BOMBESIN RECEPTORS IN NORMAL AND NEOPLASTIC TISSUES

    Project: Research project

    Description

    The bombesin-like peptides are a large family of peptides initially
    characterized in frog skin, but later found to have wide distribution and
    potent physiologic effects in mammals. The mammalian homologue of bombesin
    is gastrin-releasing peptide (GRP). GRP is widely distributed in the CNS
    and GI tract; but of greatest clinical importance, high levels of GRP are
    expressed by most small cell lung carcinomas (SCLC). Bombesin has been
    shown to be a growth factor for normal and neoplastic pulmonary cells and
    blockade of the bombesin receptor expressed by SCLC cell lines with either
    antibodies or antagonists causes inhibition of tumor growth. Thus
    characterization of the bombesin receptor expressed by SCLC will provide
    information on the growth of that tumor and may be of potential diagnostic
    importance. Receptors for bombesin-like peptides are also expressed
    throughout the GI tract and CNS, and in those tissues, GRP plays important
    roles as a neurotransmitter, paracrine regulator and growth factor. In GI
    tract and CNS there is a second mammalian bombesin-like peptide, neuromedin
    B (NMB) which will bind to the same receptor as GRP, but appears to also
    have its own distinct receptor. Thus understanding the role of bombesin-
    like peptides in those tissues will require characterization of both the
    GRP and the NMB receptor. Our objective in this proposal is first to characterize, through molecular
    cloning, the receptors for mammalian bombesin-like peptides and then to
    analyze receptor expression in normal and neoplastic tissues. Specifically
    we propose: (1), To first clone the mouse GRP receptor from Swiss 3T3 cells
    to take advantage of the high number of receptors expressed by those cells.
    (2), To use the 3T3 bombesin receptor cDNA to identify the human GRP cDNA
    in order to determine the structure of the human GRP receptor. (3), To use
    the human GRP receptor cDNA to identify the human NMB receptor cDNA in
    order to determine the structure of the human NMB receptor. (4), To
    characterize tissue specific expression of the GRP and NMB receptors in
    normal and neoplastic tissue and cell lines. Of primary importance will be
    to determine if either the structure or regulation of the GRP receptor is
    altered in SCLC. (5), To express GRP and NMB receptor constructs in Xenopus
    oocytes and SCLC cell lines. Binding of GRP, NMB and antagonists will be
    determined and the effects of receptor expression on DNA replication and
    intracellular calcium measured. Structure- function analysis will be
    performed to identify the ligand bindin and signal transduction domains.
    The approach to be used to clone the 3T3 bombesin receptor will be by
    expression in Xenopus oocytes. As described in the body of the grant,
    substantial progress towards that goal has been made. cDNA's encoding the
    human GRP and NMB receptors will be identified by hybridization and their
    identities will be confirmed by expression in Xenopus oocytes.
    StatusFinished
    Effective start/end date12/15/9011/30/93

    Funding

    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health

    Fingerprint

    Bombesin Receptors
    Gastrin-Releasing Peptide
    Small Cell Lung Carcinoma
    Bombesin
    Peptides
    Complementary DNA
    Xenopus
    Cell Line
    Oocytes
    Gastrointestinal Tract
    Intercellular Signaling Peptides and Proteins
    Clone Cells
    Organized Financing
    Growth

    ASJC

    • Medicine(all)