IDENTIFICATION OF NATURAL MONOMERIC RESPONSE ELEMENTS OF THE NUCLEAR RECEPTOR RZR ROR - THEY ALSO BIND COUP-TF HOMODIMERS/

The receptor RZR/ROR is an important member of the nuclear receptor su perfamily and has recently been shown to be the nuclear receptor for t he 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 o f known promoter regions of genes that may be involved in the physiolo gical action of melatonin have been screened for putative monomeric RZ R/ROR response elements. The binding of RZR/ROR and COUP-TF was compar ed and quantified on a set of 12 putative response elements, Interesti ngly, COUP-TF homodimers were found to bind with high affinity to some of the monomeric RZR/ROR response elements, Four RZR/ROR response ele ments, found in the genes of the mouse bifunctional enzyme, the rat bo ne sialoprotein, mouse Purkinje cell protein 2, and human p21(WAF1/CIP 1), were shown to be inducible by melatonin under conditions of low co nstitutive activity, Surprisingly, the constitutive activity of COUP-T F 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/ROR alpha in the mous e mutation staggerer and the antiproliferative action of melatonin, re spectively.