Glucose Stimulation of Protooncogene Expression and Deoxyribonucleic Acid Synthesis in Rat Islet Cell Line

Yamashita, Shunichi; Tobinaga, Tamami; Ashizawa, Kiyoto; Nagayama, Yuji; Yokota, Atsushi; Harakawa, Seijiro; Inoue, Shuji; Hirayu, Hideshi; Izumi, Motomori; Nagataki, Shigenobu

doi:10.1210/endo-123-4-1825

Cited by 21 publications

(14 citation statements)

References 25 publications

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“…Addition of insulin (from 10 Ϫ10 to 10 Ϫ8 M) in the presence of 2 mM glucose did not augment c-myc mRNA levels (data not shown), demonstrating that secreted insulin is not responsible for the glucose effect. These findings are in agreement with those reported for RINr cells, in which neither insulin nor IGF-1 is able to induce expression of the c-myc gene (55), and those reported for rat islets, in which neither addition of exogenous insulin nor inhibition of insulin secretion affects c-myc mRNA levels (23). Furthermore, as shown in Fig.…”

Section: Glucose Increases the Expression Of C-myc In 832/13 Cellssupporting

confidence: 93%

“…1, A and B, a 16-h treatment with 20 mM glucose resulted in greater than threefold higher c-myc mRNA levels than in cells treated with either 2 mM glucose or 2 mM glucose plus 18 mM mannitol, used as a control for osmotic pressure on the cells (40). These results are consistent with those obtained from other cell lines and from isolated rat islets (23,55).…”

Section: Glucose Increases the Expression Of C-myc In 832/13 Cellssupporting

confidence: 83%

“…Several laboratories have demonstrated that high glucose levels (20 -30 mM) increase c-Myc transcript and protein levels in rat islets and insulinoma cells (23,24,55). As shown in Fig.…”

Section: Glucose Increases the Expression Of C-myc In 832/13 Cellsmentioning

confidence: 82%

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c-Myc and ChREBP regulate glucose-mediated expression of the L-type pyruvate kinase gene in INS-1-derived 832/13 cells

Collier¹,

Zhang²,

Pedersen³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Increased glucose flux generates metabolic signals that control transcriptional programs through poorly understood mechanisms. Previously, we demonstrated a necessity in hepatocytes for c-Myc in the regulation of a prototypical glucose-responsive gene, L-type pyruvate kinase (L-PK) (Collier JJ, Doan TT, Daniels MC, Schurr JR, Kolls JK, Scott DK. J Biol Chem 278: 6588–6595, 2003). Pancreatic β-cells have many features in common with hepatocytes with respect to glucose-regulated gene expression, and in the present study we determined whether c-Myc was required for the L-PK glucose response in insulin-secreting (INS-1)-derived 832/13 cells. Glucose increased c-Myc abundance and association with its heterodimer partner, Max. Manipulations that prevented the formation of a functional c-Myc/Max heterodimer reduced the expression of the L-PK gene. In addition, glucose augmented the binding of carbohydrate response element binding protein (ChREBP), c-Myc, and Max to the promoter of the L-PK gene in situ. The transactivation of ChREBP, but not of c-Myc, was dependent on high glucose concentrations in the contexts of either the L-PK promoter or a heterologous promoter. The glucose-mediated transactivation of ChREBP was independent of mutations that alter phosphorylation sites thought to regulate the cellular location of ChREBP. We conclude that maximal glucose-induced expression of the L-PK gene in INS-1-derived 832/13 cells involves increased c-Myc abundance, recruitment of c-Myc, Max, and ChREBP to the promoter, and a glucose-stimulated increase in ChREBP transactivation.

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Section: Glucose Increases the Expression Of C-myc In 832/13 Cellssupporting

confidence: 93%

Section: Glucose Increases the Expression Of C-myc In 832/13 Cellssupporting

confidence: 83%

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c-Myc and ChREBP regulate glucose-mediated expression of the L-type pyruvate kinase gene in INS-1-derived 832/13 cells

Collier¹,

Zhang²,

Pedersen³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Not all ␤-cell early response genes such as c-myc and c-fos were observed in the present study (7,34). These genes were not included in the original EPCon arrays, presumably because of the low abundance of those transcripts.…”

Section: Validation Of Gene Expression Profiles By Quantitative Rt-pcmentioning

confidence: 75%

Glucose and Insulin Treatment of Insulinoma Cells Results in Transcriptional Regulation of a Common Set of Genes

et al. 2004

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Glucose and insulin are important regulators of islet ␤-cell growth and function by activating signaling pathways resulting in transcriptional changes that lead to adaptive responses. Several immediate early genes have been shown to be rapidly induced by glucose-activated depolarization in islet ␤-cells. The current studies address aspects of glucose-regulated transcription: 1) the number and characteristics of these genes, 2) if depolarization is the major mechanism, and 3) if glucosestimulated insulin secretion is responsible, because insulin per se can activate transcription. Here, the expression profiles of glucose-responsive insulinoma cells 45 min after the addition of glucose, KCl to induce depolarization, or insulin were assessed by endocrine pancreas cDNA microarrays. Glucose activated more than 90 genes, representing diverse gene ontology functions, and most were not previously known to be glucose responsive. KCl activated 80% of these same glucoseregulated genes and, along with the effects of pretreatment with diazoxide, suggested that glucose signaling is mediated primarily via depolarization. There were >150 genes activated by insulin, and remarkably 71% were also regulated by glucose. Preincubation with a phosphatidylinositol (PI) 3-kinase inhibitor resulted in almost total inhibition of depolarization and insulinactivated transcriptional responses. Thus, through gene expression profiling, these data demonstrate that glucose and insulin rapidly activate a PI 3-kinase pathway, resulting in transcription of a common set of genes. This is consistent with glucose activation of gene transcription either directly or indirectly through a paracrine/ autocrine effect via insulin release. These results illustrate that expression gene profiling can contribute to the elucidation of important ␤-cell biological functions. Diabetes 53

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“…Elevated c-Myc expression is associated with glucose stimulation of DNA synthesis in islet cell lines (31) and in insulinomas in combination with another oncogene such as ras (18,32). In combination with ras, c-Myc has been shown to stimulate ␤-cell replication in vitro (33), and as mentioned above, conditional expression of c-Myc in mice leads to increased ␤-cell proliferation (15).…”

Section: Potential Relevance Of Results In Rip-ii/c-myc Transgenic MImentioning

confidence: 99%

Overexpression of c-Myc in β-Cells of Transgenic Mice Causes Proliferation and Apoptosis, Downregulation of Insulin Gene Expression, and Diabetes

Laybutt

Weir²,

Kaneto³

et al. 2002

Diabetes

128

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To test the hypothesis that c-Myc plays an important role in ␤-cell growth and differentiation, we generated transgenic mice overexpressing c-Myc in ␤-cells under control of the rat insulin II promoter. F 1 transgenic mice from two founders developed neonatal diabetes (associated with reduced plasma insulin levels) and died of hyperglycemia 3 days after birth. In pancreata of transgenic mice, marked hyperplasia of cells with an altered phenotype and amorphous islet organization was displayed: islet volume was increased threefold versus wild-type littermates. Apoptotic nuclei were increased fourfold in transgenic versus wild-type mice, suggesting an increased turnover of ␤-cells. Very few cells immunostained for insulin; pancreatic insulin mRNA and content were markedly reduced. GLUT2 mRNA was decreased, but other ␤-cell-associated genes (IAPP [islet amyloid pancreatic polypeptide], PDX-1 [pancreatic and duodenal homeobox-1], and BETA2/ NeuroD) were expressed at near-normal levels. Immunostaining for both GLUT2 and Nkx6.1 was mainly cytoplasmic. The defect in ␤-cell phenotype in transgenic embryos (embryonic days 17-18) and neonates (days 1-2) was similar and, therefore, was not secondary to overt hyperglycemia. When pancreata were transplanted under the kidney capsules of athymic mice to analyze the long-term effects of c-Myc activation, ␤-cell depletion was found, suggesting that, ultimately, apoptosis predominates over proliferation. In conclusion, these studies demonstrate that activation of c-Myc in ␤-cells leads to 1) increased proliferation and apoptosis, 2) initial hyperplasia with amorphous islet organization, and 3) selective downregulation of insulin gene expression and the development of overt diabetes.

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Glucose Stimulation of Protooncogene Expression and Deoxyribonucleic Acid Synthesis in Rat Islet Cell Line

Cited by 21 publications

References 25 publications

c-Myc and ChREBP regulate glucose-mediated expression of the L-type pyruvate kinase gene in INS-1-derived 832/13 cells

c-Myc and ChREBP regulate glucose-mediated expression of the L-type pyruvate kinase gene in INS-1-derived 832/13 cells

Glucose and Insulin Treatment of Insulinoma Cells Results in Transcriptional Regulation of a Common Set of Genes

Overexpression of c-Myc in β-Cells of Transgenic Mice Causes Proliferation and Apoptosis, Downregulation of Insulin Gene Expression, and Diabetes

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