A NOVEL ORPHAN RECEPTOR-SPECIFIC FOR A SUBSET OF THYROID HORMONE-RESPONSIVE ELEMENTS AND ITS INTERACTION WITH THE RETINOID THYROID HORMONE-RECEPTOR SUBFAMILY/

The steroid/hormone nuclear receptor superfamily comprises several sub families of receptors that interact with overlapping DNA sequences and /or related ligands. The thyroid/retinoid hormone receptor subfamily h as recently attracted much interest because of the complex network of its receptor interactions. The retinoid X receptors (RXRs), for instan ce, play a very central role in this subfamily, forming heterodimers w ith several receptors. Here we describe a novel member of this subfami ly that interacts with RXR. Using a v-erbA probe, we obtained a cDNA w hich encodes a novel 445-amino-acid protein, RLD-1, that contains the characteristic domains of nuclear receptors. Northern (RNA) blot analy sis showed that in mature rats, the receptor is highly expressed in sp leen, pituitary, lung, liver, and fat. In addition, weaker expression is observed in several other tissues. Amino acid sequence alignment an d DNA-binding data revealed that the DNA-binding domain of the new rec eptor is related to that of the thyroid/retinoid subgroup of nuclear r eceptors. RLD-1 preferentially binds as a heterodimer with RXR to a di rect repeat of the half-site sequence 5'-G/AGGTCA-3', separated by fou r nucleotides (DR-4). Surprisingly, this binding is dependent to a hig h degree on the nature of the spacing nucleotides. None of the known n uclear receptor ligands activated RLD-1. In contrast, a DR-4-dependent constitutive transcriptional activation of a chloramphenicol acetyltr ansferase reporter gene by the RLD-1/RXR alpha heterodimer was observe d. Our data suggest a highly specific role for this novel receptor wit hin the network of gene regulation by the thyroid/retinoid receptor su bfamily.