Rapid activation of protein kinase B/Akt has a key role in antiapoptotic signaling during liver regeneration.
Liver regeneration is controlled by multiple signaling pathways induced by a variety of growth factors, hormones, and cytokines. Here we report that protein kinase B (PKB)/Akt, part of a key cell survival signaling pathway, is markedly activated after partial hepatectomy (PHX). The antiapoptotic protein Bad, a downstream target of PKB/Akt, is also phosphorylated. This cascade can be activated by various factors in primary hepatocytes, with the strongest activation by insulin and the alpha1-adrenergic agonist phenylephrine (PE), followed by IL-6, epidermal growth factor (EGF), and hepatocyte growth factor (HGF). Pretreatment of cells with the specific PI3 kinase inhibitor LY294002 abolished insulin- or PE-activation of PKB/Akt, suggesting that activation of PKB/Akt is mediated by a PI3 kinase-dependent mechanism. In vivo administration of PE, insulin, IL-6, HGF, or EGF to mice markedly stimulated PKB/Akt in the liver, with the strongest stimulation induced by insulin and PE. Moreover, HGF and insulin were able to attenuate transforming growth factor beta-induced apoptosis in hepatic cells, and these effects were antagonized by LY294002. Taken together, these findings suggest that rapid activation of PKB/Akt is a key antiapoptotic signaling pathway involved in liver regeneration.
Hong
F
F
Section on Liver Biology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892, USA.
Nguyen
V A
VA
Shen
X
X
Kunos
G
G
Gao
B
B
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D004789:Enzyme Activation; D006498:Hepatectomy; D022781:Hepatocytes / Q000201:enzymology* / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D011518:Proto-Oncogene Proteins; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt