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PMID:15574336

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Citation

Majewski, N, Nogueira, V, Bhaskar, P, Coy, PE, Skeen, JE, Gottlob, K, Chandel, NS, Thompson, CB, Robey, RB and Hay, N (2004) Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell 16:819-30

Abstract

The serine/threonine kinase Akt inhibits mitochondrial cytochrome c release and apoptosis induced by a variety of proapoptotic stimuli. The antiapoptotic activity of Akt is coupled, at least in part, to its effects on cellular metabolism. Here, we provide genetic evidence that Akt is required to maintain hexokinase association with mitochondria. Targeted disruption of this association impairs the ability of growth factors and Akt to inhibit cytochrome c release and apoptosis. Targeted disruption of mitochondria-hexokinase (HK) interaction or exposure to proapoptotic stimuli that promote rapid dissociation of hexokinase from mitochondria potently induce cytochrome c release and apoptosis, even in the absence of Bax and Bak. These effects are inhibited by activated Akt, but not by Bcl-2, implying that changes in outer mitochondrial membrane (OMM) permeability leading to apoptosis can occur in the absence of Bax and Bak and that Akt inhibits these changes through maintenance of hexokinase association with mitochondria.

Links

PubMed Online version:10.1016/j.molcel.2004.11.014

Keywords

Animals; Apoptosis; Binding, Competitive; Cell Line; Cell Proliferation; Cells, Cultured; Clotrimazole/pharmacology; Cytochromes c/metabolism; Dose-Response Relationship, Drug; Fibroblasts/metabolism; Gene Transfer Techniques; Growth Inhibitors/pharmacology; Growth Substances/metabolism; Hexokinase/chemistry; Immunoblotting; In Situ Nick-End Labeling; Intracellular Membranes/metabolism; Membrane Potentials; Mice; Microscopy, Fluorescence; Mitochondria/metabolism; Phosphocreatine/metabolism; Protein Binding; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2/metabolism; Rats; Thapsigargin/pharmacology; Time Factors; Ultraviolet Rays

Significance

Annotations

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

RAT:HXK1

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:HXK1

enables

GO:0016887: ATP hydrolysis activity

ECO:0000305: curator inference used in manual assertion

GO:0004396

F

Seeded From UniProt

complete

RAT:HXK1

enables

GO:0004340: glucokinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:HXK1

enables

GO:0005536: glucose binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:HXK1

part_of

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:HXK1

enables

GO:0005524: ATP binding

ECO:0000305: curator inference used in manual assertion

GO:0004396

F

Seeded From UniProt

complete

RAT:HXK1

involved_in

GO:0006096: glycolytic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:HXK1

enables

GO:0016887: ATPase activity

ECO:0000305: curator inference used in manual assertion

GO:0004396

F

Seeded From UniProt

complete

RAT:HXK1

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:HXK1

involved_in

GO:0046835: carbohydrate phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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