FUNCTIONAL-ANALYSIS OF RETINOID-Z RECEPTOR-BETA, A BRAIN-SPECIFIC NUCLEAR ORPHAN RECEPTOR

The retinoid Z receptor beta (RZR beta), an orphan receptor, is a memb er of the retinoic acid receptor (RAR)/thyroid hormone receptor (TR) s ubfamily of nuclear receptors. RZR beta exhibits a highly restricted b rain-specific expression pattern, So far, no natural RZR beta target g ene has been identified and the physiological role of the receptor in transcriptional regulation remains to be elucidated. Electrophoretic m obility shift assays reveal binding of RZR beta to monomeric response elements containing the sequence AnnTAGGTCA, but RZR beta-mediated tra nsactivation of reporter genes is only achieved with two properly spac ed binding sites, We present evidence that RZR beta can function as a cell-type-specific transactivator. In neuronal cells, Gal-RZR beta fus ion proteins function as potent transcriptional activators, whereas no transactivation can be observed in nonneuronal cells, Mutational anal yses demonstrate that the activation domain (AF-2) of RZR beta and RAR alpha are functionally interchangeable, However, in contrast to RAR a nd TR, the RZR beta AF-2 cannot function autonomously as a transactiva tion domain. Furthermore, our data define a novel repressor function f or the C-terminal part of the putative ligand binding domain. We propo se that the transcriptional activity of RZR beta is regulated by an in terplay of different receptor domains with coactivators and corepresso rs.