Identification of Natural Monomeric Response Elements of the Nuclear Receptor RZR/ROR. THEY ALSO BIND COUP-TF HOMODIMERS

doi:10.1074/jbc.271.33.19732

Identification of Natural Monomeric Response Elements of the Nuclear Receptor RZR/ROR. THEY ALSO BIND COUP-TF HOMODIMERS*

From the ^‡ Clinique de Dermatologie, Hôpital Cantonal Universitaire, CH-1211 Genève 14, Switzerland and
^§ Pharma-Forschung, Ciba-Geigy AG, CH-4002 Basel, Switzerland

^¶To whom correspondence should addressed. Tel.: 41-22-3729428; Fax: 41-22-7890804; E-mail: carlberg-carsten{at}diogenes.hcuge.ch.

Abstract

The receptor RZR/ROR is an important member of the nuclear receptor superfamily and has recently been shown to be the nuclear receptor for the pineal gland hormone melatonin. RZR/ROR binds as a monomer to DNA, and the human 5-lipoxygenase gene has been identified as the first RZR/ROR/melatonin-responding gene. Another prominent nuclear receptor is COUP-TF, which binds as a dimer to DNA. In this study, the sequences of known promoter regions of genes that may be involved in the physiological action of melatonin have been screened for putative monomeric RZR/ROR response elements. The binding of RZR/ROR and COUP-TF was compared and quantified on a set of 12 putative response elements. Interestingly, COUP-TF homodimers were found to bind with high affinity to some of the monomeric RZR/ROR response elements. Four RZR/ROR response elements, found in the genes of the mouse bifunctional enzyme, the rat bone sialoprotein, mouse Purkinje cell protein 2, and human p21^WAF1/CIP1, were shown to be inducible by melatonin under conditions of low constitutive activity. Surprisingly, the constitutive activity of COUP-TF was also stimulated by an unknown serum compound. The novel Purkinje cell protein 2 and p21^WAF1/CIP1 RZR/ROR/melatonin-responding genes may be the key for understanding the role of RZR/RORα in the mouse mutation staggerer and the antiproliferative action of melatonin, respectively.

Footnotes

↵* This work was supported by Ciba-Geigy AG and Swiss National Foundation Grant 3100-040314.94 (to C. C.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

1,25-(OH)₂D₃

1,25-dihydroxyvitamin D₃

RA

all-trans-retinoic acid

RAR

all-trans-retinoic acid receptor

BFE

bifunctional enzyme

BSP

bone sialoprotein

PCP-2

Purkinje cell protein 2

CAT

chloramphenicol acetyltransferase

T₃Rα

thyroid hormone receptor-α

FCS

fetal calf serum

CRBP-I

cellular retinol-binding protein I.
- Received April 3, 1996.
- Revision received May 24, 1996.