Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily.

Correction submitted by Drs. Becker-André, Schaeren-Wiemers, and André : The article reported the identification of the pineal gland hormone melatonin as a natural ligand of the nuclear orphan receptor RZRβ. The article described transient transfection assays showing stimulation of RZRβ transactivation by melatonin and in vitro binding studies showing a direct interaction between RZRβ and melatonin. We were, however, not able to reproduce any of these experiments nor could we determine the reason for this failure. As the central finding of the article is based on these assays, we do not consider the drawn conclusions valid. All other data in the publication including our studies to localize RZRβ mRNA using in situ hybridization and quantitative PCR are as published. We apologize to all investigators who have spent time and effort to reproduce parts of the work using the in vitro assays described in the article. Addition submitted by Drs. Wiesenberg, Missbach, Saurat, and Carlberg: RZRβ belongs to the RZR/ROR family of nuclear receptors (1Carlberg C. Wiesenberg I. J. Pineal Res. 1995; 18: 171-178Crossref PubMed Scopus (176) Google Scholar), where the members of this family have been shown to act as ligand-independent transcription factors that bind to monomeric binding sites mediating a high constitutive transcriptional activity (2Carlberg C. Hooft van Huijsduijnen R. Staple J. DeLamarter J.F. Becker-André M. Mol. Endocrinol. 1994; 8: 757-770Crossref PubMed Scopus (191) Google Scholar, 3Forman B.M. Chen J. Blumberg B. Kliewer S.A. Henshaw R. Ong E.S. Evans R.M. Mol. Endocrinol. 1994; 8: 1253-1261Crossref PubMed Scopus (183) Google Scholar, 4Tini M. Fraser R.A. Giguère V. J. Biol. Chem. 1995; 270: 20156-20161Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 5Medvedev A. Yan Z.-H. Hirose T. Giguère V. Jetten A.M. Gene. 1996; 181: 199-206Crossref PubMed Scopus (105) Google Scholar). Recently, Greiner et al. (6Greiner E.F. Kirfel J. Greschik H. Dörflinger U. Becker P. Mercep A. Schüle R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 10105-10110Crossref PubMed Scopus (46) Google Scholar) reported failure in observing transcriptional activity of RZRβ on monomeric sites and its modulation by melatonin. However, in some cell lines, e.g. Drosophila SL-3 cells, the constitutive activity of RZRβ and RZR/RORα can clearly be reduced, e.g. by the omission of serum to the cell culture medium (2Carlberg C. Hooft van Huijsduijnen R. Staple J. DeLamarter J.F. Becker-André M. Mol. Endocrinol. 1994; 8: 757-770Crossref PubMed Scopus (191) Google Scholar, 7Becker-André M. Wiesenberg I. Schaeren-Wiemers N. André E. Missbach M. Saurat J.-H. Carlberg C. J. Biol. Chem. 1994; 269: 28531-28534Abstract Full Text PDF PubMed Google Scholar, 8Wiesenberg I. Missbach M. Kahlen J.-P. Schräder M. Carlberg C. Nucleic Acids Res. 1995; 23: 327-333Crossref PubMed Scopus (239) Google Scholar). Under these restricted experimental conditions RZRβ and RZR/RORα reproducibly function as ligand-dependent nuclear receptors (7Becker-André M. Wiesenberg I. Schaeren-Wiemers N. André E. Missbach M. Saurat J.-H. Carlberg C. J. Biol. Chem. 1994; 269: 28531-28534Abstract Full Text PDF PubMed Google Scholar, 8Wiesenberg I. Missbach M. Kahlen J.-P. Schräder M. Carlberg C. Nucleic Acids Res. 1995; 23: 327-333Crossref PubMed Scopus (239) Google Scholar, 9Missbach M. Jagher B. Sigg I. Nayeri S. Carlberg C. Wiesenberg I. J. Biol. Chem. 1996; 271: 13515-13522Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 10Schräder M. Danielsson C. Wiesenberg I. Carlberg C. J. Biol. Chem. 1996; 271: 19732-19736Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). Ligand binding assays have been performed with cells overexpressing RZR/ROR andin vitro translated RZR/ROR (7Becker-André M. Wiesenberg I. Schaeren-Wiemers N. André E. Missbach M. Saurat J.-H. Carlberg C. J. Biol. Chem. 1994; 269: 28531-28534Abstract Full Text PDF PubMed Google Scholar, 8Wiesenberg I. Missbach M. Kahlen J.-P. Schräder M. Carlberg C. Nucleic Acids Res. 1995; 23: 327-333Crossref PubMed Scopus (239) Google Scholar), but not with the purified receptor. This suggests but does not prove that melatonin is a ligand of RZR/ROR. However, the first report of a melatonin response element in the promoter of the human 5-lipoxygenase gene (11Steinhilber D. Brungs M. Werz O. Wiesenberg I. Danielsson C. Kahlen J.-P. Nayeri S. Schräder M. Carlberg C. J. Biol. Chem. 1995; 270: 7037-7040Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar) has demonstrated an essential role of RZR/ROR as a mediator of nuclear melatonin signaling. Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily.Journal of Biological ChemistryVol. 269Issue 46PreviewNuclear orpan receptors are members of the superfamily of structurally related, ligand-inducible transcription factors for which no ligand has yet been identified. Over the past few years many nuclear orphan receptors have been cloned, but only for the retinoid X receptor (RXR) has a natural ligand (9-cis-retinoic acid) been found. Here we report the identification of melatonin as a ligand for the recently cloned orphan receptor retinoid Z receptor beta (RZR beta). We found RZR beta expression in the rat brain nearly coincident with binding sites for the pineal gland hormone melatonin (5-methoxy-N-acetyltryptamine).