Activation of Serum Response Factor in the Depolarization Induction of Egr-1 Transcription in Pancreatic Islet β-Cells

Bernal-Mizrachi, Ernesto; Wice, Burton M.; Inoue, Hiroshi; Permutt, M. A.

doi:10.1074/jbc.m003424200

Cited by 64 publications

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“…The complete list of regulated genes is shown in Table 1S in the online appendix. Glucose-stimulated genes of diverse GO functions, described more fully below, included two immediate early genes previously identified as glucose responsive in islet ␤-cells, early growth response 1 (Egr1) (10,28), and an inhibitor of DNA binding 1 (Idb1) (29). Several other immediate early genes found to respond to mitogenic stimuli in other tissues (immediate early response 2 [Ier2] and 3 [Ier3] and inhibitor of DNA binding 2 [Idb2]) were also shown to respond to glucose treatment.…”

Section: Resultsmentioning

confidence: 99%

“…In pancreatic ␤-cells, activation of expression of these IEGs was shown to depend on depolarization activation of voltage-gated Ca 2ϩ channels and subsequent influx of extracellular Ca 2ϩ . This resulted in activation of Ca 2ϩ -regulated kinases, including calmodulin-dependent kinase IV and protein kinase A, leading to phosphorylation and activation of several transcription factors (cAMP-responsive element binding pro-tein, serum response factor, and Elk-1) (9,10). The results of these experiments defined the rapid glucose-signaling pathways for a small number of IEGs whose transcription is rapidly activated by glucose, but the results now pose additional questions addressed by the current study.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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

et al. 2004

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“…Altered Glucose-regulated Gene Expression in IRKD CellsPrevious studies have shown that glucose acutely alters early gene expression in islet ␤ cells and that these effects are mediated through depolarization, influx of extracellular Ca 2ϩ , and activation of kinase cascades that result in transcriptional activation (49,50). To examine the role of glucose-stimulated insulin secretion in this process, glucose-regulated early gene expression was examined in IRKD cells.…”

Section: Fig 2 Perturbed Insulin Signaling In Irkd Cellsmentioning

confidence: 99%

“…Additionally, it would be desirable to repeat these experiments in primary cultures of islets. Whereas early response genes have been extensively evaluated in response to glucose in primary cultures (49), gene expression profiles need to be repeated in primary cultures of islets from ␤IRKO animals (62).…”

Section: Con(e)mentioning

confidence: 99%

Reduced Expression of the Insulin Receptor in Mouse Insulinoma (MIN6) Cells Reveals Multiple Roles of Insulin Signaling in Gene Expression, Proliferation, Insulin Content, and Secretion

Ohsugi

Cras-Méneur

Zhou

et al. 2005

Journal of Biological Chemistry

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The role of insulin signaling in pancreatic ␤ cells has become increasingly apparent. Stably transformed insulinoma cell lines (MIN6) were created with small interfering RNA resulting in the reduction of insulin receptor (IR) expression up to 80% (insulin receptor knockdown, IRKD⌬80). Functionally perturbed IR signaling was confirmed with the absence of insulin-stimulated insulin receptor substrate 1 tyrosine phosphorylation. Additionally, Akt phosphorylation was reduced and responded poorly to glucose stimulation. Gene expression profiling revealed that reduced IR expression was associated with alterations in expression of >1,500 genes with diverse functions. IRKD cells exhibited low rate of proliferation due to delay in transition from G 0 /G 1 to S phase, whereas susceptibility to apoptosis did not differ from that of control cells. Insulin content was reduced in proportion to the reduction of IR. IRKD cells maintained glucose responsiveness as measured by NAD(P)H generation, whereas Ca 2؉ responses and insulin secretion were enhanced. IRKD⌬80 and control cells were treated with glucose (25 mM) or insulin (100 nM) for 45 min, and gene expression profiles were assessed. Transcriptional activation of several hundred early response genes common to both glucose and insulin stimulation was observed in control cells. In IRKD⌬80 cells, insulin failed to activate any genes as anticipated. Importantly, glucose stimulation of gene expression in IRKD⌬80 cells showed that most genes previously activated by glucose were no longer activated, suggesting a major autocrine/paracrine effect of insulin on glucoseregulated gene expression. On the other hand, there were a number of glucose-regulated genes in the IRKD⌬80 cells that were not previously observed in control cells, suggesting a feedback regulation of insulin signaling on glucose-regulated gene expression. These results demonstrate important roles of the insulin receptor in islet ␤ cell gene expression and function and may serve to elucidate molecular defects in animal models with diminished ␤ cell insulin signaling.Pancreatic ␤ cells dynamically adapt to their environment (1, 2). Changes in plasma glucose concentration along with various hormones and growth factors have been shown to be major determinants of insulin secretion, biosynthesis, and islet mass (3, 4). The islet ␤ cell responds to these changes in its environment by altering its transcriptional responses, and these changes in gene expression ultimately result in altered mass and function. However, the signaling pathways activated by these environmental changes and the ensuing transcriptional events that mediate these biological responses are only beginning to be elucidated. Specifically, the relationships between the signaling pathways activated by glucose and those activated by growth factors such as insulin remain unclear.The roles of insulin as a growth factor in the modulation of ␤ cell mass and function have been implied by the results of recent experiments. Glucose stimulation of ␤ cells in culture ha...

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“…Loss of the cAMP/PKA response with mutation of the Egr-1 binding sites Pharmacological or hormonal activation of the cAMP/PKA signaling system has been reported to increase Egr-1 gene expression (mRNA and/or protein levels) in the ovary and in pheochromocytoma and insulinoma cell lines (Bernal-Mizrachi et al 2000, Espey et al 2000, Tai et al 2001. We hypothesized that cAMP-responsiveness of the LH gene may be mediated likewise by Egr-1 acting through previously identified Egr-1 ciselements in this gene.…”

Section: Activation Of the Camp/pka Signaling System Stimulates Lh Gementioning

confidence: 99%

The cAMP signaling system regulates LHbeta gene expression: roles of early growth response protein-1, SP1 and steroidogenic factor-1

Horton

Halvorson

2004

Journal of Molecular Endocrinology

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Expression of the gonadotropin genes has been shown to be modulated by pharmacological or physiological activators of both the protein kinase C (PKC) and the cAMP second messenger signaling pathways. Over the past few years, a substantial amount of progress has been made in the identification and characterization of the transcription factors and cognate cis-elements which mediate the PKC response in the LH -subunit (LH ) gene. In contrast, little is known regarding the molecular mechanisms which mediate cAMP-mediated regulation of this gene. Using pituitary cell lines, we now demonstrate that rat LH gene promoter activity is stimulated following activation of the cAMP system by the adenylate cyclase activating agent, forskolin, or by the peptide, pituitary adenylate cyclase-activating peptide. The forskolin response was eliminated with mutation of a previously identified 3′ cis-acting element for the early growth response protein-1 (Egr-1) when evaluated in the context of region −207/+5 of the LH gene. Activation of the cAMP system increased Egr-1 gene promoter activity, Egr-1 protein levels and Egr-1 binding to the LH gene promoter, supporting the role of this transcription factor in mediating the cAMP response. Analysis of a longer LH promoter construct (−797/+5) revealed additional contribution by upstream Sp1 DNA-regulatory regions. Of interest, forskolin-induced stimulation of LH gene promoter activity was observed to increase synergistically with introduction of the transcription factor, steroidogenic factor-1 (SF-1). Although SF-1 is a critical mediator of the cAMP response in other genes, mutation of the SF-1 DNA-binding sites in the rat LH gene did not alter the forskolin response nor did forskolin increase SF-1 protein levels in a gonadotrope cell line. In a further set of experiments, it was determined that forskolin-responsiveness was maintained following mutation of the previously defined homeobox-binding element at position -100. We conclude that both Egr-1 and Sp1 contribute to cAMP-dependent transcription of the rat LH gene promoter. While SF-1 does not act independently to mediate the cAMP/PKA response, SF-1 is important for magnification of this response.

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Activation of Serum Response Factor in the Depolarization Induction of Egr-1 Transcription in Pancreatic Islet β-Cells

Cited by 64 publications

References 50 publications

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

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

Reduced Expression of the Insulin Receptor in Mouse Insulinoma (MIN6) Cells Reveals Multiple Roles of Insulin Signaling in Gene Expression, Proliferation, Insulin Content, and Secretion

The cAMP signaling system regulates LHbeta gene expression: roles of early growth response protein-1, SP1 and steroidogenic factor-1

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