title: Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death.
abstract: The p53-inducible protein TIGAR (Tp53-induced Glycolysis and Apoptosis Regulator) functions as a fructose-2,6-bisphosphatase (Fru-2,6-BPase), and through promotion of the pentose phosphate pathway, increases NADPH production to help limit reactive oxygen species (ROS). Here, we show that under hypoxia, a fraction of TIGAR protein relocalized to mitochondria and formed a complex with hexokinase 2 (HK2), resulting in an increase in HK2 activity. Mitochondrial localization of TIGAR depended on mitochondrial HK2 and hypoxia-inducible factor 1 (HIF1α) activity. The ability of TIGAR to function as a Fru-2,6-BPase was independent of HK2 binding and mitochondrial localization, although both of these activities can contribute to the full activity of TIGAR in limiting mitochondrial ROS levels and protecting from cell death.
authors.affiliation: The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD,  United Kingdom.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Cheung
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ludwig
authors.forename: Karen H
authors.initials: KH
authors.lastname: Vousden
mesh_terms: D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D018938:Caco-2 Cells; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D006019:Glycolysis; D006367:HeLa Cells; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010427:Pentose Phosphate Pathway; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006593:Hexokinase; D025481:Phosphofructokinase-2; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human