MOLECULAR MECHANISM OF HUMAN CD38 GENE-EXPRESSION BY RETINOIC ACID - IDENTIFICATION OF RETINOIC ACID RESPONSE ELEMENT IN THE FIRST INTRON

CD38 is a nonlineage-restricted type II transmembrane glycoprotein pos sessing ecto-NAD(+) glycohydrolase activity. Because of its unique exp ression pattern in lymphocyte differentiation, it appears to function as an immunoregulatory molecule. We previously reported that CD38 was specifically induced by all-trans-retinoic acid (RA) in human promyelo cytic leukemia HL-60 cells. Here we studied the molecular mechanism of the RA-dependent induction of human CD38, The expression of CD38 mRNA by RA appeared to be caused by the transcriptional stimulation of the gene, since it was blocked by an RNA synthesis inhibitor, but not by a protein synthesis inhibitor. In search of the RA response element (R ARE) possibly present in human CD38 gene promoter, we isolated and seq uenced the genomic DNA covering the 5'-flanking region, exon I, and pa rtial intron 1. Transient transfection experiments revealed that the r esponsiveness to RA was conferred through an RARE consisting of two di rect repeat TGACCT-like hexamer motifs with a 5-nucleotide spacer, whi ch was located in the first intron rather than the 5'-flanking region of the CD38 gene. This RARE interacted with heterodimer composed of RA receptor and retinoid X receptor in vitro. Thus, the RA-induced expre ssion of the human CD38 gene was demonstrated to be mediated through t he RARE located in the first intron.