Activation of the orphan receptor RIP14 by retinoids

Ann Marie Zavacki, Jürgen M. Lehmann, Wongi Seol, Timothy M. Willson, Steven A. Kliewer, David D. Moore

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Retinoids are crucial regulators of a wide variety of processes in both developing and adult animals. These effects are thought to be mediated by the retinoic acid (RA) receptors and the retinoid X receptors (RXRs). We have identified an additional retinoid-activated receptors that is neither a retinoic acid receptors nor an RXR. RXR-interacting protein 14 (RIP14), a recently described orphan member of the nuclear receptor superfamily, can be activated by either all-trans-RA (tRA) or the synthetic retinoid TTNPB {[E]- 4-[2-(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalenyl)propen-1- yl]benzoic acid}. RIP14 binds to DNA as a heterodimer with RXR. In the presence of either tRA or TTNPB, the addition of 9-cis-RA or the RXR-specific agonist LG1069 {4-[1-(3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tertrahydro-2- naphthyl)ethenyl]benzoic acid} results in additional activation. Mutations of the ligand-dependent transcriptional activation functions indicate that TTNPB activates the RIP14 component of the RIP14-RXR heterodimer, that 9- cis-RA and LG1069 activate RXR, and that tRA activates via both RIP14 and RXR. Despite the very effective activation of RIP14 by tRA or TTNPB, relatively high concentrations of these compounds are required, and no evidence for direct binding of either compound was obtained using several approaches. These results suggest that RIP14 is the receptor for an as-yet- unidentified retinoid metabolite.

Original languageEnglish (US)
Pages (from-to)7909-7914
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number15
DOIs
StatePublished - Jul 22 1997

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