Mice Lacking Thioredoxin-interacting Protein Provide Evidence Linking Cellular Redox State to Appropriate Response to Nutritional Signals

Hui, To Y.; Sheth, Sonal S.; Diffley, J. Matthew; Potter, D. W.; Lusis, Aldons J.; Attie, Alan D.; Davis, Roger J.

doi:10.1074/jbc.m401280200

Cited by 117 publications

(137 citation statements)

References 57 publications

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“…A similar regulatory network could also regulate carbon utilization in other organisms, where thioredoxins are involved in regulating mitochondrial respiration (15). Recently, a thioredoxin-interacting protein has been identified in mammals that inhibits thioredoxin-mediated redox transfer from NADPH to sulfhydryl groups and affects the metabolic response to feeding and nutritional signals (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Trehalose 6-phosphate regulates starch synthesis via posttranslational redox activation of ADP-glucose pyrophosphorylase

Kolbe

Tiessen

Schluepmann³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

351

320

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Trehalose is the most widespread disaccharide in nature, occurring in bacteria, fungi, insects, and plants. Its precursor, trehalose 6-phosphate (T6P), is also indispensable for the regulation of sugar utilization and growth, but the sites of action are largely unresolved. Here we use genetic and biochemical approaches to investigate whether T6P acts to regulate starch synthesis in plastids of higher plants. Feeding of trehalose to Arabidopsis leaves led to stimulation of starch synthesis within 30 min, accompanied by activation of ADP-glucose pyrophosphorylase (AGPase) via posttranslational redox modification. The response resembled sucrose but not glucose feeding and depended on the expression of SNF1-related kinase. We also analyzed transgenic Arabidopsis plants with T6P levels increased by expression of T6P synthase or decreased by expression of T6P phosphatase (TPP) in the cytosol. Compared with wild type, leaves of T6P synthase-expressing plants had increased redox activation of AGPase and increased starch, whereas TPP-expressing plants showed the opposite. Moreover, TPP expression prevented the increase in AGPase activation in response to sucrose or trehalose feeding. Incubation of intact isolated chloroplasts with 100 M T6P significantly and specifically increased reductive activation of AGPase within 15 min. Results provide evidence that T6P is synthesized in the cytosol and acts on plastidial metabolism by promoting thioredoxin-mediated redox transfer to AGPase in response to cytosolic sugar levels, thereby allowing starch synthesis to be regulated independently of light. The discovery informs about the evolution of plant metabolism and how chloroplasts of prokaryotic origin use an intermediate of the ancient trehalose pathway to report the metabolic status of the cytosol.SNF1 kinase ͉ sugar signaling ͉ thioredoxin S tarch is the major carbon store in plants consisting of an insoluble polymer of ␣-1,4-and ␣-1,6-linked glucose units (1). In the chloroplast of leaves, starch is synthesized during the day as a transient store, which is degraded during the night to support nonphotosynthetic leaf metabolism and sucrose export. In heterotrophic storage organs such as potato tubers, most of the incoming sucrose is converted to starch as a long-term carbon store for reproductive growth. In addition to its central role in carbon metabolism of plants, starch is also of great economical importance and is used for food and feed purposes and many industrial applications (2).ADP-glucose pyrophosphorylase (AGPase) catalyzes the first committed step of starch synthesis in the plastid, converting glucose 1-phosphate and ATP to ADP-glucose and PP i . ADP-glucose is subsequently used by starch synthases and branching enzymes to elongate the glucan chains of the starch granule. AGPase is a heterotetramer that contains two large (AGPS, 51 kDa) and two slightly smaller subunits (AGPB, 50 kDa) (3, 4). Work with Arabidopsis mutants (5) and potato tubers (6) showed that the enzyme catalyzes a near rate-limiting step in the pat...

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Section: Discussionmentioning

confidence: 99%

Trehalose 6-phosphate regulates starch synthesis via posttranslational redox activation of ADP-glucose pyrophosphorylase

Kolbe

Tiessen

Schluepmann³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

351

320

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“…48 In the present study of renal carcinogenesis, loss of TBP-2 protein was induced only in a certain fraction of the renal tubular cells after Fe-NTA treatment and in the cancer cells (Figure 2e and f). Loss of TBP-2 appears advantageous in cancer cells because it results in facilitation of the glycolytic pathway 47 in addition to the promotion of cellular proliferation since hypoxia is often associated with tumor growth. In a yeast two-hybrid screening using TBP-2 as bait, several clones encoding Trx2 were identified, demonstrating the interaction of TBP-2 with Trx2 in vitro (Wang D, Masutani H and Yodoi J, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…47 On the other hand, it was shown that hyperglycemia inhibits the ROS-scavenging function of Trx through p38 MAPK-induction of TBP-2. 48 In the present study of renal carcinogenesis, loss of TBP-2 protein was induced only in a certain fraction of the renal tubular cells after Fe-NTA treatment and in the cancer cells (Figure 2e and f).…”

Section: Discussionmentioning

confidence: 99%

Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis

Dutta

Nishinaka

Masutani

et al. 2005

Laboratory Investigation

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Thioredoxin is a major component of thiol-reducing system. Recently, we identified thioredoxin-binding protein-2 (TBP-2) as a negative regulator of thioredoxin. Here, we report the role of TBP-2 in oxidative renal tubular injury and the subsequent carcinogenesis by ferric nitrilotriacetate. TBP-2 was abundantly expressed in the rat kidney. Immunohistochemical analysis revealed that TBP-2 was present in association with nuclei and mitochondrial intermembrane space in the proximal tubular cells and coimmunoprecipitated with cytochrome c. After acute oxidative tubular damage, TBP-2 protein, but not messenger RNA, markedly decreased, demonstrating shortened half-life of this protein. Most cases of the induced renal cell carcinoma showed undetectable levels of TBP-2 protein, which was associated with the methylation of CpG island in the promoter region. Genome sequence analyses identified the poly-A tract in the 3 0 untranslated region as a mutation hot spot in this rather nonselective environment. Collectively, the amounts of TBP-2 protein were inversely associated with proliferation of tubular cells, as evaluated by proliferating cell nuclear antigen. These results suggest that loss of TBP-2 is essential for proliferation of not only neoplastic but also non-neoplastic renal tubular cells, and that TBP-2 is a target gene in oxidative stress-induced renal carcinogenesis by ferric nitrilotriacetate.

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“…Txnip was first identified as the gene at the murine Hyplip1 locus responsible for ketosis and hyperlipidemia (11). Because of a nonsense mutation in Txnip, Hyplip-1 mice do not express any functionally active Txnip protein (11) and become markedly hypertriglyceridemic and hypoglycemic when subjected to prolonged fasting (12). In nonlipogenic, oxidative tissue (i.e., skeletal muscle and hearts), Txnip deficiency impairs the ability of thioredoxin NADP(H)-dependent disulfide reduction to maintain PTEN in a sufficiently active state to oppose Akt downstream signaling.…”

mentioning

confidence: 99%

Txnip balances metabolic and growth signaling via PTEN disulfide reduction

Hui

Andres

Miller

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

194

225

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Thioredoxin-interacting protein (Txnip) inhibits thioredoxin NADPH-dependent reduction of protein disulfides. Total Txnip knockout (TKO) mice adapted inappropriately to prolonged fasting by shifting fuel dependence of skeletal muscle and heart from fat and ketone bodies to glucose. TKO mice exhibited increased Akt signaling, insulin sensitivity, and glycolysis in oxidative tissues (skeletal muscle and hearts) but not in lipogenic tissues (liver and adipose tissue). The selective activation of Akt in skeletal muscle and hearts was associated with impaired mitochondrial fuel oxidation and the accumulation of oxidized (inactive) PTEN, whose activity depends on reduction of two critical cysteine residues. Whereas muscle-and heart-specific Txnip knockout mice recapitulated the metabolic phenotype exhibited by TKO mice, liverspecific Txnip knockout mice were similar to WT mice. Embryonic fibroblasts derived from knockout mice also accumulated oxidized (inactive) PTEN and had elevated Akt phosphorylation. In addition, they had faster growth rates and increased dependence on anaerobic glycolysis due to impaired mitochondrial fuel oxidation, and they were resistant to doxorubicin-facilitated respiration-dependent apoptosis. In the absence of Txnip, oxidative inactivation of PTEN and subsequent activation of Akt attenuated mitochondrial respiration, resulting in the accumulation of NADH, a competitive inhibitor of thioredoxin NADPH-reductive activation of PTEN. These findings indicate that, in nonlipogenic tissues, Txnip is required to maintain sufficient thioredoxin NADPH activity to reductively reactivate oxidized PTEN and oppose Akt downstream signaling.mitochondrial respiration ͉ redox

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Mice Lacking Thioredoxin-interacting Protein Provide Evidence Linking Cellular Redox State to Appropriate Response to Nutritional Signals

Cited by 117 publications

References 57 publications

Trehalose 6-phosphate regulates starch synthesis via posttranslational redox activation of ADP-glucose pyrophosphorylase

Trehalose 6-phosphate regulates starch synthesis via posttranslational redox activation of ADP-glucose pyrophosphorylase

Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis

Txnip balances metabolic and growth signaling via PTEN disulfide reduction

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