IDENTIFICATION OF RVR, A NOVEL ORPHAN NUCLEAR RECEPTOR THAT ACTS AS A NEGATIVE TRANSCRIPTIONAL REGULATOR

A novel member of the steroid/thyroid/retinoid superfamily of nuclear receptors has been isolated as part of a screen to identify genes related to the recently characterized orphan receptor ROR alpha. This new orphan receptor, cloned from a mouse brain cDNA library, is closely related to the rat Rev-ErbA alpha gene product (97% and 68% identity in the DNA-and ligand-binding domains, respectively) and referred to as RVR. Northern blot analysis reveals that two RVR mRNA species are expressed during mouse embryogenesis and widely expressed in adult tissues. Studies with in vitro translated RVR protein show that it binds the DNA sequence ATAACTAGGTCA, a hormone response element composed of a 6-base pair AT-rich sequence preceding a single nuclear receptor recognition half-site core motif PuGGTCA. We show that RVR recognizes this hormone response element with a specificity similar to that of the orphan receptor ROR alpha 2. However, cotransfection studies indicate that RVR does not activate transcription when this hormone response element is linked to a reporter gene but rather acts as a potent competitive repressor of ROR alpha function. These results indicate the existence of an orphan nuclear receptor-based signaling pathway with the intrinsic ability to regulate the expression of specific gene networks through competition between transcriptional activators and repressors for the same recognition site.