Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38.
The serine/threonine kinase Akt/PKB is a potent regulator of cell survival and has oncogenic transformation potential. Previously, it has been shown that Akt can activate the transcription factor NF-kappaB and that this functions to block apoptosis induced by certain stimuli. The mechanism whereby Akt activates NF-kappaB has been controversial, with evidence supporting induction of nuclear translocation of NF-kappaB via activation of IkappaB kinase activity and/or the stimulation of the transcription function of NF-kappaB. Here we demonstrate that Akt targets the transactivation function of NF-kappaB by stimulating the transactivation domain of RelA/p65 in a manner that is dependent on IkappaB kinase beta activity and on the mitogen-activated protein kinase p38 (p38). Activation of RelA/p65 transactivation function requires serines 529 and 536, sites shown previously to be inducibly phosphorylated. Consistent with the requirement of p38 in the activation of NF-kappaB transcriptional function, expression of activated Akt induces p38 activity. Furthermore, the ability of IL-1beta to activate NF-kappaB is known to involve Akt, and we show here that IL-1beta induces p38 activity in manner dependent on Akt and IkappaB kinase activation. Interestingly, activated Akt and the transcriptional co-activators CBP/p300 synergize in the activation of the RelA/p65 transactivation domain, and this synergy is blocked by p38 inhibitors. These studies demonstrate that Akt, functioning through IkappaB kinase and p38, induces the transcription function of NF-kappaB by stimulating the RelA/p65 transactivation subunit of NF-kappaB.
Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, Department of Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
L V
LV
Madrid
M W
MW
Mayo
J Y
JY
Reuther
A S
AS
Baldwin
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D050881:E1A-Associated p300 Protein; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015534:Trans-Activators / Q000378:metabolism; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D016328:NF-kappa B; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051996:Transcription Factor RelA; D008156:Luciferases; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases