cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2

Jhala, Ulupi S.; Canettieri, Gianluca; Screaton, Robert A.; Kulkarni, Rohit; Krajewski, Stan; Reed, John C.; Walker, John R.; Lin, Xueying; White, Morris F.; Montminy, Marc

doi:10.1101/gad.1097103

Cited by 525 publications

(517 citation statements)

References 26 publications

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“…IGF-1 is a known regulator of PI3-K/PKB, whereas the mechanisms that link the G protein-coupled GLP-1 receptor to cell survival pathways are not well understood. It has been suggested that activation of CREB, a cAMP-dependent transcription factor, may provide a direct link between the GLP-1 receptor and the PI3-K/PKB pathway through the enhanced synthesis of the upstream effector, insulin receptor substrate-2 [43]. Furthermore, cytokines have been reported to inhibit CREB activation [44].…”

Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B

et al. 2005

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Aims/hypothesis: The gut hormone glucagonlike peptide-1 (GLP-1) decreases beta cell apoptosis in a protein kinase B (PKB)-dependent fashion, and increases islet cell mass and function in vivo. In contrast, cytokines induce beta cell apoptosis, leading to decreased islet mass and type 1 diabetes. In the present study we used rat INS-1E beta cells and primary rat islet cells to examine the potential role of PKB as a mediator of the effect of GLP-1 on cytokine-induced apoptosis. Methods: Cell viability was determined by MTTassay, and apoptosis and necrosis by Hoechst 33342-propidium iodide staining. Immunoblot analysis was used to detect changes in protein expression, including active (phosphorylated) and total PKB, phosphorylated and total glycogen synthase kinase-3β, activated caspase-3 and inducible nitric oxide synthase. Reactive oxygen species were determined by 1,7-dichlorofluorescein (DCF) analysis, and mutant forms of PKB were introduced into cells using adenoviral vectors. Results: Incubation of INS-1E cells with cytokines (IL-1β, TNF-α and interferon-γ; 10-50 ng/ml) for 18 h significantly decreased cell viability (by 44%, p<0.001), cell proliferation (by 80%, p<0.001), and activation of PKB (by 67%, p<0.001). Pre-treatment with exendin-4 (10 −7 mol/l), a long-acting GLP-1 receptor agonist, partially protected the cells against cytokine-induced toxicity (p<0.01) in association with a reduction in cytokine-induced inhibition of PKB phosphorylation (p<0.05). Exendin-4 pre-treatment did not change cell proliferation. Cytokine treatment increased apoptosis (by 156%, p<0.05) and necrosis (from undetectable to 2.6% of cells). These increases were both reduced by pre-treatment with exendin-4 (p<0.05-0.01). Furthermore, cytokine-induced apoptosis and necrosis were significantly increased in cells infected with kinase-dead PKB (p<0.05), and the protective effect of exendin-4 on both parameters was fully abolished in these cells. Similar changes were observed in primary islet cells. In parallel with these changes, exendin-4 decreased the cytokine-induced activation of caspase-3 (by 46%, p<0.05), and decreased levels of inducible nitric oxide synthase (by 71%, p<0.05) and reactive oxygen species (by 27%, p< 0.05). Conclusions/interpretation: The results of our study indicate that GLP-1 plays a protective role against cytokineinduced apoptosis and necrosis in beta cells through a PKB-dependent signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B

et al. 2005

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“…In fact, the CRE (cyclic AMP-responsive element) and c-Ets sites, located at −48 and −16, respectively, have been demonstrated to be involved in induction of the transcriptional activity of human Ccnd1 [28,29]. In particular, promotion of beta cell survival by GLP1 via the second messenger cyclic AMP was significantly reduced in mice deficient in CREB activity, leading to diabetes [30]. Thus, the increased activities of the −73 and −34 constructs in our promoter assay can be explained by the presence of these sites, which are conserved in both human and rat promoters (Fig.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of rat Ccnd1 gene by exendin-4 in pancreatic beta cell line INS-1: interaction of early growth response-1 with cis-regulatory element

Kang

Kim

et al. 2006

Diabetologia

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Aims/hypothesis: The aim of this study was to investigate the effect of exendin-4 on the expression of cyclin D1 gene (Ccnd1), which is critical in regulating the progression of the cell cycle in INS-1 cells. Materials and methods: INS-1 cells were stimulated with exendin-4 (10 nmol/l). Transient transfection and luciferase reporter assays were performed to measure promoter activities of rat Ccnd1. Electrophoretic mobility shift and chromatin immunoprecipitation assays were used to examine the binding of transcription factors to sites responsive to exendin-4 in vitro and in vivo, respectively. Results: Exendin-4 increased both Ccnd1 mRNA and its protein levels in a time-dependent manner. The region from −174 to +130 of the promoter was found to contain cis-regulatory elements responsible for exendin-4-mediated gene induction. Early growth response-1 (EGR1) protein was bound to the region from −153 to −134, which includes the putative EGR1 binding site (5′-CACCCCCGC-3′). Moreover, exendin-4 recruited EGR1 protein to the promoter in vivo. Conclusions/ interpretation: These findings suggest that exendin-4 activates Ccnd1 transcription through induction of EGR1 binding to a cis-regulatory element between −153 and −134 on the rat Ccnd1 promoter. These results provide an important indication that exendin-4 is a growth factor regulating beta cell proliferation.

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“…Elevations in blood glucose provide the most potent stimulus. Upon its uptake into beta cells, glucose oxidation in the pancreatic beta cell induces closure of K ATP channels, membrane depolarisation, calcium entry via voltage-sensitive L-type calcium channels, and consequent phosphorylation and thus activation of the transcription factor CREB [5,15,29], which is essential for beta cell function [1][2][3][4][5]. Two mechanisms for linking membrane depolarisation-induced elevations of intracellular calcium to the activation of CREB have been proposed, mostly based on studies in neuronal systems.…”

Section: Discussionmentioning

confidence: 99%

“…Among the multiple factors required for normal beta cell function is the transcription factor cyclic AMP response element binding protein (CREB) [1][2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…CREB participates in glucose homeostasis by stimulating glucose production in the liver [11] and activating glucagon gene transcription in pancreatic islet alpha cells [12]. In pancreatic islet beta cells CREB maintains beta cell function by binding to and activating the insulin gene [1][2][3][4]13], as well as by inhibiting apoptosis and promoting beta cell survival [5].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line

et al. 2005

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Aims/hypothesis: The activation of the transcription factor cyclic AMP response element binding protein (CREB) by protein kinase A is inhibited by the human orthologue of the mitogen-activated protein kinase, dualleucine-zipper-bearing kinase (DLK) in teratocarcinoma cells. However, pancreatic beta cells are electrically excitable and a major pathway regulating CREB in these cells is membrane depolarisation, leading to calcium influx and activation of the calcium/calmodulin-dependent protein phosphatase calcineurin. Therefore, the effect of DLK on CREB activity induced by membrane depolarisation was investigated in the beta cell line HIT. Materials and methods: Reporter gene assays and biochemical techniques were used. Results: RT-PCR, Western blot analysis and immunohistochemistry demonstrated the expression of DLK in HIT cells and primary mouse islets. In transient transfection experiments, DLK inhibited both GAL4-CREB activity induced by membrane depolarisation, and transcription directed by the CREB binding site, the cyclic AMP response element. Furthermore, DLK inhibited the transcriptional activity conferred by the CREB coactivator, CREB binding protein, both under basal conditions and after membrane depolarisation. DLK was also effective in response to glucose, the most potent physiological stimulus and known to cause membrane depolarisation of beta cells. Inhibition of calcineurin enhanced DLK activity, whereas overexpression of calcineurin reduced the inhibition by DLK of transcription directed by cyclic AMP response element after membrane depolarisation. Conclusions/interpretation: These results demonstrate a calcineurin-sensitive inhibition by DLK of CREB activity after membrane depolarisation in pancreatic islet beta cells. This inhibition may, at least partially, be mediated at the coactivator level. The results thus suggest that DLK plays a role in the regulation of beta cell function, including insulin gene transcription and beta cell apoptosis.

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cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2

Cited by 525 publications

References 26 publications

Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B

Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B

Upregulation of rat Ccnd1 gene by exendin-4 in pancreatic beta cell line INS-1: interaction of early growth response-1 with cis-regulatory element

Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line

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