Glucagon, originally discovered as a hyperglycemia-producing peptide in the pancreas, is now known to belong to a multigenic family of structurally-related peptides present in the pancreas, intestinal tract and the brain. These peptides include in addition to the glucagons, fasoactive intestinal peptide, gastric inhibitory peptide and secretion. Multiple forms of immunoreactive glucagon-like peptides ranging in molecular weight from 3,500 to 200,000 have been identified in these tissues and partially characterized by structural analyses. Recently, we have discovered two separate precursors to islet glucagon, pre-proglucagons, among the cell-free translation products of anglerfish islet mRNAs. We have prepared and cloned in bacterial hosts cDNAs encoding these islet pre-proglucagons and are sequencing the cDNAs in order to determine the structures of the pre-proglucagons. We also have identified a mRNA in extracts of intestines that cross-hybridizes with the islet cDNA that encodes the sequence of glucagon. We propose to: (1) select and sequence glucagon-related cDNAs from among cloned cDNA Libraries prepared from the intestine and brain of anglerfish; (2) prepare a genomic (gDNA) library from anglerfish and to select and determine the sequences of glucagon-related genes, and (3) to use the fish cDNAs as hybridization probes to identify both cDNAs prepared from rat pancreatic islets and cloned genomic sequences from human and rat gene libraries. Information of the structures of the glucagon-relaged polypeptides and genes is a useful first step in analyses of the organization and expression of the genes encoding the glucagons as well as in the design of studies to investigate the role of glucagon in the pathogenesis of diabetes mellitus.
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