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β-Apo-13-carotenone Regulates Retinoid X Receptor Transcriptional Activity through Tetramerization of the Receptor.

Authors :
Sun, Jian
Narayanasamy, Sureshbabu
Curley Jr., Robert W.
Harrison, Earl H.
Source :
Journal of Biological Chemistry. 11/28/2014, Vol. 289 Issue 48, p33118-33124. 7p.
Publication Year :
2014

Abstract

Retinoid X receptor (RXRα) is activated by 9-cis-retinoic acid (9cRA) and regulates transcription as a homodimer or as a heterodimer with other nuclear receptors. We have previously demonstrated that β-apo-13-carotenone, an eccentric cleavage product of α-carotene, antagonizes the activation of RXRα by 9cRA in mammalian cells overexpressing this receptor. However, the molecular mechanism of β-apo-13-carotenone's modulation on the transcriptional activity of RXRαis not understood and is the subject of this report. We performed transactivation assays using full-length RXRαand reporter gene constructs (RXRE-Luc) transfected into COS-7 cells, and luciferase activity was examined. β-apo-13-carotenone was compared with the RXRα antagonist UVI3003. The results showed that both β-apo-13-carotenone and UVI3003 shifted the dose-dependent RXRαactivation by 9cRA. In contrast, the results of assays using a hybrid Gal4-DBD:RXRαLBD receptor reporter cell assay that detects 9cRA-induced coactivator binding to the ligand binding domain demonstrated that UVI3003 significantly inhibited 9cRA-induced coactivator binding to RXRαLBD, but β-apo-13-carotenone did not. However, both β-apo-13-carotenone and UVI3003 inhibited 9-cRA induction of caspase 9 gene expression in the mammary carcinoma cell line MCF-7.Toresolve this apparent contradiction, we investigated the effect of β-apo-13-carotenone on the oligomeric state of purified recombinant RXRαLBD. β-apo-13-carotenone induces tetramerization of the RXRαLBD, although UVI3003 had no effect on the oligomeric state. These observations suggest that β-apo-13-carotenoneregulates RXR αtranscriptional activity by inducing the formation of the "transcriptionally silent" RXRαtetramer. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00219258
Volume :
289
Issue :
48
Database :
Academic Search Index
Journal :
Journal of Biological Chemistry
Publication Type :
Academic Journal
Accession number :
99746192
Full Text :
https://doi.org/10.1074/jbc.M114.610501