Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.1 (hexokinase)
 5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulinoma beta-cell line INS-1 expresses the L-type pyruvate kinase gene at high level and responds to a rise in extracellular glucose by strong induction of gene expression. Following the addition of glucose to the culture medium in the 3.5-33 mM concentration range, the cellular level of L-type pyruvate kinase mRNA increases within 2 h and reaches a maximum 15-fold above basal in 8-12 h. By run-on nuclear assay, the relative transcription rate of the pyruvate kinase gene is shown to increase 4-fold at maximal stimulation, suggesting that both transcriptional and post-transcriptional effects contribute to mRNA accumulation. The glucose effect is totally suppressed by the hexokinase inhibitor mannoheptulose, indicating a requirement for glucose phosphorylation. The mRNA induction is not inhibited in glutamine-free culture medium or by azaserine, suggesting that the hexosamine biosynthetic pathway is not involved. Moreover, metabolism along the glycolytic pathway does not appear to be an absolute requisite, since 2-deoxyglucose partly mimics the inductive effect of glucose. The glucose effect on the pyruvate kinase gene is reversibly antagonized by agents increasing intracellular cAMP. In addition, the effect is highly specific to the pyruvate kinase gene. Neither proinsulin I mRNA nor glucokinase mRNA are increased in glucose-stimulated INS-1 cells. Short term transfection with CAT plasmids driven by the pyruvate kinase L promoter reveals specific glucose-inducible reporter activity with the 183-base pair promoter region upstream of the cap site. Within this region, the previously described L4 cis-acting element is crucial for glucose responsiveness, as demonstrated by the fact that a plasmid with a mutation in this element does not elicit glucose-inducible CAT activity. Induction of L-type pyruvate kinase mRNA occurs in the islets of rats subjected to fasting and carbohydrate refeeding. In conclusion, the L-type pyruvate kinase gene provides an interesting model of glucose-regulated gene in the endocrine beta-cell type.
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PMID:The pyruvate kinase gene as a model for studies of glucose-dependent regulation of gene expression in the endocrine pancreatic beta-cell type. 822 28

The transcription factor Foxa2 is implicated in blood glucose homeostasis. Conditional expression of Foxa2 or its dominant-negative mutant DN-Foxa2 in INS-1 cells reveals that Foxa2 regulates the expression of genes important for glucose sensing in pancreatic beta-cells. Overexpression of Foxa2 results in blunted glucose-stimulated insulin secretion, whereas induction of DN-Foxa2 causes a left shift of glucose-induced insulin release. The mRNA levels of GLUT2 and glucokinase are drastically decreased after induction of Foxa2. In contrast, loss of Foxa2 function leads to up-regulation of hexokinase (HK) I and II and glucokinase (HK-IV) mRNA expression. The glucokinase and the low K(m) hexokinase activities as well as glycolysis are increased proportionally. In addition, induction of DN-Foxa2 also reduces the expression of beta-cell K(ATP) channel subunits Sur1 and Kir6.2 by 70%. Furthermore, in contrast to previous reports, induction of Foxa2 causes pronounced decreases in the HNF4alpha and HNF1alpha mRNA levels. Foxa2 fails to regulate the expression of Pdx1 transcripts. The expression of insulin and islet amyloid polypeptide is markedly suppressed after induction of Foxa2, while the glucagon mRNA levels are significantly increased. Conversely, Foxa2 is required for glucagon expression in these INS-1-derived cells. These results suggest that Foxa2 is a vital transcription factor evolved to control the expression of genes essential for maintaining beta-cell glucose sensing and glucose homeostasis.
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PMID:Foxa2 (HNF3beta ) controls multiple genes implicated in metabolism-secretion coupling of glucose-induced insulin release. 1187 61