Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-kappa B through utilization of the I kappa B kinase and activation of the mitogen-activated protein kinase p38
Lv. Madrid et al., Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-kappa B through utilization of the I kappa B kinase and activation of the mitogen-activated protein kinase p38, J BIOL CHEM, 276(22), 2001, pp. 18934-18940
The serine/threonine kinase Akt/PKB is a potent regulator of cell survival
and has oncogenic transformation potential. Previously, it has been shown t
hat Akt can activate the transcription factor NF-kappaB and that this funct
ions to block apoptosis induced by certain stimuli. The mechanism whereby A
kt activates NF-kappaB has been controversial, with evidence supporting ind
uction of nuclear translocation of NF-kappaB via activation of I kappaB kin
ase activity and/or the stimulation of the transcription function of NF-kap
paB. Here we demonstrate that Akt targets the transactivation function of N
F-kappaB by stimulating the transactivation domain of RelA/p65 in a manner
that is dependent on I kappaB kinase beta activity and on the mitogen-activ
ated protein kinase p38 (p38), Activation of RelA/ p65 transactivation func
tion requires serines 529 and 536, sites shown previously to be inducibly p
hosphorylated. 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-I beta to activate NF-kappaB is k
nown to involve Akt, and we show here that IL-1 beta induces p38 activity i
n manner dependent on Akt and I kappaB kinase activation. Interestingly, ac
tivated Akt and the transcriptional coactivators CBP/p300 synergize in the
activation of the RelA/p65 transactivation domain, and this synergy is bloc
ked by p38 inhibitors. These studies demonstrate that Akt, functioning thro
ugh I kappaB kinase and p38, induces the transcription function of NF-kappa
B by stimulating the RelA/p65 transactivation subunit of NF-kappaB.