Glucose modulates the binding activity of the <i>β</i>-cell transcription factor IUF1 in a phosphorylation-dependent manner

Macfarlane, Wendy M.; Read, Martin; Gilligan, Moira G.; Bujalska, Iwona; Docherty, Kevin

doi:10.1042/bj3030625

Cited by 133 publications

(95 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, phosphorylation of PDX-1 in glucose-induced ␤ cells appears to stimulate its DNA binding activity (25,26,35). In addition, RIPE3b1 binding activity is reduced by CIAP and BPP treatment, suggesting that activation of this insulin gene transcription factor is also mediated by phosphorylation, specifically of the 46-kDa DNA binding subunit (9).…”

Section: Resultsmentioning

confidence: 99%

“…RIPE3b1 DNA binding is mediated by a ␤ cellenriched protein(s) of ϳ46 kDa, whose activity is reduced by either calf intestinal alkaline phosphatase (CIAP) 1 or a brainenriched phosphatase preparation (BPP) treatment (9). These results suggested that RIPE3b1 binding is regulated by phosphorylation, a posttranslational modification mechanism also utilized in controlling PDX-1 activation (25,26). In an effort to more fully understand the role that phosphorylation plays in RIPE3b1 function, we have characterized the phosphatase activity that affects RIPE3b1 binding within the ␤ cell.…”

mentioning

confidence: 82%

See 1 more Smart Citation

The DNA Binding Activity of the RIPE3b1 Transcription Factor of Insulin Appears to Be Influenced by Tyrosine Phosphorylation

Matsuoka

Zhao

Stein

2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

The RIPE3b1 DNA binding factor plays a critical role in pancreatic islet ␤ cell-specific and glucose-regulated transcription of the insulin gene. Recently it was shown that RIPE3b1 binding activity in ␤ cell nuclear extracts is reduced by treatment with either calf intestinal alkaline phosphatase (CIAP) or a brain-enriched phosphatase preparation (BPP) (Zhao, L., Cissell, M. A., Henderson, E., Colbran, R., and Stein, R. (2000) J. Biol. Chem. 275, 10532-10537). Evidence is presented here suggesting that a tyrosine phosphatase(s) influences the ability of RIPE3b1 to bind to the insulin C1 element in ␤ cells. We found that RIPE3b1 binding was inhibited upon incubating ␤ cell nuclear extracts at 30°C. In contrast, PDX-1 and MLTF-1 transcription factor binding activity was unaffected under these conditions. The loss in RIPE3b1 binding activity was prevented by inhibitors of tyrosine phosphatases (sodium orthovanadate and sodium molybdate) but not by inhibitors of serine/threonine phosphatases (sodium fluoride, okadaic acid, and microcystin LR). CIAP-and BPP-catalyzed inhibition of RIPE3b1 binding was also blocked by these tyrosine phosphatase inhibitors. Collectively, the data suggested that removal of a tyrosine(s) within RIPE3b1 prevented activator binding to insulin C1 control element sequences. The presence of a key phosphorylated tyrosine(s) within this transcription factor was further supported by the ability of the 4G10 anti-phosphotyrosine monoclonal antibody to immunoprecipitate RIPE3b1 DNA binding activity. We discuss how tyrosine phosphorylation, a very rare and highly significant regulatory modification, may control RIPE3b1 activator function.Insulin is a polypeptide hormone that plays a critical role in glucose homeostasis by stimulating the uptake of glucose into cells. Expression of insulin in adults is limited to pancreatic islet ␤ cells primarily because of the recognition, by specific positive-acting transcription factors, of its enhancer region, which is located between nucleotides Ϫ340 and Ϫ91 relative to the insulin gene transcription start site (1-3). Selective activation from this region is predominantly mediated by the C2 (Ϫ317 to Ϫ311 base pairs) (2), A3 (Ϫ205 to Ϫ189 base pairs) (4 -6), C1 (Ϫ115 to Ϫ107 base pairs) (7-9), and E elements (Ϫ100 to Ϫ91 base pairs) (4, 7, 10). (These insulin cis-elements are labeled in accordance with the nomenclature proposed by German et al. (11).) The factors that act at A3, C1, and E also control glucose-inducible transcription (5,8,(12)(13)(14)(15), the primary metabolic regulator of insulin gene expression in vivo.The C2 (i.e. PAX6 (2)) and A3 (i.e. PDX-1 (6, 16, 17)) activators are islet ␤ cell-enriched homeodomain proteins, whereas a basic helix-loop-helix-containing protein controls E element stimulation (i.e. BETA2 (18)). Strikingly, these proteins regulate gene expression within islet cell types and during pancreogenesis. Thus, an inactivating mutation in the pdx-1 locus affects a very early development step that prevents both exocrine and endocrine p...

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 82%

The DNA Binding Activity of the RIPE3b1 Transcription Factor of Insulin Appears to Be Influenced by Tyrosine Phosphorylation

Matsuoka

Zhao

Stein

2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In contrast to the relatively slow glucose-induced increase in bHLH heterodimer binding to the E element, PDX-1 binding increases acutely in response to a rise in glucose concentration (26,29). The glucose-stimulated increase in DNA binding by PDX-1 is reportedly due to phosphorylation that is dependent on phosphatidylinositol 3-kinase and the p38 MAP kinase (26,30), although neither kinase was found to directly phosphorylate PDX-1. Glucose also causes PDX-1 to shift into the nucleus (31,32) and increases its transcriptional activation capacity (33).…”

mentioning

confidence: 86%

“…A elements bind any of several homeodomain transcription factors found in ␤ cells, the most abundant being PDX-1 (25)(26)(27)(28). In contrast to the relatively slow glucose-induced increase in bHLH heterodimer binding to the E element, PDX-1 binding increases acutely in response to a rise in glucose concentration (26,29).…”

mentioning

confidence: 97%

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

Khoo

Griffen

Xia

et al. 2003

Journal of Biological Chemistry

146

142

View full text Add to dashboard Cite

We show that the mitogen-activated protein kinases ERK1/2 are components of the mechanism by which glucose stimulates insulin gene expression. ERK1/2 activity is required for glucose-dependent transcription from both the full-length rat insulin I promoter and the glucose-sensitive isolated E2A3/4 promoter element in intact islets and ␤ cell lines. Dominant negative ERK2 and MEK inhibitors suppress glucose stimulation of the rat insulin I promoter and the E2A3/4 element. Overexpression of ERK2 is sufficient to stimulate transcription from the E2A3/4 element. The glucose-induced response is dependent upon ERK1/2 phosphorylation of a subset of transcription factors that include Beta2 (also known as NeuroD1) and PDX-1. Phosphorylation increases their functional activity and results in a cumulative transactivation of the promoter. Thus, ERK1/2 act at multiple points to transduce a glucose signal to insulin gene transcription.

show abstract

“…Insulin promoter factor 1 (IPF-1) (also known as STF-1, IDF-1, IDX-1, and PDX-1) is a homeodomain transcription factor that is absolutely required for the development of the pancreas (8,9) and also mediates glucose-responsive stimulation of insulin gene transcription (10)(11)(12)(13)(14)(15). IPF-1 is also implicated in the transcriptional regulation of other key ␤-cell specific genes, including GLUT2 (16), islet amyloid polypeptide (17,18), and glucokinase (19).…”

Section: Impaired Insulin Secretion and Increased Insulin Sensitivitymentioning

confidence: 99%

Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).

et al. 2000

View full text Add to dashboard Cite

Diabetes resulting from heterozygosity for an inactivating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due to a genetic defect of ␤-cell function referred to as maturity-onset diabetes of the young 4. IPF-1 is required for the development of the pancreas and mediates glucose-responsive stimulation of insulin gene transcription. To quantitate islet cell responses in a family harboring a Pro63fsdelC mutation in IPF-1, we performed a five-step (1-h intervals) hyperglycemic clamp on seven heterozygous members (NM) and eight normal genotype members (NN). During the last 30 min of the fifth glucose step, glucagon-like peptide 1 (GLP-1) was also infused (1.5 pmol · kg -1 · min -1 ). Fasting plasma glucose levels were greater in the NM group than in the NN group (9.2 vs. 5.9 mmol/l, respectively; P < 0.05). Fasting insulin levels were similar in both groups (72 vs. 105 pmol/l for NN vs. NM, respectively). First-phase insulin and C-peptide responses were absent in individuals in the NM group, who had markedly attenuated insulin responses to glucose alone compared with the NN group. At a glucose level of 16.8 mmol/l above fasting level, GLP-1 augmented insulin secretion equivalently (fold increase) in both groups, but the insulin and C-peptide responses to GLP-1 were sevenfold less in the NM subjects than in the NN subjects. In both groups, glucagon levels fell during each glycemic plateau, and a further reduction occurred during the GLP-1 infusion. Sigmoidal dose-response curves of glucose clearance versus insulin levels during the hyperglycemic clamp in the two small groups showed both a left shift and a lower maximal response in the NM group compared with the NN group, which is consistent with an increased insulin sensitivity in the NM subjects. A sharp decline occurred in the doseresponse curve for suppression of nonesterified fatty acids versus insulin levels in the NM group. We conclude that the Pro63fsdelC IPF-1 mutation is associated with a severe impairment of ␤-cell sensitivity to glucose and an apparent increase in peripheral tissue sensitivity to insulin and is a genetically determined cause of ␤-cell dysfunction. Diabetes 49:1856-1864, 2000 T ype 2 diabetes is a highly prevalent and heterogeneous disorder of glucose homeostasis characterized by an imbalance between insulin synthesis and secretion by the endocrine pancreatic ␤-cells and peripheral tissue sensitivity to insulin. Diabetes has long been recognized as a genetic disorder with complex modes of inheritance. Recent advances reveal the genetic basis for a monogenic type of diabetes referred to as maturity-onset diabetes of the young (MODY), which is characterized by diagnosis at <25 years of age, autosomal dominant inheritance, and lack of a requirement for insulin therapy for at least 5 years after initial diagnosis (1). To date, five MODY genes have been identified, four of which encode endocrine pancreatic transcription factors (2-5) and one that encodes the pancreatic and hepatic glycolytic enzyme glucokina...

show abstract

Glucose modulates the binding activity of the β-cell transcription factor IUF1 in a phosphorylation-dependent manner

Cited by 133 publications

References 34 publications

The DNA Binding Activity of the RIPE3b1 Transcription Factor of Insulin Appears to Be Influenced by Tyrosine Phosphorylation

The DNA Binding Activity of the RIPE3b1 Transcription Factor of Insulin Appears to Be Influenced by Tyrosine Phosphorylation

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

Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).

Contact Info

Product

Resources

About