Induction of c-Myc Expression Suppresses Insulin Gene Transcription by Inhibiting NeuroD/BETA2-mediated Transcriptional Activation

Kaneto, Hideaki; Sharma, Arun; Suzuma, Kiyoshi; Laybutt, D. Ross; Xu, Gang; Bonner-Weir, Susan; Weir, Gordon C.

doi:10.1074/jbc.m111148200

Cited by 65 publications

(34 citation statements)

References 55 publications

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“…A potential mechanism is suggested by studies showing that c-Myc can suppress insulin gene transcription by inhibiting BETA2-mediated transcriptional activation (52). If c-Myc does exert a potent inhibitory influence on insulin gene expression, why are a few ␤-cells positively stained for insulin?…”

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

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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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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

Self Cite

128

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“…If pdx-1 is not involved in this process of loss of beta-cell differentiated functions, which other genes could participate in it? c-Myc was detected as up-regulated in the array, and increased expression of this oncogene suppresses insulin gene transcription by inhibiting NeuroD/BETA2 [75]. Another intriguing finding was the up-regulation of Notch1, delta-1 (both induced by dsRNA + IFN-γ at 6 h), and of presenilin-2 (induced by dsRNA and IFN-γ at 24 h).…”

Section: Discussionmentioning

confidence: 96%

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

et al. 2003

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Aims/hypothesis. Viral infections and local production of IFN-γ might contribute to beta-cell dysfunction/ death in Type 1 Diabetes. Double stranded RNA (dsRNA) accumulates in the cytosol of viral-infected cells, and exposure of purified rat beta cells to dsRNA (tested in the form of polyinosinic-polycytidylic acid, PIC) in combination with IFN-γ results in beta-cell dysfunction and apoptosis. To elucidate the molecular mechanisms involved in PIC + IFN-γ-effects, we determined the global profile of genes modified by these agents in primary rat beta cells. Methods. FACS-purified rat beta cells were cultured for 6 or 24 h in control condition or with IFN-γ, PIC or a combination of both agents. The gene expression profile was analysed in duplicate by high-density oligonucleotide arrays representing 5000 full-length genes and 3000 EST's. Changes of greater than or equal to 2.5-fold were considered as relevant.Results. Following a 6-or 24-h treatment with IFN-γ, PIC or IFN-γ and PIC, we observed changes in the expression of 51 to 189 genes. IFN-γ modified the expression of MHC-related genes, and also of genes involved in beta-cell metabolism, protein processing, cytokines and signal transduction. PIC affected preferentially the expression of genes related to cell adhesion, cytokines and dsRNA signal transduction, transcription factors and MHC. PIC and/or IFN-γ up-regulated the expression of several chemokines and cytokines that could contribute to mononuclear cell homing and activation during viral infection, while IFN-γ induced a positive feedback on its own signal transduction. PIC + IFN-γ inhibited insulin and GLUT-2 expression without modifying pdx-1 mRNA expression. Conclusion/interpretation. This study provides the first comprehensive characterization of the molecular responses of primary beta cells to dsRNA + IFN-γ, two agents that are probably present in the beta cell milieu during the course of virally-induced insulitis and Type 1 Diabetes. Based on these findings, we propose an integrated model for the molecular mechanisms involved in dsRNA + IFN-γ induced beta-cell dysfunction and death. [Diabetologia (2003[Diabetologia ( ) 46:1641[Diabetologia ( -1657

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“…Changes in the transcription factor composition occur in cells in long-term high glucose, including increases in C/EBP-␤ and Myc, and decreases in PDX-1 (2,13,(31)(32)(33). Myc has been shown to compete with Beta2 for binding to E-boxes but lacks the transactivating activity or the capacity to bind to p300.…”

Section: Discussionmentioning

confidence: 99%

Chromatin-bound mitogen-activated protein kinases transmit dynamic signals in transcription complexes in β-cells

Lawrence

McGlynn

Shao

et al. 2008

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

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MAPK pathways regulate transcription through phosphorylation of transcription factors and other DNA-binding proteins. In pancreatic ␤-cells, ERK1/2 are required for transcription of the insulin gene and several other genes in response to glucose. We show that binding of glucose-sensitive transcription activators and repressors to the insulin gene promoter depends on ERK1/2 activity. We also find that glucose and NGF stimulate the binding of ERK1/2 to the insulin gene and other promoters. An ERK1/2 cascade module, including MEK1/2 and Rsk, are found in complexes bound to these promoters. These findings imply that MAPK-containing signaling complexes are positioned on sensitive promoters with their protein substrates to modulate transcription in situ in response to incoming signals.c-fos ͉ C/EBP-␤ ͉ ERK1/2 ͉ hyperglycemia ͉ insulin gene transcription

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Induction of c-Myc Expression Suppresses Insulin Gene Transcription by Inhibiting NeuroD/BETA2-mediated Transcriptional Activation

Cited by 65 publications

References 55 publications

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

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

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

Chromatin-bound mitogen-activated protein kinases transmit dynamic signals in transcription complexes in β-cells

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