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At least 19 recordsLinked to original sources

PubMed1992

Alterations in proglucagon processing and inhibition of proglucagon gene expression in transgenic mice which contain a chimeric proglucagon-SV40 T antigen gene.

The proglucagon gene is expressed in A cells of the pancreas and L cells of the large and small intestine. Transgenic mice expressing SV40 large T antigen under the control of proglucagon regulatory sequences develop neuroendocrine carcinoma of the large intestine. To determine the consequences of coexpression of SV40 large T antigen and proglucagon in different cell types, the levels of proglucagon mRNA transcripts and proglucagon-derived peptides were determined in tumor-bearing transgenic mice and in age-matched paired controls. Plasma levels of proglucagon-derived peptides (glicentin, oxyntomodulin, and glucagon, as determined by high pressure liquid chromatography and radioimmunoassay) were markedly elevated in association with tumor growth (p < 0.001). Northern blot analysis demonstrated that the increased concentration of proglucagon-derived peptides was associated with significant inhibition of the endogenous proglucagon gene in pancreas, and to a lesser extent, small intestine. Concomitantly, the concentrations of proglucagon-derived peptides fell to 1-10% of control values in pancreas (p < 0.001) and to 62% of control values in small intestine (p < 0.001). Analysis of proglucagon-derived peptides in mice of different ages demonstrated that tumor growth was associated with a switch in the post-translational processing of proglucagon. Compared with normal mouse intestine, tumors contained increased proportions of glucagon and glucagon-like peptide-1(7-37) relative to glicentin, oxyntomodulin, and glucagon-like peptide-1(1-37). The results of these studies provide evidence for humorally-mediated tissue-specific inhibition of proglucagon gene expression.

Animals↗

PubMed2002

Pax-2 activates the proglucagon gene promoter but is not essential for proglucagon gene expression or development of proglucagon-producing cell lineages in the murine pancreas or intestine.

Tissue-specific proglucagon gene transcription is achieved through combinations of transcription factors expressed in pancreatic A cells and enteroendocrine L cells of the small and large intestine. Cell transfection and electrophoretic mobility shift assay experiments previously identified Pax-2 as a regulator of islet proglucagon gene expression. We examined whether Pax-2 regulates gut proglucagon gene expression using enteroendocrine cell lines and Pax2(1NEU) mutant mice. Immunoreactive Pax-2 was detected in STC-1 enteroendocrine cells, and Pax-2 activated proglucagon promoter activity in transfected baby hamster kidney and GLUTag cells. Pax-2 antisera diminished the formation of a Pax-2-G3 complex in electrophoretic mobility shift assay studies using nuclear extracts from islet and enteroendocrine cell lines. Surprisingly, Pax-2 mRNA transcripts were not detected by RT-PCR in RNA isolated from adult rat pancreas, rat islets, embryonic d 19 or adult murine pancreas and gastrointestinal tract. Furthermore, embryonic d 19 or neonatal d 1 Pax2(1NEU) mice exhibited normal islet A cells and gut endocrine L cells, and no decrement in pancreatic or intestinal glucagon gene expression. These findings demonstrate that Pax-2 is not essential for the developmental formation of islet A or gut L cells and does not play a role in the physiological control of proglucagon gene expression in vivo.

Animals↗

PubMed2002

Foxa3 (HNF-3gamma) binds to and activates the rat proglucagon gene promoter but is not essential for proglucagon gene expression.

Members of the Forkhead box a (Foxa) transcription factor family are expressed in the liver, pancreatic islets and intestine and both Foxa1 and Foxa2 regulate proglucagon gene transcription. As Foxa proteins exhibit overlapping DNA-binding specificities, we examined the role of Foxa3 [hepatocyte nuclear factor (HNF)-3gamma] in control of proglucagon gene expression. Foxa3 was detected by reverse transcriptase PCR in glucagon-producing cell lines and binds to the rat proglucagon gene G2 promoter element in GLUTag enteroendocrine cells. Although Foxa3 increased rat proglucagon promoter activity in BHK fibroblasts, augmentation of Foxa3 expression did not increase proglucagon promoter activity in GLUTag cells. Furthermore, adenoviral Foxa3 expression did not affect endogenous proglucagon gene expression in islet or intestinal endocrine cell lines. Although Foxa3(-/-) mice exhibit mild hypoglycaemia during a prolonged fast, the levels of proglucagon-derived peptides and proglucagon mRNA transcripts were comparable in tissues from wild-type and Foxa3(-/-) mice. These findings identify Foxa3 as a member of the proglucagon gene G2 element binding-protein family that, unlike Foxa1, is not essential for control of islet or intestinal proglucagon gene expression in vivo.

Animals↗

PubMed1995

The proglucagon gene upstream enhancer contains positive and negative domains important for tissue-specific proglucagon gene transcription.

The gene encoding proglucagon is restricted in expression to the central nervous system, endocrine pancreas, and intestine. Transgenic experiments indicate that the proglucagon gene upstream enhancer (GUE) element is a principal determinant of both the tissue specificity and the relative level of proglucagon gene transcription. We have now sequenced the rat proglucagon GUE and analyzed the transcriptional properties of proglucagon-luciferase fusion genes (that contain 5'- and 3'-deletions in the GUE) after transfection of islet (InR1-G9) and enteroendocrine (STC-1 and GLUTag) cell lines. The GUE contains both positive and negative elements that are recognized differentially in islet vs. intestinal cell lines. The transcriptional properties of the GUE sequences were more similar in cell lines of intestinal (STC-1 and GLUTag) compared with islet (InR1-G9) phenotypes. The electrophoretic mobility shift assay was used to identify specific domains of the GUE that interacted with nuclear proteins from islet and intestinal cells. Several GUE sequences recognized proteins present in both fibroblast and endocrine cell lines. In contrast, electrophoretic mobility shift assay experiments also identified 1) GUE-protein complexes common to both islet and intestinal cell lines and 2) GUE-protein complexes specific to either islet or intestinal lineages. One of the GUE subdomains, designated GLUE1, displayed enhancer-like activity in InR1-G9 and GLUTag, but not BHK, cell lines. Taken together, these observations demonstrate that the proglucagon GUE is comprised of multiple positive and negative domains that likely function in a combinatorial fashion to regulate islet and intestinal-specific proglucagon gene transcription.

Animals↗

PubMed2003

Expression, purification, and PC1-mediated processing of human proglucagon, glicentin, and major proglucagon fragment.

To examine the cleavage specificity of different members of the furin/propeptide convertase (PC) family of enzymes, we have selected proglucagon (PG) as a model substrate. PG was selected because it is subject to differential processing in vivo. PG is thought to be cleaved initially at an interdomain site to produce glicentin and the major proglucagon fragment (MPGF). These intermediates are subsequently cleaved, most likely by the convertases PC2 and PC1, respectively. To determine the exact sites within PG that are cleaved by PC1 and PC2, we attempted to produce milligram quantities of human PG, glicentin, and MPGF for use in an in vitro conversion assay. A methionine residue was added to the N-terminus of each protein to initiate translation. Purification was achieved using cation exchange and reversed-phase chromatography, and the integrity of the methionylated proteins was confirmed by both electrospray ionization-mass spectrometry and amino acid analysis. The combined expression and purification scheme is fast, efficient, and results in milligram quantities of > or =95% pure proglucagon, > or =95% pure MPGF, and > or =93% pure glicentin. These prohormones are cleaved by PC1 to produce product peptides consistent with the processing of PG observed in vivo, and should therefore be suitable for further analysis of the post-translational processing of PG.

Electrophoresis, Polyacrylamide Gel↗

PubMed1984

Conversion of proglucagon in pancreatic alpha cells: the major endproducts are glucagon and a single peptide, the major proglucagon fragment, that contains two glucagon-like sequences.

It has previously been shown by biosynthetic labeling studies that glucagon is synthesized in mammalian islets via an 18-kDa precursor, proglucagon, that during processing gives rise to glucagon and a secreted peptide of 10 kDa (the major proglucagon fragment, MPGF). We have now developed a simple procedure for the isolation of this peptide from rat pancreatic islets and have characterized it more fully. On the basis of its amino acid composition, MPGF is identified as the COOH-terminal portion of proglucagon that contains two glucagon-related sequences. These sequences do not appear to be liberated from MPGF in alpha cells of the islets of Langerhans but MPGF may be processed further elsewhere in the body or in other cells of the gastrointestinal tract that produce glucagon precursors.

Amino Acid Sequence↗

PubMed2003

Regulation of proglucagon transcription by activated transcription factor (ATF) 3 and a novel isoform, ATF3b, through the cAMP-response element/ATF site of the proglucagon gene promoter.

Glucagon, the second major glucose-regulated hormone in the control of glucose homeostasis, functions as a counter-regulator to insulin and is specifically produced by the pancreatic alpha cells. Its excessive biosynthesis and secretion is associated with diabetes mellitus. The expression of the proglucagon gene has been demonstrated to be regulated by a cAMP-dependent pathway through cAMP-response element-binding protein (CREB) and possibly other transcription factors bound to its cAMP-response element (CRE)/activated transcription factor (ATF) site. Elsewhere we have shown that ATF3, a member of the ATF/CREB subfamily of the basic leucine zipper domain proteins, is expressed predominantly in the alpha cells of the pancreatic islets. In our attempts to further dissect the role of ATF3 proteins in alpha cells, we have identified and characterized a novel alternatively spliced form, ATF3b, and have compared the specific binding ability of ATF3 and ATF3b on the CRE/ATF motif of the proglucagon promoter. Our findings indicate the existence of a novel mechanism by which the transcription of the proglucagon gene is regulated in response to cAMP signals, in addition to CREB and in relation to glucose fluctuations in pancreatic alpha cells.

3T3 Cells↗

PubMed1993

Region- and age-specific differences in proglucagon gene expression in the central nervous system of wild-type and glucagon-simian virus-40 T-antigen transgenic mice.

The gene encoding proglucagon is expressed in the A-cells of the endocrine pancreas and the L-cells of the gastrointestinal tract. Proglucagon-derived peptides have also been detected in different regions of the central nervous system; however, proglucagon mRNA transcripts have been localized predominantly to the brainstem and hypothalamus. We have studied proglucagon gene expression in the brain of mice using the reverse transcription-polymerase chain reaction technique. Proglucagon mRNA transcripts were detected in the cortex, cerebellum, and brainstem of embryonic day 19 mouse brain and in the cortex, cerebellum, brainstem, and hypothalamus of 2- to 12-week-old wild-type mice. Age-specific changes in proglucagon gene expression were observed, with a progressive decrease in the levels of proglucagon mRNA transcripts detected in the cortex of older mice. In contrast, a progressive increase in the levels of proglucagon mRNA transcripts was detected with increasing age in the brainstem. Proglucagon gene expression was also examined in the brain of glucagon-simian virus-40 (SV40) T-antigen transgenic mice. The levels of proglucagon gene expression in transgenic cerebellum and brainstem were relatively greater than those in wild-type mice on embryonic day 19, and increased levels of proglucagon mRNA transcripts were observed in transgenic cerebellum, brainstem, and hypothalamus at 2 weeks. In contrast, the levels of proglucagon mRNA transcripts were markedly reduced in the brain of 5-week-old transgenic mice. A reduction in the levels of SV40 T-antigen mRNA transcripts was also detected in the brain of transgenic mice at 5 weeks, but no suppression of the mRNA transcripts for the neuropeptide somatostatin was observed in 5-week-old transgenic brain. The results of these studies suggest that proglucagon mRNA transcripts are more widely distributed in the mouse central nervous system than previously demonstrated and that proglucagon gene expression in the brain appears to be regulated in a region- and age-specific manner. The coordinate region-specific expression and regulation of mRNA transcripts derived from the endogenous mouse proglucagon gene and a glucagon-SV40 T antigen transgene in the central nervous system of mice harboring a transgene containing 2.0 kilobases of rat proglucagon gene 5'-flanking sequences fused to the coding sequence of SV-4 large T-antigen suggest that neural-specific elements residing within the first 2.0 kilobases of glucagon gene 5'-flanking sequences are sufficient for the correct targeting and regulation of proglucagon gene expression in the brain.

Aging↗

PubMed1996

Proglucagon gene expression is induced by gastrin-releasing peptide in a mouse enteroendocrine cell line.

The proglucagon gene is expressed in a cell-specific manner in the A cells of the islets and the L cells of the intestine; however, the physiological factors that regulate proglucagon gene expression are not well understood. Although insulin inhibits proglucagon gene transcription in the islets, peptides that stimulate proglucagon gene expression have not been identified. We show here that gastrin-releasing peptide (GRP) induces proglucagon messenger RNA transcripts in STC-1 enteroendocrine cells. The GRP induction of proglucagon gene expression was dose dependent, detectable by 4 h after GRP treatment, and sustained, i.e. detectable after a 24-h GRP incubation. GRP also induced the transcriptional activity of rat proglucagon promoter-luciferase plasmids in transfected STC-1 cells. The GRP induction of proglucagon promoter activity was attenuated, but not eliminated, after deletion of 5'-flanking sequences containing the proglucagon gene cAMP response element (CRE). A mutation in the CRE previously shown to abrogate cAMP responsiveness and CRE-binding protein binding was associated with a reduction in the transcriptional response to GRP. The proglucagon CRE also conferred GRP responsiveness to a truncated proglucagon promoter in STC-1 cells. These observations identify GRP as a peptide activator of proglucagon gene expression and provide evidence linking the proglucagon gene CRE to the physiological control of proglucagon gene expression.

Animals↗

PubMed1996

Effects of fasting, refeeding, and intraluminal triglyceride on proglucagon expression in jejunum and ileum.

Intestinal proglucagon is thought to be synthesized primarily by the distal gut, although the role of proglucagon-derived glucagon-like peptide I (GLP-I) as a major physiological incretin would seem to be associated with production in proximal small bowel. To better characterize the sites of production of proglucagon and GLP-I in the small intestine and evaluate nutrient regulation of small bowel proglucagon and derived peptides, we evaluated the effects of fasting for 72 h and subsequent refeeding or jejunal infusion of long-chain triglyceride (LCT) for 24 h on local expression of proglucagon in proximal and distal small bowel. Proglucagon mRNA abundance and cellular localization were determined and correlated with wet weight of bowel. In jejunum, proglucagon mRNA abundance decreased by 40% with fasting (P < 0.005) and increased with refeeding to levels similar to those of ad libitum-fed animals. In ileum, fasting resulted in a 20% decrease in proglucagon mRNA (P < 0.005); in contrast to jejunum, refeeding did not result in a significant rise in ileal proglucagon mRNA abundance from fasting values. In jejunum, signal intensity of proglucagon mRNA per cell, determined by in situ hybridization, decreased with fasting (P < 0.05) and increased with refeeding (P < 0.005) in proportion to changes in mRNA abundance. Plasma enteroglucagon and GLP-I levels correlated with jejunal proglucagon mRNA. Intrajejunal infusion of LCT increased expression of proglucagon to a greater extent in jejunum than in ileum. In conclusion, enteral nutrient intake stimulates small bowel proglucagon expression; this effect is greater in jejunum than ileum, consistent with greater intraluminal nutrient exposure and the role of jejunum as a source of the major incretin GLP-I.

Animals↗

PubMed2004

Fish proglucagon genes have differing coding potential.

Regulation of tissue-specific hormone production involves transcription, post-translational and physiological regulation. The proglucagon gene has been an ideal molecule for understanding many aspects of regulation of hormone production. Gene duplications often allow the evolution of new gene function, and the proglucagon gene has been duplicated on the lineage leading to teleost fish, while most other vertebrates have only a single proglucagon gene. The recent characterization of near complete pufferfish and zebrafish genomes allowed us to determine the structure of the duplicated genes. We searched the pufferfish and zebrafish genomes for proglucagon-like sequences. Our searches identified two proglucagon-like genes in both the pufferfish and zebrafish genomes. In pufferfish the proglucagon-like genes are surrounded by genes that are similar to genes that flank the proglucagon gene in mammalian genomes, indicating that gene order near the proglucagon gene has been maintained since the fish-mammal divergence approximately 450 million years ago. Characterization of the duplicated fish proglucagon genes indicates that one of the two genes is predicted to encode glucagon, GLP-1 and GLP-2. In contrast, the second proglucagon gene is predicted to encode only glucagon and GLP-1, but not GLP-2. Thus the two fish proglucagon genes have different coding potential, and, therefore likely differ in function. Regulation of gene expression potentially has a role in the regulation of production of proglucagon derived peptides in fish.

Amino Acid Sequence↗

PubMed2006

Role of the exchange protein directly activated by cyclic adenosine 5'-monophosphate (Epac) pathway in regulating proglucagon gene expression in intestinal endocrine L cells.

Although proglucagon gene expression and the synthesis of proglucagon encoded peptide hormones could be activated by protein kinase A (PKA) activators such as forskolin/3-isobutyl-1-methylxanthine (IBMX) and cholera toxin, whether the activation is entirely attributed to PKA has not been previously examined. We found that forskolin/IBMX also activate ERK1/2 phosphorylation in intestinal and pancreatic proglucagon-producing cell lines. The MEK inhibitors PD98059 and U0126 were found to repress the expression of proglucagon promoter as well as endogenous proglucagon mRNA in two intestinal proglucagon-producing cell lines and to block the stimulatory effect of forskolin/IBMX on proglucagon mRNA expression. The repressive effect of the PKA-specific inhibitors H-89 and KT-5720, however, was either not observable or much less potent. Forskolin could activate ERK1/2 phosphorylation and proglucagon gene transcription on its own, whereas forskolin plus IBMX are required to effectively activate the PKA pathway in the proglucagon-producing cells. Exchange protein directly activated by cyclic AMP 2 (Epac2, or cAMP-binding guanine nucleotide exchange factor-2) was found to be expressed in gut and pancreatic proglucagon-producing cell lines, whereas the Epac-pathway-specific cAMP analog, 8-pMeOPT-2'O-Me-cAMP, effectively stimulated ERK1/2 phosphorylation as well as proglucagon mRNA expression. We therefore suggest that cAMP at least partially regulates proglucagon gene expression via the Epac-Ras/Rap-Raf-MEK-ERK signaling pathway.

1-Methyl-3-isobutylxanthine↗

PubMed2001

cDNA cloning of proglucagon from the stomach and pancreas of the dog.

In human and rat, tissue-specific proteolytic processing of identical proglucagon precursors yield tissue-specific proglucagon-derived peptides. In contrast, in many non-mammalian vertebrates alternative mRNA splicing yields different proglucagon precursors in different tissues. Thus alternative mRNA splicing, in part, limits the choices of proglucagon-derived peptides that can be produced by proteolytic processing. Stomach proglucagon mRNAs from the rainbow trout and Xenopus laevis were found not to encode the proglucagon-derived peptide glucagon-like peptide 2 (GLP-2). To determine if the absence of GLP-2 was a general feature of stomach proglucagons we isolated and characterized proglucagon cDNAs from the stomach and the pancreas of the dog, a mammal that expresses the proglucagon gene in the stomach. A major proglucagon transcript of about 1100 bases and a minor transcript of about 800 bases were identified in both stomach and pancreas. The coding sequences of both the stomach and pancreatic proglucagon transcripts were identical. Therefore, tissue-specific proteolytic processing, and not alternative mRNA splicing, must regulate the production of tissue-specific proglucagon-derived peptides from the stomach of the dog.

Amino Acid Sequence↗

PubMed1988

Naturally occurring products of proglucagon 111-160 in the porcine and human small intestine.

Recent studies have revealed that the glucagon gene is expressed in the mammalian intestine. Here it codes for "glicentin" (proglucagon 1-69) and a glucagon-like peptide, proglucagon 78-107, recently isolated from porcine intestine. We studied the fate of the remaining COOH-terminal part of proglucagon (proglucagon 111-160) using radioimmunoassays against proglucagon 111-123 and 126-160. Two peptides were isolated from acid ethanol extracts of porcine ileal mucosa and sequenced: one corresponding to proglucagon 126-158 and one probably corresponding to proglucagon 111-158. By comparing human and porcine proglucagon sequences, Ala117 is replaced by Thr, and Ile138, Ala144, Ile152 and Gln153 are replaced by Val, Thr, Leu, and His. By gel filtration and radioimmunoassay of intestinal extracts it was established that a large part of porcine and virtually all of human proglucagon are processed to release proglucagon 111-123 (designated spacer peptide 2), which, like proglucagon 126-158 must be considered a potential hormonal entity. By isocratic high pressure liquid chromatography human spacer peptide 2 was indistinguishable from synthetic proglucagon 111-122 amide, suggesting that this is the structure of the naturally occurring human peptide.

Amino Acid Sequence↗

PubMed1994

Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line.

The gene encoding proglucagon is expressed predominantly in the pancreas and intestine. The physiological importance of glucagon secreted from the islets of Langerhans has engendered considerable interest in the molecular control of proglucagon gene transcription in the endocrine pancreas. In contrast, little is known about the molecular control of proglucagon gene expression in the intestine. The recent demonstration that glucagon-like peptide-1 (GLP-1) secreted from the intestine is a potent regulator of insulin secretion and glucose homeostasis has stimulated renewed interest in the factors that control GLP-1 synthesis in the intestinal L-cell. To develop a model for the analysis of intestinal proglucagon gene expression, we have targeted expression of a proglucagon gene-simian virus-40 large T-antigen fusion gene to enteroendocrine cells in transgenic mice. These mice develop intestinal tumors that were used to derive a novel cell line, designated GLUTag, that expresses the proglucagon gene and secretes immunoreactive GLP-1 in vitro. GLUTag cells demonstrate morphological characteristics of enteroendocrine cells by electron microscopy and are plurihormonal, as shown by immunocytochemistry and RNA analyses. GLUTag cells express the proglucagon and cholecystokinin genes, consistent with the pattern of lineage-specific enteroendocrine differentiation described for mouse intestine. Proglucagon gene expression was induced by activators of the protein kinase-A pathway, and a combination of messenger RNA half-life and nuclear run-on experiments demonstrated that the protein kinase-A-induction is mediated by an increase in proglucagon gene transcription. In contrast, activators of protein kinase-C stimulated secretion, but not biosynthesis of the PGDPs in GLUTag cell cultures. Analysis of proglucagon processing in GLUTag cells demonstrated the liberation of glucagon, oxyntomodulin, glicentin, and multiple forms of GLP-1. These observations provide evidence for the direct induction of proglucagon gene transcription by a cAMP-dependent pathway and suggest that the GLUTag cell line represents a useful model for the analysis of the molecular determinants of enteroendocrine gene expression.

1-Methyl-3-isobutylxanthine↗

PubMed2005

Structure and expression of the chicken proglucagon gene.

The rat and human proglucagon gene immediate promoter regions have differing transcriptional activities in islet cell lines. It is unclear upon which lineage the expression changes have occurred, or which base changes and transcription factors explain the changes in promoter activity. We have studied the expression of the chicken proglucagon gene to better understand changes in mammalian proglucagon gene promoter activity. The chicken proglucagon gene is composed of seven exons, and contains an additional exon that contains much of intervening peptide 1 that has not been seen in any other proglucagon gene. Despite very limited sequence identity between chicken and rat proglucagon promoters, the chicken proglucagon promoter supports reporter gene expression in rodent glucagon-expressing cell lines. These results suggest that the immediate proglucagon promoter region likely has retained ability to be expressed in islet cells, but a few changes to this sequence on the human lineage have extinguished expression of the immediate promoter region. Our work also demonstrate that in contrast to the conserved human proglucagon promoter region which has lost promoter activity that significant changes in proglucagon promoter sequence can occur yet retain expression potential.

Animals↗

PubMed1989

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

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 AMP-dependent pathway. These observations suggest that tissue-specific differences in both the regulation of proglucagon gene expression and the posttranslational processing of proglucagon contribute to the diversity of glucagon gene expression.

Animals↗

PubMed1994

Inhibition of pancreatic proglucagon gene expression in mice bearing subcutaneous endocrine tumors.

The proglucagon-derived peptides (PGDPs) play key roles in the regulation of carbohydrate metabolism and insulin secretion, yet the factors important for the regulation of proglucagon gene expression remain poorly understood. Recent experiments demonstrated that nude mice carrying subcutaneous proglucagon-SV40 T antigen tumors contained markedly reduced levels of the pancreatic PGDPs. To determine if elevated circulating levels of the PGDPs are consistently associated with inhibition of endogenous pancreatic proglucagon gene expression, we have now studied islet hormone gene expression in mice bearing three different endocrine tumors (InR1-G9, RIN1056A, and STC-1) that express the proglucagon gene. All tumors synthesized large amounts of the PGDPs. Plasma levels of the PGDPs were elevated in all tumor-bearing mice (8- to 22-fold greater than controls, P < 0.001), and this was associated with marked inhibition of mouse pancreatic proglucagon gene expression. The levels of pancreatic PGDPs were also significantly lower in tumor-bearing mice compared with controls (71 +/- 4, 38 +/- 6, and 18 +/- 2% of controls for InR1-G9-, RIN1056A-, and STC-1-bearing mice, respectively, P < 0.05-0.001). This inhibition of proglucagon gene expression was highly specific, in that no consistent change in pancreatic insulin or somatostatin gene expression was detected. Examination of proglucagon posttranslational processing in the tumors demonstrated that proglucagon was processed differently in each tumor to yield a unique profile of PGDPs. These observations demonstrate that elevated circulating levels of the PGDPs are associated with reduction in islet size and inhibition of proglucagon gene expression and PGDP synthesis in the pancreatic A cell.

Animals↗