Liver regeneration following partial hepatectomy provides one of the few systems for analysis of mitogenesis in the fully developed, intact animal. Immediate-early growth response genes, induced in the absence of prior protein synthesis, play an important regulatory role in the regenerative process. During screening of a subtracted cDNA library of immediate-early genes induced during liver regeneration, a novel member of the thyroid/steroid receptor superfamily, RNR-1 (regenerating liver nuclear receptor), was identified. This gene is not expressed in quiescent liver but is rapidly induced following partial hepatectomy and is specific to hepatic growth as it is not induced in other mitogen-treated cells. RNR-1 is also expressed in brain. A full-length cDNA clone of RNR-1 encodes a 66-kDa, 597-amino acid protein as verified by in vitro translation in reticulocyte lysate. RNR-1 is highly homologous to r-NGFI-B/m-Nur77 particularly in the DNA binding (94%) and putative ligand binding (59%) domains. Using a mobility shift assay, we have shown that RNR-1 specifically binds to the NGFI-B DNA half-site and forms a complex very similar in size to the Nur77 complex, suggesting that RNR-1 also may bind as a monomer. Consistent with this finding, the A box region important in mediating half-site binding is 100% conserved between r-NGFI-B/m-Nur77. Both RNR-1 and Nur77 strongly transactivate a reporter driven by a consensus r-NGFI-B/Nur77 binding site, and their effect together is additive. As both the RNR-1 and r-NGFI/m-nur77 genes are induced during liver regeneration, it is very possible that RNR-1 acts concomitantly with r-NGFI/m-Nur77 in regulating the expression of delayed-early genes during liver regeneration.