THE MOLECULAR BIOLOGY OF THE MAMMALIAN GRP GENE

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Gastrin releasing peptide (GRP), a 27 amino acid neuropeptide is a mammalian homologue of the amphibian tetradecapeptide bombesin (1). The carboxy terminal fourteen amino acid residues of mammalian GRP are very similar to amphibian bombesin, particularly the terminal heptapeptide which appears to be the biologically active region of the molecule that is critical for binding to receptors (2). Bombesin/GRP has been detected in mammalian brain (3) and also in peripheral nerve cells of the gut (4) where it is known to stimulate the release of gastrin from G cells in the gastric mucosa in dogs and humans. In addition, bombesin/GRP has been detected in the pulmonary endocrine cells of normal bronchial epithelium (5), as well as in lung carcinoid tumors (6,7) and human small cell lung cancer (SCLC) (8,9,10). Under certain circumstances, GRP can stimulate the growth of human SCLC cell lines (11,12), normal human bronchial epithelial cells (13), and mouse Swiss 3T3 cells (14) where its growth promoting properties appear to be mediated by a cell surface receptor (15). GRP is both synthesized and secreted by some SCLC cell lines and can also stimulate cell growth, indicating this neuropeptide may function as an autocrine growth factor that contributes to the transformed growth properties of SCLC (12). Our group focused its attention on extending these studies by exploring the molecular biology of the pre-pro GRP gene. As a first step in this analysis, we obtained a collection of about 25 GRP cDNA clones from several human SCLC cDNA libraries generated in this laboratory. Analysis of these clones revealed a pre-pro GRP translation product consisting of a signal sequence, the predicted 27 amino acid GRP neuropeptide, and a novel GRP-associated peptide representing the carboxy portion of the translational reading frame encoding GRP (16,17).