Structure of the human ghicagon gene

White, J. W.; Saunders, Grady F.

doi:10.1093/nar/14.12.4719

Cited by 117 publications

(62 citation statements)

References 26 publications

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“…Specifically, a sequence identical to that of the core sequence of the PAX6 paired domain consensus recognition site (Epstein et al 1994) was found at position -262 to -248 bp relative to the start site of transcription of the rat glucagon gene (Fig. 3A), and is also conserved in the h u m a n glucagon promoter (White and Saunders 1986). This sequence is part of the A site of the glucagon G3 promoter element, which is similar to sequences also found in the rodent insulin I and insulin II and somatostatin promoters, and therefore has been referred to as the pancreatic islet cell (n = 27) (n = 10) 12.2 • 1.3 9.1 • 0.92 (75%) 1.6 • 0.08 (13%) (n = 11) (n = 27) (n = 10) 74.4 • 4.0 74.5 • 9.7 (100%) (n = 6) (n = 6) 57.3 x 106 + 12.5 x 106 (8%) 34.1 x 106 + 5.7 x 106 (60%) 4.58 X 10 6 + 0.94 x 106 (n = 6) (n --14) (n = 6) aThe average number of glucagon-or insulin-positive cells per section (as detected by immunohistochemical staining) was determined by counting stained cells in eight sections from an individual pancreas (approximately every twentieth section).…”

Section: Pax6 Binds To Glucagon Insulin and Somatostatin Gene Regulmentioning

confidence: 90%

Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development.

Sander¹,

Neubüser²,

Kalamaras³

et al. 1997

Genes Dev.

522

459

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We present genetic and biochemical evidence that PAX6 is a key regulator of pancreatic islet hormone gene transcription and is required for normal islet development. In embryos homozygous for a mutant allele of the Pax6 gene, Small eye (SeyNeU), the numbers of all four types of endocrine cells in the pancreas are decreased significantly, and islet morphology is abnormal. In the remaining islet cells, hormone production, particularly glucagon production, is markedly reduced because of decreased gene transcription. These effects appear to result from a lack of PAX6 protein in the mutant embryos. Biochemical studies identify wild-type PAX6 protein as the transcription factor that binds to a common element in the glucagon, insulin, and somatostatin promoters, and show that PAX6 transactivates the glucagon and insulin promoters.

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Section: Pax6 Binds To Glucagon Insulin and Somatostatin Gene Regulmentioning

confidence: 90%

Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development.

Sander¹,

Neubüser²,

Kalamaras³

et al. 1997

Genes Dev.

522

459

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“…Interestingly, no such consensus sequence was detected in the 5' flanking region of the human glucagon gene (5 respectively (36,37). These regulatory peptides are known to exert their effects through cyclic AMP-and protein kinase GLI as both intact fetal intestine and adult C-dependent pathways, respectively (28,38).…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of the cDNAs and genes that encode proglucagon (3)(4)(5)(6) has shown that this prohormone resembles other polyproteins in that it encodes multiple peptides separated from each other by pairs of basic amino acids characteristic of the sites commonly cleaved by prohormone-processing enzymes. Posttranslational processing of proglucagon is also highly tissue-specific, with the liberation of glucagon in the pancreas and glicentin and the glucagon-like peptides in the intestine (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine.

Drucker

Brubaker

1989

Proc. Natl. Acad. Sci. U.S.A.

121

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Expression of the gene encoding preproglucagon gives rise to different glucagon-related peptides in the pancreas and intestine. Glucagon gene expression is regulated by a protein kinase C-dependent pathway in rat islet cell lines, whereas activation of the adenylate cyclase pathway in islet cell lines is without effect. To elucidate the factors important for the control of proglucagon biosynthesis in the intestine, we have studied proglucagon gene expression and proglucagon biosynthesis in rat intestine. Analysis of intestinal cDNA clones encoding preproglucagon indicated that pancreatic and intestinal glucagon mRNA transcripts were identical. The regulation of proglucagon gene expression in rat intestine differed markedly from that previously observed in islet cell lines. Phorbol esters increased the secretion of glucagon-like immunoreactive peptides (GLI) but had no effect on proglucagon mRNA levels in rat intestinal cells. Bombesin also increased the secretion of GLI without affecting proglucagon mRNA levels or biosynthesis. In contrast, dibutyryl cyclic AMP, forskolin, and cholera toxin increased both proglucagon mRNA levels and GLI biosynthesis and secretion, suggesting that proglucagon gene expression in the intestine is regulated by a cyclic AMPdependent pathway. These observations suggest that tissuespecific differences in both the regulation of proglucagon gene expression and the posttranslational processing of proglucagon contribute to the diversity of glucagon gene expression.A variety of different mechanisms contribute to the diversification of peptide biosynthesis, including gene duplication, conservation of functional peptide domains in coding exons, and tissue-specific exon splicing (1). Tissue-specific posttranslational processing of polyprotein precursorF provides an additional mechanism for increasing the diversity of gene expression (2). To analyze the molecular determinants of peptide hormone biosynthesis, we have been studying the biosynthesis of glucagon and the glucagon-related peptides.The glucagon gene is transcribed in a highly tissue-specific manner, being expressed in the A cells of the pancreatic islets, the neuroendocrine L cells of the intestine, and in hypothalamic and brainstem neurons. Analysis of the cDNAs and genes that encode proglucagon (3-6) has shown that this prohormone resembles other polyproteins in that it encodes multiple peptides separated from each other by pairs of basic amino acids characteristic of the sites commonly cleaved by prohormone-processing enzymes. Posttranslational processing of proglucagon is also highly tissue-specific, with the liberation of glucagon in the pancreas and glicentin and the glucagon-like peptides in the intestine (7-9). The glucagonlike peptides appear to be present as larger, incompletely processed forms in the pancreas, whereas processing in the intestine generates authentic GLP-I and GLP-II. The observation that a truncated form of GLP-I released from the gut has potent insulinotropic properties (10-13) has stimulated much i...

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“…Comparison of the 5'-flanking sequences of the rat and human glucagon genes indicates that Gl and G2 have been highly conserved throughout evolution, with 95 and 97% homology, respectively (42) (Fig. 8).…”

Section: Discussionmentioning

confidence: 99%

Alpha-cell-specific expression of the glucagon gene is conferred to the glucagon promoter element by the interactions of DNA-binding proteins.

et al. 1988

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The glucagon gene is expressed specifically in the alpha cells of the pancreatic islets. We show here that 300 base pairs of the 5'-flanking region of the rat glucagon gene, linked to a chloramphenicol acetyltransferase reporter plasmid transfected into islet cell lines of different hormone-producing phenotypes, directs transcription only in glucagon-producing islet cells. Deletional and linker-scanning mutations and DNase I footprinting assays identify three transcriptional control elements within these 300 base pairs. Two of these elements (G2 and G3) independently display enhancerlike functions on both homologous and heterologous promoters in glucagon (alpha) cells, but only on heterologous promoters in insulin-(beta) and somatostatin-(delta) expressing cells, and not in non-islet cells. The proximal promoter element (GI), characterized by low intrinsic transcriptional activity, is critical for specific expression of the glucagon gene in alpha cells. However, nuclear extracts prepared from all three islet cell phenotypes give similar protection to the three control elements of the glucagon 5'-flanking sequence. We conclude that these phenotypically distinct islet cell lines all contain regulatory DNA-binding proteins interacting with the three control elements of the glucagon gene, but that factors interacting with the glucagon promoter result in transcriptional activation only in alpha cells, to restrict glucagon gene expression to these cells. These observations suggest that interactions of nuclear proteins with cis-control elements are involved in the programmed developmental expression of the islet polypeptide hormone genes.A consequence of developmental differentiation is the expression of specific subsets of genes in terminally differentiated cells. It is well established that the factors that determine both cell-specific and regulated expression of genes consist of complexes of proteins bound to cognate DNA control elements (8,19,21). Studies of the transcriptional expression of deletionally mutated fusion genes introduced into animal cell lines and in mice have identified specific control elements within the 5'-and 3'-flanking regions, introns, and exons of genes (4,21,30 potentiality for differentiating into cell lineages expressing one or more of the three major islet hormones (31). Thus, cell lines derived from rat and hamster islet tumors are useful models for studies of the factors responsible for cellular differentiation and cell-specific expression of these hormone genes.Glucagon is a 29-amino-acid peptide that raises blood glucose levels through its actions on hepatic glycogenolysis and gluconeogenesis (18,39,40 Utilizing both homologous and heterologous promoters, we have identified cis-acting transcriptional elements of the glucagon gene and trans-acting nuclear factors capable of interacting with these elements in a sequence-specific manner to confer islet and alpha cell-specific expression. Three such cis-acting control DNA elements are found within the first 300 bp of the 5'-flanking regi...

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Structure of the human ghicagon gene

Cited by 117 publications

References 26 publications

Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development.

Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development.

Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine.

Alpha-cell-specific expression of the glucagon gene is conferred to the glucagon promoter element by the interactions of DNA-binding proteins.

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