Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappa B

Citation
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
Citations number
71
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Molecular Biology & Genetics
Journal title
MOLECULAR AND CELLULAR BIOLOGY
ISSN journal
0270-7306 → ACNP
Volume
20
Issue
5
Year of publication
2000
Pages
1626 - 1638
Database
ISI
SICI code
0270-7306(200003)20:5<1626:ASABST>2.0.ZU;2-3
Abstract
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.