Lv. Madrid et al., Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappa B, MOL CELL B, 20(5), 2000, pp. 1626-1638
It is well established that cell survival signals stimulated by growth fact
ors, cytokines, and oncoproteins are initiated by phosphoinositide 3-kinase
(PI3K)- and Akt-dependent signal transduction pathways. Oncogenic Ras, an
upstream activator of Akt, requires NF-kappa B to initiate transformation,
at least partially through the ability of NF-kappa B to suppress transforma
tion-associated apoptosis. In this study, we show that oncogenic H-Ras requ
ires PI3K and Akt to stimulate the transcriptional activity of NF-kappa B.
Activated forms of H-Ras and MEKK stimulate signals that result in nuclear
translocation and DNA binding of NF-kappa B as well as stimulation of the N
F-kappa B transactivation potential. In contrast, activated PI3K or Akt sti
mulates NF-kappa B-dependent transcription by stimulating transactivation d
omain 1 of the p65 subunit rather than inducing NF-kappa B nuclear transloc
ation via I kappa B degradation. Inhibition of I kappa B kinase (IKK), usin
g an IKK beta dominant negative protein, demonstrated that activated Akt re
quires IKK to efficiently stimulate the transactivation domain of the p65 s
ubunit of NF-kappa B. Inhibition of endogenous Akt activity sensitized cell
s to H-Ras(V12)-induced apoptosis, which was associated with a loss of NF-k
appa B transcriptional activity. Finally, Akt-transformed cells were shown
to require NF-kappa B to suppress the ability of etoposide to induce apopto
sis. Our work demonstrates that, unlike activated Ras, which can stimulate
parallel pathways to activate both DNA binding and the transcriptional acti
vity of NF-kappa B, Akt stimulates NF-kappa B predominantly by upregulating
of the transactivation potential of p65.