The tumor promoter phorbol 12-myristate 13-acetate (PMA) inhibits the growth of human endothelial cells and induces differentiation into capillary-like, tubular structures. We have isolated cDNA clones induced by PMA in the presence of cycloheximide and report the characterization of a novel immediate-early cDNA clone, termed edg-1, from human endothelial cells. The 3-kilobase edg-1 transcript is rapidly induced when endothelial cells are treated with PMA and superinduced in the presence of cycloheximide. While superinduction is due, at least in part, to the stabilization of the edg-1 transcript, nuclear run-on analysis demonstrates that the transcription of edg-1 is stimulated by PMA. Although the edg-1 transcript is very abundant in endothelial cells, transcripts related to human edg-1 are also detected at lower levels in vascular smooth muscle cells, fibroblasts, melanocytes, and cells of epithelioid origin. The deduced polypeptide sequence of edg-1 contains seven transmembrane domains with significant structural similarities to G-protein-coupled receptors (GPRs). Although the identity of the ligand for edg-1 is presently unknown, the structure of edg-1 polypeptide strongly implies that the edg-1 translation product is an inducible endothelial cell GPR. Since GPRs are involved in diverse biological processes such as signal transduction, cell proliferation, and differentiation, the characterization of human edg-1 as a highly inducible and abundant endothelial cell GPR suggest that it may be involved in the processes that regulate the differentiation of endothelial cells.