The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Peng Jiang - One of the best experts on this subject based on the ideXlab platform.
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regulation of the Pentose Phosphate pathway in cancer
Protein & Cell, 2014Co-Authors: Peng Jiang, Wenjing Du, Mian WuAbstract:Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the promotion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The Pentose Phosphate pathway (PPP) is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxidative branch and produces a reduced form of nicotinamide adenine dinucleotide Phosphate (NADPH), an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-Phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell proliferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous factors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.
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tap73 enhances the Pentose Phosphate pathway and supports cell proliferation
Nature Cell Biology, 2013Co-Authors: Michael D Brewer, Mian Wu, Andy J Minn, Anthony Mancuso, Wenjing Du, Aaron J Stonestrom, Peng Jiang, Xiaolu YangAbstract:The p53 homologue TAp73 is frequently overexpressed in tumours, suggesting it provides an advantage to cancer cells. Yang and colleagues have investigated the role of TAp73 in tumour cell proliferation and showed that TAp73, but not p53, is a transcriptional activator of glucose-6-Phosphate dehydrogenase. Increased expression of this gene promotes the Pentose Phosphate pathway flux, leading to enhanced biosynthesis and antioxidant defence, both of which have been shown to support optimal cell proliferation and tumour formation.
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tap73 enhances the Pentose Phosphate pathway and supports cell proliferation
Nature Cell Biology, 2013Co-Authors: Michael D Brewer, Andy J Minn, Aaron J Stonestrom, Peng Jiang, Anthony A Mancuso, Tak W Mak, Xiaolu YangAbstract:TAp73 is a structural homologue of the pre-eminent tumour suppressor p53. However, unlike p53, TAp73 is rarely mutated, and instead is frequently overexpressed in human tumours. It remains unclear whether TAp73 affords an advantage to tumour cells and if so, what the underlying mechanism is. Here we show that TAp73 supports the proliferation of human and mouse tumour cells. TAp73 activates the expression of glucose-6-Phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the Pentose Phosphate pathway (PPP). By stimulating G6PD, TAp73 increases PPP flux and directs glucose to the production of NADPH and ribose, for the synthesis of macromolecules and detoxification of reactive oxygen species (ROS). The growth defect of TAp73-deficient cells can be rescued by either enforced G6PD expression or the presence of nucleosides plus an ROS scavenger. These findings establish a critical role for TAp73 in regulating metabolism, and connect TAp73 and the PPP to oncogenic cell growth.
Valeria C Culotta - One of the best experts on this subject based on the ideXlab platform.
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the yeast copper zinc superoxide dismutase and the Pentose Phosphate pathway play overlapping roles in oxidative stress protection
Journal of Biological Chemistry, 1996Co-Authors: Kimberly Hudak Slekar, Daniel J Kosman, Valeria C CulottaAbstract:Next Section Abstract In Saccharomyces cerevisiae, loss of cytosolic superoxide dismutase (Sod1) results in several air-dependent mutant phenotypes, including methionine auxotrophy and oxygen sensitivity. Here we report that these two sod1Δ phenotypes were specifically suppressed by elevated expression of the TKL1 gene, encoding transketolase of the Pentose Phosphate pathway. The apparent connection between Sod1 and the Pentose Phosphate pathway prompted an investigation of mutants defective in glucose-6-Phosphate dehydrogenase (Zwf1), which catalyzes the rate-limiting NADPH-producing step of this pathway. We confirmed that zwf1Δ mutants are methionine auxotrophs and report that they also are oxygen-sensitive. We determined that a functional ZWF1 gene product was required for TKL1 to suppress sod1Δ, leading us to propose that increased flux through the oxidative reactions of the Pentose Phosphate pathway can rescue sod1 methionine auxotrophy. To better understand this methionine growth requirement, we examined the sulfur compound requirements of sod1Δ and zwf1Δ mutants, and noted that these mutants exhibit the same apparent defect in sulfur assimilation. Our studies suggest that this defect results from the impaired redox status of aerobically grown sod1 and zwf1 mutants, implicating Sod1 and the Pentose Phosphate pathway as being critical for maintenance of the cellular redox state.
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the yeast copper zinc superoxide dismutase and the Pentose Phosphate pathway play overlapping roles in oxidative stress protection
Journal of Biological Chemistry, 1996Co-Authors: Kimberly Hudak Slekar, Daniel J Kosman, Valeria C CulottaAbstract:In Saccharomyces cerevisiae, loss of cytosolic superoxide dismutase (Sod1) results in several air-dependent mutant phenotypes, including methionine auxotrophy and oxygen sensitivity. Here we report that these two sod1Δ phenotypes were specifically suppressed by elevated expression of the TKL1 gene, encoding transketolase of the Pentose Phosphate pathway. The apparent connection between Sod1 and the Pentose Phosphate pathway prompted an investigation of mutants defective in glucose-6-Phosphate dehydrogenase (Zwf1), which catalyzes the rate-limiting NADPH-producing step of this pathway. We confirmed that zwf1Δ mutants are methionine auxotrophs and report that they also are oxygen-sensitive. We determined that a functional ZWF1 gene product was required for TKL1 to suppress sod1Δ, leading us to propose that increased flux through the oxidative reactions of the Pentose Phosphate pathway can rescue sod1 methionine auxotrophy. To better understand this methionine growth requirement, we examined the sulfur compound requirements of sod1Δ and zwf1Δ mutants, and noted that these mutants exhibit the same apparent defect in sulfur assimilation. Our studies suggest that this defect results from the impaired redox status of aerobically grown sod1 and zwf1 mutants, implicating Sod1 and the Pentose Phosphate pathway as being critical for maintenance of the cellular redox state.
Markus Ralser - One of the best experts on this subject based on the ideXlab platform.
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methionine metabolism alters oxidative stress resistance via the Pentose Phosphate pathway
Antioxidants & Redox Signaling, 2016Co-Authors: Kate Campbell, Markus A Keller, Markus Ralser, Jakob VowinckelAbstract:Nutrient uptake and metabolism have a significant impact on the way cells respond to stress. The amino acid methionine is, in particular, a key player in the oxidative stress response, and acting as a reactive oxygen species scavenger, methionine is implicated in caloric restriction phenotypes and aging. We here provide evidence that some effects of methionine in stress situations are indirect and caused by altered activity of the nicotinamide adenine dinucleotide Phosphate (NADPH) producing oxidative part of the Pentose Phosphate pathway (PPP). In Saccharomyces cerevisiae, both methionine prototrophic (MET15) and auxotrophic (met15Δ) cells supplemented with methionine showed an increase in PPP metabolite concentrations downstream of the NADPH producing enzyme, 6-phosphogluconate dehydrogenase. Proteomics revealed this enzyme to also increase in expression compared to methionine self-synthesizing cells. Oxidant tolerance was increased in cells preincubated with methionine; however, this effect was abolished when flux through the oxidative PPP was prevented by deletion of its rate limiting enzyme, ZWF1. Stress resistance phenotypes that follow methionine supplementation hence involve the oxidative PPP. Effects of methionine on oxidative metabolism, stress signaling, and aging have thus to be seen in the context of an altered activity of this NADP reducing pathway.
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methionine metabolism alters oxidative stress resistance via the Pentose Phosphate pathway
Antioxidants & Redox Signaling, 2016Co-Authors: Kate Campbell, Markus A Keller, Markus Ralser, Jakob VowinckelAbstract:Abstract Nutrient uptake and metabolism have a significant impact on the way cells respond to stress. The amino acid methionine is, in particular, a key player in the oxidative stress response, and acting as a reactive oxygen species scavenger, methionine is implicated in caloric restriction phenotypes and aging. We here provide evidence that some effects of methionine in stress situations are indirect and caused by altered activity of the nicotinamide adenine dinucleotide Phosphate (NADPH) producing oxidative part of the Pentose Phosphate pathway (PPP). In Saccharomyces cerevisiae, both methionine prototrophic (MET15) and auxotrophic (met15Δ) cells supplemented with methionine showed an increase in PPP metabolite concentrations downstream of the NADPH producing enzyme, 6-phosphogluconate dehydrogenase. Proteomics revealed this enzyme to also increase in expression compared to methionine self-synthesizing cells. Oxidant tolerance was increased in cells preincubated with methionine; however, this effect wa...
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non enzymatic glycolysis and Pentose Phosphate pathway like reactions in a plausible archean ocean
Molecular Systems Biology, 2014Co-Authors: Markus A Keller, Alexandra V Turchyn, Markus RalserAbstract:The reaction sequences of central metabolism, glycolysis and the Pentose Phosphate pathway provide essential precursors for nucleic acids, amino acids and lipids. However, their evolutionary origins are not yet understood. Here, we provide evidence that their structure could have been fundamentally shaped by the general chemical environments in earth’s earliest oceans. We reconstructed potential scenarios for oceans of the prebiotic Archean based on the composition of early sediments. We report that the resultant reaction milieu catalyses the interconversion of metabolites that in modern organisms constitute glycolysis and the Pentose Phosphate pathway. The 29 observed reactions include the formation and/or interconversion of glucose, pyruvate, the nucleic acid precursor ribose-5-Phosphate and the amino acid precursor erythrose-4-Phosphate, antedating reactions sequences similar to that used by the metabolic pathways. Moreover, the Archean ocean mimetic increased the stability of the phosphorylated intermediates and accelerated the rate of intermediate reactions and pyruvate production. The catalytic capacity of the reconstructed ocean milieu was attributable to its metal content. The reactions were particularly sensitive to ferrous iron Fe(II), which is understood to have had high concentrations in the Archean oceans. These observations reveal that reaction sequences that constitute central carbon metabolism could have been constrained by the iron-rich oceanic environment of the early Archean. The origin of metabolism could thus date back to the prebiotic world.
Xiaolu Yang - One of the best experts on this subject based on the ideXlab platform.
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tap73 enhances the Pentose Phosphate pathway and supports cell proliferation
Nature Cell Biology, 2013Co-Authors: Michael D Brewer, Mian Wu, Andy J Minn, Anthony Mancuso, Wenjing Du, Aaron J Stonestrom, Peng Jiang, Xiaolu YangAbstract:The p53 homologue TAp73 is frequently overexpressed in tumours, suggesting it provides an advantage to cancer cells. Yang and colleagues have investigated the role of TAp73 in tumour cell proliferation and showed that TAp73, but not p53, is a transcriptional activator of glucose-6-Phosphate dehydrogenase. Increased expression of this gene promotes the Pentose Phosphate pathway flux, leading to enhanced biosynthesis and antioxidant defence, both of which have been shown to support optimal cell proliferation and tumour formation.
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tap73 enhances the Pentose Phosphate pathway and supports cell proliferation
Nature Cell Biology, 2013Co-Authors: Michael D Brewer, Andy J Minn, Aaron J Stonestrom, Peng Jiang, Anthony A Mancuso, Tak W Mak, Xiaolu YangAbstract:TAp73 is a structural homologue of the pre-eminent tumour suppressor p53. However, unlike p53, TAp73 is rarely mutated, and instead is frequently overexpressed in human tumours. It remains unclear whether TAp73 affords an advantage to tumour cells and if so, what the underlying mechanism is. Here we show that TAp73 supports the proliferation of human and mouse tumour cells. TAp73 activates the expression of glucose-6-Phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the Pentose Phosphate pathway (PPP). By stimulating G6PD, TAp73 increases PPP flux and directs glucose to the production of NADPH and ribose, for the synthesis of macromolecules and detoxification of reactive oxygen species (ROS). The growth defect of TAp73-deficient cells can be rescued by either enforced G6PD expression or the presence of nucleosides plus an ROS scavenger. These findings establish a critical role for TAp73 in regulating metabolism, and connect TAp73 and the PPP to oncogenic cell growth.
Wenjing Du - One of the best experts on this subject based on the ideXlab platform.
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regulation of the Pentose Phosphate pathway in cancer
Protein & Cell, 2014Co-Authors: Peng Jiang, Wenjing Du, Mian WuAbstract:Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the promotion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The Pentose Phosphate pathway (PPP) is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxidative branch and produces a reduced form of nicotinamide adenine dinucleotide Phosphate (NADPH), an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-Phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell proliferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous factors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.
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tap73 enhances the Pentose Phosphate pathway and supports cell proliferation
Nature Cell Biology, 2013Co-Authors: Michael D Brewer, Mian Wu, Andy J Minn, Anthony Mancuso, Wenjing Du, Aaron J Stonestrom, Peng Jiang, Xiaolu YangAbstract:The p53 homologue TAp73 is frequently overexpressed in tumours, suggesting it provides an advantage to cancer cells. Yang and colleagues have investigated the role of TAp73 in tumour cell proliferation and showed that TAp73, but not p53, is a transcriptional activator of glucose-6-Phosphate dehydrogenase. Increased expression of this gene promotes the Pentose Phosphate pathway flux, leading to enhanced biosynthesis and antioxidant defence, both of which have been shown to support optimal cell proliferation and tumour formation.