التفاصيل البيبلوغرافية
| العنوان: |
Assessment of Novel Vitamin D Receptor Antagonists that Mediate Suppression of Vitamin D Signaling |
| المؤلفون: |
Staniszewski, Lech J.P., Shahani, Pritika, Heck, Michael, Hasan, Dania S., Wagner, Carl, Jurutka, Peter W. |
| المصدر: |
The FASEB Journal ; volume 32, issue S1 ; ISSN 0892-6638 1530-6860 |
| بيانات النشر: |
Wiley |
| سنة النشر: |
2018 |
| المجموعة: |
Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: |
Antagonists are chemical compounds that bind to receptors without eliciting activation of signaling, therefore the biochemical response to the receptor ligand can be blocked or significantly decreased. Receptor antagonists display varying levels of binding affinity but do not produce the agonist‐mediated response upon binding. The vitamin D receptor (VDR) binds with high affinity to its endocrine agonist, 1,25‐dihydroxyvitamin D 3 (1,25D) to regulate the expression of a suite of genes in target tissues including kidney, intestine, and bone to control biological processes such as calcium and phosphate bone mineral homeostasis. In conditions of VDR hyperactivity, excess vitamin D production, or significantly increased intake via diet or supplementation, there are risks associated with potential resultant hypercalcemia including kidney stones, GI dysfunction, behavioral changes such as depression, and cardiac problems. In the present study, we synthesized novel VDR antagonists to create synthetic ligands that have high affinity for VDR, and consequently inhibit the activation of 1,25D‐VDR regulated genes that lead to hypercalcemia. It is well established that agonist‐bound VDR forms a functional DNA‐binding heterodimer with the retinoid X receptor (RXR) that associates with vitamin D responsive elements (VDREs) to either induce or repress transcription. Therefore, we exploited this agonist‐dependent VDR‐RXR heterodimerization pathway as an initial screening assay to evaluate the efficacy of our putative VDR antagonists. The initial test employed the mammalian two‐hybrid assay (M2H), which can assess if the novel antagonists compete with 1,25D and bind to VDR to prevent the formation of a heterodimer with RXR, a prerequisite step in VDR signaling. A second assay utilized VDRE‐linked luciferase reporter plasmids to measure antagonist activity in the more natural environment of the VDRE DNA platform. This assay was followed by a third screen to determine the specificity of antagonist binding to VDR versus other ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1096/fasebj.2018.32.1_supplement.lb98 |
| الاتاحة: |
http://dx.doi.org/10.1096/fasebj.2018.32.1_supplement.lb98 |
| Rights: |
http://onlinelibrary.wiley.com/termsAndConditions#vor |
| رقم الانضمام: |
edsbas.3BD9D2CB |
| قاعدة البيانات: |
BASE |