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Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species
by
Suzuki, Sawako
, Mayama, Takafumi
, Sugano, Sumio
, Lokshin, Maria
, Ohkubo, Shuichi
, Prives, Carol
, Poyurovsky, Masha V.
, Suzuki, Yutaka
, Tatsuno, Ichiro
, Hosokawa, Hiroyuki
, Nagao, Toshitaka
, Yokote, Koutaro
, Tanaka, Tomoaki
, Nakayama, Toshinori
, Sato, Eiichi
, Nagano, Hidekazu
in
Amino acids
/ Animals
/ Antioxidants
/ Antioxidants - metabolism
/ Apoptosis
/ Biological Sciences
/ Cell lines
/ Cellular metabolism
/ Delta cells
/ Deoxyribonucleic acid
/ DNA
/ DNA damage
/ energy
/ Energy metabolism
/ Enzymes
/ Gene expression
/ Gene expression regulation
/ genes
/ genotoxicity
/ glutamic acid
/ glutaminase
/ Glutaminase - metabolism
/ glutamine
/ Glutamine - metabolism
/ glutathione
/ Glutathione - metabolism
/ HCT116 cells
/ homeostasis
/ Humans
/ liver neoplasms
/ Metabolism
/ Mice
/ Mitochondria - metabolism
/ neoplasm cells
/ Oligonucleotide Array Sequence Analysis
/ Oxidation
/ Oxidative stress
/ Oxygen
/ Promoter Regions, Genetic
/ Reactive Oxygen Species
/ RNA Interference
/ small interfering RNA
/ Tumor Suppressor Protein p53 - metabolism
/ Tumors
2010
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Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species
by
Suzuki, Sawako
, Mayama, Takafumi
, Sugano, Sumio
, Lokshin, Maria
, Ohkubo, Shuichi
, Prives, Carol
, Poyurovsky, Masha V.
, Suzuki, Yutaka
, Tatsuno, Ichiro
, Hosokawa, Hiroyuki
, Nagao, Toshitaka
, Yokote, Koutaro
, Tanaka, Tomoaki
, Nakayama, Toshinori
, Sato, Eiichi
, Nagano, Hidekazu
in
Amino acids
/ Animals
/ Antioxidants
/ Antioxidants - metabolism
/ Apoptosis
/ Biological Sciences
/ Cell lines
/ Cellular metabolism
/ Delta cells
/ Deoxyribonucleic acid
/ DNA
/ DNA damage
/ energy
/ Energy metabolism
/ Enzymes
/ Gene expression
/ Gene expression regulation
/ genes
/ genotoxicity
/ glutamic acid
/ glutaminase
/ Glutaminase - metabolism
/ glutamine
/ Glutamine - metabolism
/ glutathione
/ Glutathione - metabolism
/ HCT116 cells
/ homeostasis
/ Humans
/ liver neoplasms
/ Metabolism
/ Mice
/ Mitochondria - metabolism
/ neoplasm cells
/ Oligonucleotide Array Sequence Analysis
/ Oxidation
/ Oxidative stress
/ Oxygen
/ Promoter Regions, Genetic
/ Reactive Oxygen Species
/ RNA Interference
/ small interfering RNA
/ Tumor Suppressor Protein p53 - metabolism
/ Tumors
2010
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Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species
by
Suzuki, Sawako
, Mayama, Takafumi
, Sugano, Sumio
, Lokshin, Maria
, Ohkubo, Shuichi
, Prives, Carol
, Poyurovsky, Masha V.
, Suzuki, Yutaka
, Tatsuno, Ichiro
, Hosokawa, Hiroyuki
, Nagao, Toshitaka
, Yokote, Koutaro
, Tanaka, Tomoaki
, Nakayama, Toshinori
, Sato, Eiichi
, Nagano, Hidekazu
in
Amino acids
/ Animals
/ Antioxidants
/ Antioxidants - metabolism
/ Apoptosis
/ Biological Sciences
/ Cell lines
/ Cellular metabolism
/ Delta cells
/ Deoxyribonucleic acid
/ DNA
/ DNA damage
/ energy
/ Energy metabolism
/ Enzymes
/ Gene expression
/ Gene expression regulation
/ genes
/ genotoxicity
/ glutamic acid
/ glutaminase
/ Glutaminase - metabolism
/ glutamine
/ Glutamine - metabolism
/ glutathione
/ Glutathione - metabolism
/ HCT116 cells
/ homeostasis
/ Humans
/ liver neoplasms
/ Metabolism
/ Mice
/ Mitochondria - metabolism
/ neoplasm cells
/ Oligonucleotide Array Sequence Analysis
/ Oxidation
/ Oxidative stress
/ Oxygen
/ Promoter Regions, Genetic
/ Reactive Oxygen Species
/ RNA Interference
/ small interfering RNA
/ Tumor Suppressor Protein p53 - metabolism
/ Tumors
2010
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Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species
Journal Article
Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species
2010
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Overview
We identified a p53 target gene, phosphate-activated mitochondrial glutaminase (GLS2), a key enzyme in conversion of glutamine to glutamate, and thereby a regulator of glutathione (GSH) synthesis and energy production. GLS2 expression is induced in response to DNA damage or oxidative stress in a p53-dependent manner, and p53 associates with the GLS2 promoter. Elevated GLS2 facilitates glutamine metabolism and lowers intracellular reactive oxygen species (ROS) levels, resulting in an overall decrease in DNA oxidation as determined by measurement of 8-OH-dG content in both normal and stressed cells. Further, siRNA down-regulation of either GLS2 or p53 compromises the GSH-dependent antioxidant system and increases intracellular ROS levels. High ROS levels following GLS2 knockdown also coincide with stimulation of p53-induced cell death. We propose that GLS2 control of intracellular ROS levels and the apoptotic response facilitates the ability of p53 to protect cells from accumulation of genomic damage and allows cells to survive after mild and repairable genotoxic stress. Indeed, overexpression of GLS2 reduces the growth of tumor cells and colony formation. Further, compared with normal tissue, GLS2 expression is reduced in liver tumors. Thus, our results provide evidence for a unique metabolic role for p53, linking glutamine metabolism, energy, and ROS homeostasis, which may contribute to p53 tumor suppressor function.
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