Akt Stimulates the Transactivation Potential of the RelA/p65 Subunit of NF-κB through Utilization of the IκB Kinase and Activation of the Mitogen-activated Protein Kinase p38

Abstract

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-κB and that this functions to block apoptosis induced by certain stimuli. The mechanism whereby Akt activates NF-κB has been controversial, with evidence supporting induction of nuclear translocation of NF-κB via activation of IκB kinase activity and/or the stimulation of the transcription function of NF-κB. Here we demonstrate that Akt targets the transactivation function of NF-κB by stimulating the transactivation domain of RelA/p65 in a manner that is dependent on IκB kinase β 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-κB transcriptional function, expression of activated Akt induces p38 activity. Furthermore, the ability of IL-1β to activate NF-κB is known to involve Akt, and we show here that IL-1β induces p38 activity in manner dependent on Akt and IκB kinase activation. Interestingly, activated Akt and the transcriptional coactivators 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 IκB kinase and p38, induces the transcription function of NF-κB by stimulating the RelA/p65 transactivation subunit of NF-κB.