Glucagon stimulates expression of the inducible cAMP early repressor and suppresses insulin gene expression in pancreatic beta-cells.

Hussain, Mehboob A.; Daniel, Philip B.; Habener, Joel F.

doi:10.2337/diabetes.49.10.1681

Cited by 40 publications

(33 citation statements)

References 58 publications

(45 reference statements)

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“…1-3). Only a few previous studies on ICER gene expression have analyzed both mRNA and protein expression (3,7,9). In most of these studies, a close correlation was observed between mRNA and protein expression except for forskolin-treated AtT20 cells (3) and, as shown in this study, in macrophages.…”

Section: Discussionmentioning

confidence: 49%

“…ICER then inhibits both its own transcription and the expression of other CRE-containing promoters (1)(2)(3). Indeed, the induced expression of ICER through the cAMP signaling pathway has been implicated in several responses, including the suppression of T lymphocyte function (4,5), attenuation of Fas ligand expression in T and NK lymphocytes (6), glucagonmediated suppression of insulin gene expression in pancreatic B cells (7), and the noradrenaline-triggered suppression of ␤2-adrenoreceptor in brown adipocytes (8). The expression of ICER has also recently been shown to be induced by cAMPindependent pathways, and includes the action of nerve growth factor, epidermal growth factor, and the gastrointestinal peptides gastrin and cholecystokinin (9 -11).…”

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confidence: 99%

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Interferon-γ Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2

Mead

Hughes

Irvine

et al. 2003

Journal of Biological Chemistry

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Interferon-␥ (IFN-␥) is a pleiotropic cytokine that modulates the immune function, cell proliferation, apoptosis, macrophage activation, and numerous other cellular responses. These biological actions of IFN-␥ are characterized by both the activation and the inhibition of gene transcription. Unfortunately, in contrast to gene activation, the mechanisms through which the cytokine suppresses gene transcription remain largely unclear. We show here for the first time that exposure of macrophages to IFN-␥ leads to a dramatic induction in the expression of the inducible cAMP early repressor (ICER), a potent inhibitor of gene transcription. In addition, a synergistic action of IFN-␥ and calcium in the activation of ICER expression was identified. The IFN-␥-mediated activation of ICER expression was not blocked by H89, bisindoylmaleimide, SB202190, PD98059, W7, and AG490, which inhibit protein kinase A, protein kinase C, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, calcium-calmodulin-dependent protein kinase, and Janus kinase-2, respectively. In contrast, apigenin, a selective casein kinase 2 (CK2) inhibitor, was found to inhibit response. Consistent with this finding, IFN-␥ stimulated CK2 activity and the level of phosphorylated cAMP response element-binding protein, which is known to induce ICER gene transcription, and this response was inhibited in the presence of apigenin. These studies, therefore, identify a previously uncharacterized pathway, involving the IFN-␥-mediated stimulation of CK2 activity, activation of cAMP response element-binding protein, and increased production of ICER, which may then play an important role in the inhibition of macrophage gene transcription by this cytokine.

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Section: Discussionmentioning

confidence: 49%

mentioning

confidence: 99%

Interferon-γ Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2

Mead

Hughes

Irvine

et al. 2003

Journal of Biological Chemistry

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“…Plasma glucagon concentrations are sometimes increased in Type II diabetic patients; it is therefore of interest that glucagon induced the expression of ICER in beta cells, thus reducing insulin gene expression [73]. Whether such a mechanism contributes to decreased insulin production in Type II diabetes is not clear.…”

Section: Ripe3 Bmentioning

confidence: 98%

Regulation of insulin gene transcription

2002

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Insulin, synthesized by the beta cells of pancreatic islets, is of major physiological importance in metabolic homeostasis. While mature insulin consists of two polypeptide chains joined by disulphide bridges, the gene encodes for a highly conserved single chain precursor, preproinsulin [1]. In most species preproinsulin exists as a single gene, whereas in the mouse and the rat two non-allelic insulin genes are present. The human insulin gene is located on the short arm of chromosome 11 (p15.5) [2], the rat insulin I and II genes are colocalized on chromosome 1 [3] and the mouse genes are positioned on two different chromosomes, insulin I on chromosome 19 [4] and insulin II on chromosome 7 [5]. In adult islets, the nonallelic genes appear to be coordinately expressed and regulated [6, 7]. The rodent insulin II and the human genes contain three exons and two introns, whilst insulin I lacks the second intron. The organisation and structure of the insulin gene has been reviewed in detail [8]. Insulin is regulat- AbstractThe mammalian insulin gene is exclusively expressed in the beta cells of the endocrine pancreas. Two decades of intensive physiological and biochemical studies have led to the identification of regulatory sequence motifs along the insulin promoter and to the isolation of transcription factors which interact to activate gene transcription. The majority of the islet-restricted (BETA2, PDX-1, RIP3b1-Act/C1) and ubiquitous (E2A, HEB) insulin-binding proteins have been characterized. Transcriptional regulation results not only from specific combinations of these activators through DNA-protein and protein-protein interactions, but also from their relative nuclear concentrations, generating a cooperativity and transcriptional synergism unique to the insulin gene. Their DNA binding activity and their transactivating potency can be modified in response to nutrients (glucose, NEFA) or hormonal stimuli (insulin, leptin, glucagon like peptide-1, growth hormone, prolactin) through kinase-dependent signalling pathways (PI3-K, p38MAPK, PKA, CaMK) modulating their affinities for DNA and/or for each other. From the overview of the research presented, it is clear that much more study is required to fully comprehend the mechanisms involved in the regulated-expression of the insulin gene in the beta cell to prevent its impairment in diabetes. [Diabetologia (2002) 45: 309±326]

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“…While CREB is a transcriptional activator, CREM ␣ is a transcriptional repressor. CREM is present in many tissues and has been shown to be constitutively active in spermatocytes and the brain (11)(12)(13). The expression of various isoforms of CREM is regulated by four different promoters and alternative splicing (14).…”

mentioning

confidence: 99%

The Cyclic Adenosine 5′-Monophosphate Response Element Modulator Suppresses IL-2 Production in Stimulated T Cells by a Chromatin-Dependent Mechanism

Tenbrock

Juang

Tolnay

et al. 2003

The Journal of Immunology

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The production of IL-2 is tightly controlled by several transcription factors that bind to the IL-2 promoter. The cAMP response element modulator (CREM) is known to form complexes with CREB and bind to the −180 site of the IL-2 promoter in anergic and in systemic lupus erythematosus T cells. In this study we show that CREM is transcriptionally induced in T cells following stimulation through CD3 and CD28, binds to the IL-2 promoter in vivo, and suppresses IL-2 production. Transfection of an antisense CREM plasmid into T cells blocked the expression and binding of CREM to the IL-2 promoter and the decrease of IL-2 production, which follows the early increase after T cell stimulation with CD3 and CD28. In addition, as assessed by chromatin immunoprecipitation experiments, antisense CREM prevented the binding of protein 300 and cAMP response element binding protein and promoted the acetylation of histones. Antisense CREM also enhanced the accessibility of the IL-2 promoter to endonucleases and prevented the condensation of chromatin in vivo. Our data suggest that upon T cell activation, CREM gradually replaces phosphorylated CREB at the −180 site of the IL-2 promoter. CREM, in turn, binds protein 300 and cAMP response element binding protein, but CREM is unable to activate its histone acetyltransferase activity, which results in condensation of chromatin and down-regulation of IL-2 production.

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Glucagon stimulates expression of the inducible cAMP early repressor and suppresses insulin gene expression in pancreatic beta-cells.

Cited by 40 publications

References 58 publications

Interferon-γ Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2

Interferon-γ Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2

Regulation of insulin gene transcription

The Cyclic Adenosine 5′-Monophosphate Response Element Modulator Suppresses IL-2 Production in Stimulated T Cells by a Chromatin-Dependent Mechanism

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