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The Bovine Chromogranin A Gene: Structural Basis for Hormone Regulation and Generation of Biologically Active Peptides

Unit on Molecular and Cellular Neurobiology, Laboratory of Cell Biology, National Institute of Mental Health Bethesda, Maryland 20892
Department of Biochemistry and Biophysics, University of California San Francisco, California 94143

Address requests for reprints to: Anna L. lacangelo and Dr. Lee E. Eiden, Laboratory of Cell Biology, National Institute of Mental Health, National Institutes of Health, Building 36, Room 3A-17, Bethesda, Maryland 20892.

Abstract

The structure of the gene encoding bovine chromogranin-A has been determined by characterization of two isolated genomic clones. Chromogranin-A is encoded by eight exons, which organize the coding region into several distinct structural and functional domains. Exons 1–5 represent the highly conserved signal peptide and N-terminal domain, which are separated into regions corresponding to the signal peptide, N-terminal sequence, disulfide-bonded loop, and remainder of the conserved N-terminal domain. Exon 6 represents the variable domain and encodes a region that is identical to the novel chromogranin-A-derived peptide chromostatin. Exon 7 encodes the biologically active peptide pancreastatin as well as most of the conserved C-terminal domain, with the remainder found on exon 8. The mRNA sequence obtained from the gene contains five nucleotide differences from the consensus sequence of four reported bovine chromogranin-A cDNA clones. Two of the differences in the gene result in two amino acid changes in the region encoded by exon 6. The structural organization of the chromogranin-A gene resembles that of the chromogranin-B gene in the exons corresponding to the signal peptide, N-terminal sequence, disulfide loop, and C-terminal sequence. Sequence analysis of the promoter region reveals the presence of a cAMPresponsive element located 24 bases up-stream of the TATA box, a site positioned 125 bases from the cAMP-responsive element that is similar to the consensus sequence established for glucocorticoid-responsive elements, and two elements located further up-stream which each match six of seven bases of the AP-1-binding consensus sequence TGAG/CTCA, a heptanucleotide sequence in which the fourth base is G or C. Changes in chromogranin-A mRNA abundance after treatment with dexamethasone, forskolin, and phorbol ester indicate a potential role for all of these elements in the regulation of the chromogranin-A gene in endocrine cells.

Received for publication March 21, 1991. Revision received August 22, 1991.

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