of vitamin D is now seen in the general population and at all stages of CKD. There is emerging evidence that vitamin D may in fact have a therapeutic window, and at least from the effects on the cardiovascular system, more is not necessarily better. In this review, we discuss the role of nutritional vitamin D (ergocalciferol or cholecalciferol) supplementation in CKD patients, interpreting the clinical studies in the light of the vitamin D metabolic pathway and its pluripotent effects. While nutritional vitamin D compounds clearly have numerous beneficial effects, randomised controlled studies are required to determine the effectiveness and optimal dose at different stages of CKD, its concurrent use with activated vitamin D compounds and its safety profile.

show abstract

“…These differences could be multifactorial, e.g., different affinity to VDR (113), different magnitude of the transactivation of several genes (15), secondary to differences in the conformational changes and corepressors or coactivators recruitment. In fact, it has been demonstrated that VDR bound to paricalcitol or 22-oxacalcitriol recruits different coactivators from those recruited by the same receptor when bound to calcitriol (51,117).…”

Section: Present Use Of Vdras In Patients With Ckdmentioning

confidence: 99%

A new role for vitamin D receptor activation in chronic kidney disease

Valdivielso

Cannata-Andía

Coll

et al. 2009

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Valdivielso JM, Cannata-Andía J, Coll B, Fernández E. A new role for vitamin D receptor activation in chronic kidney disease. Am J Physiol Renal Physiol 297: F1502-F1509, 2009. First published July 22, 2009 doi:10.1152/ajprenal.00130.2009.-Vitamin D has proven to be much more than a simple "calcium hormone." The fact that the vitamin D receptor has been found in cells not related to mineral metabolism supports that statement. The interest of nephrologists in vitamin D and its effects beyond mineral metabolism has increased over the last few years, evidencing the importance of this so-called "sunshine hormone." In the present review, we highlight the most recent developments in the traditional use of vitamin D in chronic kidney disease (CKD) patients, namely, the control of secondary hyperparathyroidism (sHPT). Furthermore, we also explore the data available regarding the new possible therapeutic uses of vitamin D for the treatment of other complications present in CKD patients, such as vascular calcification, left ventricular hypertrophy, or proteinuria. Finally, some still scarce but very promising data regarding a possible role of vitamin D in kidney transplant patients also are reviewed. The available data point to a potential beneficial effect of vitamin D in CKD patients beyond the control of mineral metabolism.VITAMIN D IS A STEROID HORMONE that has long been known for its important role in regulating body levels of calcium (Ca) and phosphorus (P) and in mineralization of bone. However, there is an increasing amount of data proving that vitamin D exerts its effects beyond kidney, intestine, and bone (Fig. 1). The active form of vitamin D (calcitriol) mediates its biological effects by binding to the vitamin D receptor (VDR), which then translocates to the nuclei of target cells (for review, see Ref. 47). The VDR is a ligand-activated transcription factor that, after activation, recruits cofactor molecules and binds to specific DNA binding sites to modify the expression of target genes. Ligand-mediated conformational changes of the VDR contribute to specific mechanisms in its signaling cascade. Thus the structural chemical modification of active vitamin D is a powerful tool in discovering new compounds that show selective activation of the VDR. Over the last years, a number of new VDR activators (VDRAs), defined as compounds that can bind to VDR and induce its activation, have been synthesized and used in several diseases, including in patients with CKD. Their potential as new therapeutic agents has boosted this area of research. Moreover, new evidence suggests that VDR polymorphisms may influence the response to VDRAs (125). Present Use of VDRAs in Patients with CKDOne of the main complications in patients with CKD is the development of secondary hyperparathyroidism (sHPT). In the past, the increase in parathyroid gland (PTG) size and parathyroid hormone (PTH) synthesis were attributed to a decrease in circulating Ca. As a result, patients with sHPT were treated with oral vitamin D metabolites to correct ...

show abstract

Vitamin D Analogue-Specific Recruitment of Vitamin D Receptor Coactivators

Cited by 51 publications

References 40 publications

Superagonistic Action of 14-epi-Analogs of 1,25-Dihydroxyvitamin D Explained by Vitamin D Receptor-Coactivator Interaction

Superagonistic Action of 14-epi-Analogs of 1,25-Dihydroxyvitamin D Explained by Vitamin D Receptor-Coactivator Interaction

The virtues of vitamin D—but how much is too much?

A new role for vitamin D receptor activation in chronic kidney disease

Contact Info

Product

Resources

About