Regulation of Insulin Gene Transcription by ERK1 and ERK2 in Pancreatic β Cells

Khoo, Shih; Griffen, Steven C.; Xia, Ying; Baer, Richard; German, Michael S.; Cobb, Melanie H.

doi:10.1074/jbc.m301198200

Cited by 145 publications

(160 citation statements)

References 66 publications

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“…Values are expressed as means ± SEM (n=12 rats/group). *p<0.001 treated diabetic vs untreated diabetic rats that p38 cascade could affect PDX-1 in response to other agents [27]. Our data prove that tungstate treatment in diabetic rats is able to activate the islet p38 protein by increasing its phosphorylation state, without changing total p38 concentrations.…”

Section: Discussionsupporting

confidence: 51%

“…We assessed the molecular mechanism of tungstate action in islets cultured in vitro with tungstate, and also in islets from treated diabetic rats. Activation of PDX-1 involves phosphorylation and this event is dependent on p38 protein [26] and ERK1/2 [27], although some disagreements with the role of PDX-1 phosphorylation have arisen [28]. The control PDX-1 activity may integrate signals from multiple pathways: for example, glucose-stimulated PDX-1 transactivation is ERK1/2 dependent and it has been suggested after the last administration tungstemia is undetectable.…”

Section: Tungstate Effects Persist After Withdrawal Of Treatmentmentioning

confidence: 99%

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Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

et al. 2004

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Aims/hypothesis. Sodium tungstate has recently emerged as an effective oral treatment for diabetes. We examined the effects of tungstate administration in the beta-cell mass of the pancreas as well as its therapeutic potential. Methods. Sodium tungstate was administered via drinking water to healthy and neonatal streptozotocin (nSTZ)-diabetic rats for one month. The pancreas from each rat was removed and morphometric and immunocytochemical studies were carried out. The molecular mechanism of tungstate's action was also studied. Results. In nSTZ rats administration of this compound normalised glycaemia, and increased insulinaemia and islet insulin content. Blood glucose concentrations were normalised as early as on day 4 of treatment, and tungstate treatment produced a partial recovery of beta-cell mass. The rats remained normoglycaemic after tungstate withdrawal. Morphometric studies showed that the increase in beta-cell mass was not due to beta-cell hypertrophy but to hyperplasia, with an increase in islet density in treated diabetic rats. Tungstate treatment increased extra-islet beta-cell replication without modifying intra-islet beta-cell replication rates. Moreover, the treatment induced increases in insulin-positive cells located close to ducts; and in PDX-1 positive cells scattered in the exocrine tissue, suggesting active neogenesis. In islets from treated diabetic rats, tungstate is able to increase the phosphorylation state of PDX-1 through the activation of p38. Conclusion/interpretation. These observations indicate that tungstate treatment is able to regenerate a stable, functional pancreatic beta-cell population which leads to and maintains normoglycaemia. [Diabetologia (2004)

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Section: Discussionsupporting

confidence: 51%

Section: Tungstate Effects Persist After Withdrawal Of Treatmentmentioning

confidence: 99%

Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

et al. 2004

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“…nuclear-cytoplasmic shuttling) or function would allow for acute alterations to target gene transcription, where control on the order of seconds to minutes might be crucial. At least 3 different reversible post-translational modifications, including phosphorylation [86,108,[110][111][112][113][114], sumoylation [115], and glycosylation [116], have been proposed to explain nuclearcytoplasmic shuttling and/or other functions of Pdx1. Consistent with these modifications, different molecular weight species of Pdx1 have been described in immunoblots [115].…”

Section: Mechanism Of Pdx1 Action Posttranslational Modifications Of mentioning

confidence: 99%

“…Of the three modifications, phosphorylation is perhaps the best-studied. Elevated glucose levels have been suggested to promote Pdx1 phosphorylation through one or a combination of several pathways, including the stress-activated protein kinase (SAPK) and extracellular signalregulated kinase (ERK) 1/2 pathways [86,108,112], phosphatidylinositol 3-kinase pathway [117,118], and/or the Per-Arnt-Sim (PAS) kinase [110]. Although the role of phosphorylation of specific residues within Pdx1 has not been rigorously analyzed, phosphorylation of Ser61 and Ser66 of Pdx1 via glycogen synthase kinase 3 appears to target Pdx1 for proteosomal degradation, thereby decreasing its half-life.…”

Section: Mechanism Of Pdx1 Action Posttranslational Modifications Of mentioning

confidence: 99%

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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Emerging evidence over the past decade indicates a central role for transcription factors in the embryonic development of pancreatic islets and the consequent maintenance of normal glucose homeostasis. Pancreatic and duodenal homeobox 1 (Pdx1) is the best studied and perhaps most important of these factors. Whereas deletion or inactivating mutations of the Pdx1 gene causes whole pancreas agenesis in both mice and humans, even haploinsufficiency of the gene or alterations in its expression in mature islet cells causes substantial impairments in glucose tolerance and the development of a late-onset form of diabetes known as maturity onset diabetes of the young. The study of Pdx1 has revealed crucial phenotypic interrelationships of the varied cell types within the pancreas, particularly as these impinge upon cellular differentiation in the embryo and neogenesis and regeneration in the adult. In this review, we describe the actions of Pdx1 in the developing and mature pancreas and attempt to unify these actions with its known roles in modulating transcriptional complex formation and chromatin structure at the molecular genetic level.

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“…For instance, they mediate some of the pro-apoptotic effects of chronically elevated glucose and cytokines on beta-cells 29 , and the Erk pathway has been recently shown to be involved in the regulation of insulin gene transcription by glucose 30 .…”

Section: The Map Kinase Pathwaymentioning

confidence: 99%

Characterization of the Human Pancreatic Islet Proteome by Two-Dimensional LC/MS/MS

et al. 2006

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The pancreatic beta-cell plays a central role in the maintenance of glucose homeostasis and in the pathogenesis of both type 1 and type 2 diabetes mellitus. Elucidation of the insulin secretory defects observed in diabetes first requires a better understanding of the complex mechanisms regulating insulin secretion, which are only partly understood. While there have been reports detailing proteomic analyses of islet cell lines or isolated rodent islets, the information gained is not always applicable to humans. Therefore, definition of the human islet proteome could contribute to a better understanding of islet biology and lead to more effective treatment strategies. We have applied a two-dimensional LC-MS/MS-based analysis to the characterization of the human islet proteome, resulting in the confident identification of 29,021 different tryptic peptides covering 3,365 proteins (≥ 2 unique peptide identifications per protein). As expected, the three major islet hormones (insulin, glucagon, and somatostatin) were detected, as well as various beta-cell enriched secretory products, ion channels, and transcription factors. In addition, significant proteome coverage of metabolic enzymes and cellular pathways was observed, including the integrin signaling cascade and the MAP kinase, NF-κβ, and JAK/STAT pathways. The resulting peptide reference library provides a resource for future higher throughput and quantitative studies of islet biology.

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Regulation of Insulin Gene Transcription by ERK1 and ERK2 in Pancreatic β Cells

Cited by 145 publications

References 66 publications

Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Characterization of the Human Pancreatic Islet Proteome by Two-Dimensional LC/MS/MS

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