The effects of retinoids such as all-trans-retinoic acid (ATRA) on cell growth, differentiation, and apoptosis are thought to be mediated by nuclear retinoid receptors, which are involved in ligand-dependent transcriptional activation of target genes. Using differential display, we identified the cDNA of a novel gene, designated retinoic acid-inducible gene 1 (RAIG1), which was induced by ATRA in the squamous carcinoma cell line UMSCC-22B. Two RAIG1 transcripts of 2.4 and 6.8 kilobase pairs, respectively, have the same ORF that encodes a 357-amino acid polypeptide. RAIG1 mRNA is expressed at high level in fetal and adult lung tissues. Induction of RAIG1 expression by ATRA is rapid (within 2 h) and dose-dependent in the range between 1 nM to 1 microM. The constitutive RAIG1 mRNA levels, which were low in three of five head and neck and four of six lung cancer cell lines, increased after ATRA treatment in most cell lines. The deduced RAIG1 protein sequence contains seven transmembrane domains, characteristic of G protein-coupled receptors. A fusion protein of RAIG1 and the green fluorescent protein was localized in the cell surface membrane and perinuclear vesicles in transiently transfected cells. RAIG1 was mapped to chromosome 12p12. 3-p13. Our results provide novel evidence for a possible interaction between retinoid and G protein signaling pathways.