Enhanced sensitivity of protein kinase B/Akt to insulin in hypoxia is independent of HIF1alpha and promotes cell viability

Maintenance of oxygen homeostasis is a key requirement to ensure normal mammalian cell growth and differentiation. Hypoxia arises when oxygen demand exceeds supply, and is a feature of multiple human diseases including stroke, cancer and renal fibrosis. We have investigated the effect of hypoxia on...

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Bibliographic Details
Published in:European journal of cell biology 2007-07, Vol.86 (7), p.393-403
Main Authors: Barry, Robert E, Allan, Bernard B, Cummins, Eoin P, Kattla, Jayesh J, Giblin, Aoife, Scally, Niamh, Taylor, Cormac T, Brazil, Derek P
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Animals
Antimycin A - pharmacology
Cell Hypoxia - drug effects
Cell Survival - drug effects
Cells, Cultured
Enzyme Activation - drug effects
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Insulin - pharmacology
Membrane Proteins - metabolism
Mitochondria - drug effects
Mitochondria - metabolism
Phosphorylation - drug effects
Proto-Oncogene Proteins c-akt - metabolism
Rats
Signal Transduction - drug effects
Thiolester Hydrolases
Time Factors
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Summary:Maintenance of oxygen homeostasis is a key requirement to ensure normal mammalian cell growth and differentiation. Hypoxia arises when oxygen demand exceeds supply, and is a feature of multiple human diseases including stroke, cancer and renal fibrosis. We have investigated the effect of hypoxia on kidney cells, and observed that insulin-induced cell viability is increased in hypoxia. We have characterized the role of protein kinase B (PKB/Akt) in these cells as a potential mediator of this effect. PKB/Akt activity was increased by low oxygen concentrations in kidney cells, and insulin-stimulated activation of PKB/Akt was stronger, more rapid and more sustained in hypoxia. Reduction of HIF1alpha levels using antimycin-A or siRNA targeting HIF1alpha did not affect PKB/Akt activation in hypoxia. Pharmacologic stabilization of HIF1alpha independent of hypoxia did not increase insulin-stimulated PKB/Akt activation. Although increased insulin-stimulated cell viability was observed in hypoxia, no differences in the degree of insulin-stimulated glucose uptake were observed in L6 muscle cells in hypoxia compared to normoxia. Thus, PKB/Akt may regulate specific cellular responses to growth factors such as insulin under adverse conditions such as hypoxia.
ISSN:0171-9335