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Kmt2a cooperates with menin to suppress tumorigenesis in mouse pancreatic islets.

ABSTRACT: The reported incidence of pancreatic neuroendocrine tumors (PanNETs) has increased, due in large part to improvements in detection and awareness. However, therapeutic options are limited and a critical need exists for understanding a more thorough characterization of the molecular pathology underlying this disease. The Men1 knockout mouse model recapitulates the early stage of human PanNET development and can serve as a foundation for the development of advanced mouse models that are necessary for preclinical testing. Menin, the product of the MEN1 gene, has been shown to physically interact with the KMT2A and KMT2B histone methyltransferases. Both the KMT2A and MEN1 genes are located on chromosome 11q, which frequently undergoes loss of heterozygosity (LOH) in PanNETs. We report herein that inactivation of Kmt2a in Men1-deficient mice accelerated pancreatic islet tumorigenesis and shortened the average life span. Increases in cell proliferation were observed in mouse pancreatic islet tumors upon inactivation of both Kmt2a and Men1. The Kmt2a/Men1 double knockout mouse model can be used as a mouse model to study advanced PanNETs.

SUBMITTER: Lin W

PROVIDER: S-EPMC5199165 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Kmt2a cooperates with menin to suppress tumorigenesis in mouse pancreatic islets.

Lin Wenchu W Francis Joshua M JM Li Hong H Gao Xiaoping X Pedamallu Chandra Sekhar CS Ernst Patricia P Meyerson Matthew M

Cancer biology & therapy 20161101 12

The reported incidence of pancreatic neuroendocrine tumors (PanNETs) has increased, due in large part to improvements in detection and awareness. However, therapeutic options are limited and a critical need exists for understanding a more thorough characterization of the molecular pathology underlying this disease. The Men1 knockout mouse model recapitulates the early stage of human PanNET development and can serve as a foundation for the development of advanced mouse models that are necessary f ...[more]

PMID: 27801610

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Project description:1. Rates of glucose oxidation, lactate output and the intracellular concentration of glucose 6-phosphate were measured in mouse pancreatic islets incubated in vitro. 2. Glucose oxidation rate, measured as the formation of (14)CO(2) from [U-(14)C]glucose, was markedly dependent on extracellular glucose concentration. It was especially sensitive to glucose concentrations between 1 and 2mg/ml. Glucose oxidation was inhibited by mannoheptulose and glucosamine but not by phlorrhizin, 2-deoxyglucose or N-acetylglucosamine. Glucose oxidation was slightly stimulated by tolbutamide but was not significantly affected by adrenaline, diazoxide or absence of Ca(2+) (all of which may inhibit glucose-stimulated insulin release), by arginine or glucagon (which may stimulate insulin release) or by cycloheximide (which may inhibit insulin synthesis). 3. Rates of lactate formation were dependent on the extracellular glucose concentration and were decreased by glucosamine though not by mannoheptulose; tolbutamide increased the rate of lactate output. 4. Islet glucose 6-phosphate concentration was also markedly dependent on extracellular glucose concentration and was diminished by mannoheptulose or glucosamine; tolbutamide and glucagon were without significant effect. Mannose increased islet fructose 6-phosphate concentration but had little effect on islet glucose 6-phosphate concentration. Fructose increased islet glucose 6-phosphate concentration but to a much smaller extent than did glucose. 5. [1-(14)C]Mannose and [U-(14)C]fructose were also oxidized by islets but less rapidly than glucose. Conversion of [1-(14)C]mannose into [1-(14)C]glucose 6-phosphate or [1-(14)C]glucose could not be detected. It is concluded that metabolism of mannose is associated with poor equilibration between fructose 6-phosphate and glucose 6-phosphate. 6. These results are consistent with the idea that glucose utilization in mouse islets may be limited by the rate of glucose phosphorylation, that mannoheptulose and glucosamine may inhibit glucose phosphorylation and that effects of glucose on insulin release may be mediated through metabolism of the sugar.

Project description:The aim of the present study was to evaluate the role of polyamines in the metabolism and insulin production of pancreatic-islet cells. For this purpose islets were prepared from adult mice and used either immediately or after tissue culture. There was a significant decrease in the islet content of spermidine during culture, although the effect was less pronounced in a high glucose concentration. Furthermore, a stimulatory effect of a high glucose concentration, as compared with low guclose, on the content of spermine was observed. To elucidate further the role of polyamaines in beta-cell physiology, the ornithine decarboxylase inhibitors difuoromethylornithine (DFMO) and methylacetylenic putrescine (MAP) and the S-adenosylmethionine decarboxylase inhibitor ethylglyoxal bis(guanylhydrazone) (EGBG) were added to the culture media. Addition of DFMO together with MAP decreased the cellular contents of putrescine and spermidine, whereas the content of sperimine was unaffected. When EGBG was added in combination with DFMO and MAP, there was a decrease in the content of spermine also. Cell viability in the islets depleted of their polyamine contents was not impaired, as assessed by determinations of oxygen-uptake rates and ATP contents. Depletion of putescine plus spermidine by addition of DFMO+MAP was associated with decreased biosynthesis of (pro)insulin and total protein. When the content of spermine was decreased also by the further addition of EGBG, the decrease in (pro) insulin biosynthesis was more pronounced and was paralleled by a decrease in the insulin-mRNA content. Under these conditions, the glucose-stimulated insulin release, the insulin content and the rates of islet DNA synthesis were also decreased. It is concluded that putrescine and spermidine are necessary for the maintenance of normal insulin and protein biosynthesis, whereas spermine may exert a role in some other cellular processes, such as DNA replication, RNA transcription and glucose-stimulated insulin release.

Project description:1. Glucose-phosphorylating and glucose 6-phosphatase activities, glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, NADP(+)-linked isocitrate dehydrogenase, ;malic' enzyme and pyruvate carboxylase were assayed in homogenates of normal mouse islets. 2. Two glucose-phosphorylating activities were detected; the major activity had K(m) 0.075mm for glucose and was inhibited by glucose 6-phosphate (non-competitive with glucose) and mannoheptulose (competitive with glucose). The other (minor) activity had a high K(m) for glucose (mean value 16mm) and was apparently not inhibited by glucose 6-phosphate. 3. Glucose 6-phosphatase activity was present in amounts comparable with the total glucose-phosphorylating activity, with K(m) 1mm for glucose 6-phosphate. Glucose was an inhibitor and the inhibition showed mixed kinetics. No inhibition of glucose 6-phosphate hydrolysis was observed with mannose, citrate or tolbutamide. The inhibition by glucose was not reversed by mannoheptulose. 4. 6-Phosphogluconate dehydrogenase had K(m) values of 2.5 and 21mum for NADP(+) and 6-phosphogluconate respectively. 5. Glucose 6-phosphate dehydrogenase had K(m) values of 4 and 22mum for NADP(+) and glucose 6-phosphate. The K(m) for glucose 6-phosphate was considerably below the intra-islet concentration of glucose 6-phosphate at physiological extracellular glucose concentrations. The enzyme had no apparent requirement for cations. Of a number of possible modifiers of glucose 6-phosphate dehydrogenase, only NADPH was inhibitory. The inhibition by NADPH was competitive with NADP(+) and apparently mixed with respect to glucose 6-phosphate. 6. NADP(+)-isocitrate dehydrogenase was present but the islet homogenate contained little, if any, ;malic' enzyme. The presence of pyruvate carboxylase was also demonstrated. 7. The results obtained are discussed with reference to glucose phosphorylation and glucose 6-phosphate oxidation in the intact mouse islet, and the possible nature of the beta-cell glucoreceptor mechanism.

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Kmt2a cooperates with menin to suppress tumorigenesis in mouse pancreatic islets.

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Kmt2a cooperates with menin to suppress tumorigenesis in mouse pancreatic islets.

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