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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 (HIF1?) 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.

SUBMITTER: Cheung EC

PROVIDER: S-EPMC3528527 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death.

Cheung Eric C EC Ludwig Robert L RL Vousden Karen H KH

Proceedings of the National Academy of Sciences of the United States of America 20121126 50

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 mito ...[more]

PMID: 23185017

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