Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.9 (glucose-6-phosphatase)
 3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A bioartificial liver (BAL) based on viable porcine hepatocytes can serve as a bridge to liver transplantation in patients with acute liver failure (ALF). To support liver functions, an adequate mass of hepatocytes is needed, which depends upon the cell density in the BAL device. This study evaluated the optimal density of hepatocytes within BAL devices that were constructed by perfusing porcine hepatocyte suspensions mixed with cytodex-3 into polysulfon hollow-fibers. The BAL devices were prepared with 6 different cell densities. The mass of hepatocytes in each device was evaluated for (a) cell viability, (b) ability to degrade diazepam, (c) ability to synthesize urea, (d) incorporation of [3H]-leucine into protein, (e) glucose-6-phosphatase activity, (f) total RNA content, and (g) p53 gene expression. Hepatocyte viability was about 90% in each device. With increasing hepatocyte density, the diazepam concentration in the medium decreased from 9.26 +/- 0.96 mg/L at 1 x 10(5) cells/ml to a minimum of 5.25 +/- 1.02 mg/L at 5 x 10(6) cells/ml and thereafter remained at low levels. Urea production and [3H]-leucine incorporation into protein increased progressively until the cell density reached 5 x 10(6)/ml and thereafter remained at high levels. Glucose-6-phosphatase activity and total RNA content stayed at high levels until the cell density reached 5 x 10(6)/ml and then progressively decreased. p53 gene expression differed from the other parameters, since it increased only when the cell density reached 5 x 10(7)/ml. In conclusion, the density of 5 x 10(6) cells/ml is a critical inflection point for most of the functional parameters, although p53 gene expression is not elevated at this cell density. These findings suggest that 5 x 10(6) cells/ml is the optimal hepatocyte density in the hollow-fiber BAL device.
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PMID:The optimal hepatocyte density for a hollow-fiber bioartificial liver. 1503 73

Mouse models are important tools in toxicologic research. Differences between species in pathways contributing to tumor development, however, raise the question in how far mouse models are valid for human risk assessment. One striking difference relates to the frequency of spontaneous liver cancer which is high in certain mouse strains but rather low in humans. Similarly, mutation frequencies in cancer genes are characteristically different, i.e. P53 mutations are frequent in human but very rare in murine liver tumors, whereas Ras genes are often mutated in mouse liver tumors but hardly ever in human liver cancers. Since P53 has been shown to control oncogenic RAS in human cells, we hypothesized that this function of the tumor suppressor could differ in mouse hepatocytes. To test this hypothesis, we used hupki (human p53 knock-in) mice which carry a partly humanized P53 sequence (P53KI). In this study, we report the results of the first hepatocarcinogenesis experiment with this strain of mice. Mice of the genotypes P53KI/KI, P53WT/KI and P53WT/WT were treated with N-nitrosodiethylamine at 2 weeks of age and killed 35 weeks later. The frequency of liver tumors and glucose-6-phosphatase-altered liver lesions was almost identical in all three P53 genotypes and approximately 40-50% of liver tumors showed activating mutations in codon 61 of the Ha-Ras gene independent of genotype. Moreover, only very few P53-positive lesions were observed but without nuclear localization of the protein, suggesting the absence of P53 mutations. These data suggest that the hupki allele behaves like its murine ortholog in mouse hepatocarcinogenesis.
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PMID:Human p53 knock-in (hupki) mice do not differ in liver tumor response from their counterparts with murine p53. 1591 4

For the application of microarray technology as an additional endpoint in toxicological studies, there is a need to understand associations between pathological processes and gene expression alterations. In the current study, we investigated gentamicin as a nephrotoxic model compound. Gene expression changes of the kidney in response to a dose of 80 mg/kg gentamicin were analyzed by using DNA microarray technology and alterations in gene expression were associated with results from conventional histopathological investigations and with the described pathomechanisms of gentamicin. Under the conditions of our experiment, the mRNA level of 211 genes were found to be deregulated by gentamicin. The gentamicin-induced affection of proximal convoluted tubules was associated with a strong up-regulation of mRNAs encoding for proteins which are used as nephrotoxicity markers in urine and plasma such as Kim-1, Osteopontin and TIMP1. Candidate marker genes for nephrotoxicity such as GATM were deregulated. Gentamicin-induced lysosomal phospholipidosis was indicated by deregulation of lysosomal located gene products such as ATP6V1D, a subunit of the lysosomal H+ transporting ATPase. Effects on glucose transport and metabolism were indicated by the down-regulation on SGLT-2 and glucose-6-phosphatase. Renal cell apoptosis was indicated by up-regulated genes as TP53 and BAX. The role of oxidative stress in gentamicin toxicity was reflected by deregulation of transferrin receptor and heme oxygenase. The results of the study show the potential of microarray technology to study a complex mechanism of toxicity in a single study.
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PMID:Identification of genes involved in gentamicin-induced nephrotoxicity in rats--a toxicogenomic investigation. 1966 12

In mammalian cells, tumor suppressor p53 plays critical roles in the regulation of glucose metabolism, including glycolysis and oxidative phosphorylation, but whether and how p53 also regulates gluconeogenesis is less clear. Here, we report that p53 efficiently down-regulates the expression of phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), which encode rate-limiting enzymes in gluconeogenesis. Cell-based assays demonstrate the p53-dependent nuclear exclusion of forkhead box protein O1 (FoxO1), a key transcription factor that mediates activation of PCK1 and G6PC, with consequent alleviation of FoxO1-dependent gluconeogenesis. Further mechanistic studies show that p53 directly activates expression of the NAD(+)-dependent histone deacetylase sirtuin 6 (SIRT6), whose interaction with FoxO1 leads to FoxO1 deacetylation and export to the cytoplasm. In support of these observations, p53-mediated FoxO1 nuclear exclusion, down-regulation of PCK1 and G6PC expression, and regulation of glucose levels were confirmed in C57BL/J6 mice and in liver-specific Sirt6 conditional knockout mice. Our results provide insights into mechanisms of metabolism-related p53 functions that may be relevant to tumor suppression.
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PMID:Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. 2526 55

The activation of TP53 is well known to exert tumor suppressive effects. We have detected a primate-specific adrenal androgen-mediated tumor suppression system in which circulating DHEAS is converted to DHEA specifically in cells in which TP53 has been inactivated DHEA is an uncompetitive inhibitor of glucose-6-phosphate dehydrogenase (G6PD), an enzyme indispensable for maintaining reactive oxygen species within limits survivable by the cell. Uncompetitive inhibition is otherwise unknown in natural systems because it becomes irreversible in the presence of high concentrations of substrate and inhibitor. In addition to primate-specific circulating DHEAS, a unique, primate-specific sequence motif that disables an activating regulatory site in the glucose-6-phosphatase (G6PC) promoter was also required to enable function of this previously unrecognized tumor suppression system. In human somatic cells, loss of TP53 thus triggers activation of DHEAS transport proteins and steroid sulfatase, which converts circulating DHEAS into intracellular DHEA, and hexokinase which increases glucose-6-phosphate substrate concentration. The triggering of these enzymes in the TP53-affected cell combines with the primate-specific G6PC promoter sequence motif that enables G6P substrate accumulation, driving uncompetitive inhibition of G6PD to irreversibility and ROS-mediated cell death. By this catastrophic 'kill switch' mechanism, TP53 mutations are effectively prevented from initiating tumorigenesis in the somatic cells of humans, the primate with the highest peak levels of circulating DHEAS. TP53 mutations in human tumors therefore represent fossils of kill switch failure resulting from an age-related decline in circulating DHEAS, a potentially reversible artifact of hominid evolution.
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PMID:Detection of a novel, primate-specific 'kill switch' tumor suppression mechanism that may fundamentally control cancer risk in humans: an unexpected twist in the basic biology of TP53. 2994 76

We recently reported our detection of an anthropoid primate-specific, 'kill switch' tumor suppression system that reached its greatest expression in humans, but that is fully functional only during the first twenty-five years of life, corresponding to the primitive human lifespan that has characterized the majority of our species' existence. This tumor suppression system is based upon the kill switch being triggered in cells in which p53 has been inactivated; such kill switch consisting of a rapid, catastrophic increase in ROS caused by the induction of irreversible uncompetitive inhibition of glucose-6- phosphate dehydrogenase (G6PD), which requires high concentrations of both inhibitor (DHEA) and G6P substrate. While high concentrations of intracellular DHEA are readily available in primates from the importation and subsequent de-sulfation of circulating DHEAS into p53-affected cells, both an anthropoid primate-specific sequence motif (GAAT) in the glucose-6-phosphatase (G6PC) promoter, and primate-specific inactivation of de novo synthesis of vitamin C by deletion of gulonolactone oxidase (GLO) were required to enable accumulation of G6P to levels sufficient to enable irreversible uncompetitive inhibition of G6PD. Malignant transformation acts as a counterforce opposing vertebrate speciation, particularly increases in body size and lifespan that enable optimized exploitation of particular niches. Unique mechanisms of tumor suppression that evolved to enable niche exploitation distinguish vertebrate species, and prevent one vertebrate species from serving as a valid model system for another. This here-to-fore unrecognized element of speciation undermines decades of cancer research data, using murine species, which presumed universal mechanisms of tumor suppression, independent of species. Despite this setback, the potential for pharmacological reconstitution of the kill switch tumor suppression system that distinguishes our species suggests that 'normalization' of human cancer risk, from its current 40% to the 4% of virtually all other large, long-lived species, represents a realistic near-term goal.
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PMID:Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the 'war on cancer'. 3040 61