GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:23564345

From GONUTS
Jump to: navigation, search
Citation

Yoshida, S, Tsutsumi, S, Muhlebach, G, Sourbier, C, Lee, MJ, Lee, S, Vartholomaiou, E, Tatokoro, M, Beebe, K, Miyajima, N, Mohney, RP, Chen, Y, Hasumi, H, Xu, W, Fukushima, H, Nakamura, K, Koga, F, Kihara, K, Trepel, J, Picard, D and Neckers, L (2013) Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis. Proc. Natl. Acad. Sci. U.S.A. 110:E1604-12

Abstract

TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidation, and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial molecular chaperone may act as a tumor suppressor.

Links

PubMed PMC3637790 Online version:10.1073/pnas.1220659110

Keywords

Animals; COS Cells; Cercopithecus aethiops; Glycolysis; HSP90 Heat-Shock Proteins; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Mice; Mice, Knockout; Mitochondria/metabolism; Mitochondrial Proteins/genetics; Mitochondrial Proteins/metabolism; Molecular Chaperones/genetics; Molecular Chaperones/metabolism; NIH 3T3 Cells; Neoplasm Invasiveness/genetics; Oxidative Phosphorylation; RNA Interference; Transfection; src-Family Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SRC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q12931

F

Seeded From UniProt

complete

HUMAN:TRAP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12931

F

Seeded From UniProt

complete

HUMAN:TRAP1

located_in

GO:0005759: mitochondrial matrix

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TRAP1

located_in

GO:0005743: mitochondrial inner membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TRAP1

part_of

GO:0005743: mitochondrial inner membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TRAP1

part_of

GO:0005759: mitochondrial matrix

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TRAP1

involved_in

GO:1901856: negative regulation of cellular respiration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

See Help:References for how to manage references in GONUTS.