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 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.
Barry
Robert E
RE
UCD School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Allan
Bernard B
BB
Cummins
Eoin P
EP
Kattla
Jayesh J
JJ
Giblin
Aoife
A
Scally
Niamh
N
Taylor
Cormac T
CT
Brazil
Derek P
DP
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013869:Thiolester Hydrolases; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D008565:Membrane Proteins; D000968:Antimycin A; D051057:Proto-Oncogene Proteins c-akt; C437985:THEM4 protein, human; D013869:Thiolester Hydrolases