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A novel class of retinoid antagonists and their mechanism of action
- Source :
- The Journal of biological chemistry. 271(20)
- Publication Year :
- 1996
-
Abstract
- Retinoids regulate a broad range of biological processes through two subfamilies of nuclear retinoid receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Recently, we reported a novel type of retinoic acid antagonist (SR11335) and showed that this compound can inhibit retinoic acid (RA)-induced activation of a human immunodeficiency virus type 1 (HIV-1) promoter construct that contains a special RA response element (RARE). We have now further characterized the antagonism mediated by SR11335 and of newly synthesized structurally related compounds. Two compounds, SR11330 and SR11334, which are poor transactivators, also showed antagonist activities, inhibiting all-trans-RA (tRA) and 9-cis-RA. The retinoids inhibited transcriptional activation of RAR/RXR heterodimers effectively, while inhibition of RXR homodimers was less efficient. Inhibition was observed on several RAREs, including the TREpal, betaRARE, apoAI-RARE, and CRBPI-RARE. In addition, the antagonists inhibited tRA-induced differentiation of HL-60 cells. The antagonist did not interfere with DNA binding of the receptors. In limited proteolytic digestion assays, SR11335 induced resistance of the receptors to proteolysis, but the pattern of the degradation was not altered from that induced by tRA, suggesting that these antagonists induce their biological effects by competing with agonists for binding to RARs, thereby preventing the induction of conformational changes of the receptors necessary for transcriptional activation.
- Subjects :
- medicine.drug_class
Protein Conformation
Receptors, Retinoic Acid
Molecular Sequence Data
Retinoic acid
HL-60 Cells
Biology
Retinoid X receptor
Biochemistry
chemistry.chemical_compound
Mice
Retinoids
Structure-Activity Relationship
medicine
Animals
Humans
Retinoid
Receptor
Molecular Biology
Retinoid X receptor alpha
Base Sequence
Proteolytic enzymes
Cell Differentiation
Cell Biology
DNA
Retinoid X receptor gamma
chemistry
Mechanism of action
embryonic structures
Trans-Activators
medicine.symptom
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 271
- Issue :
- 20
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....6656d18b7bde918b91cc6115a3cff8f3