Akt-mediated regulation of NFκB and the essentialness of NFκB for the oncogenicity of PI3K and Akt

The serine/threonine kinase Akt (cellular homolog of murine thymoma virus akt8 oncogene), also known as PKB (protein kinase B), is activated by lipid products of phosphatidylinositol 3-kinase (PI3K). Akt phosphorylates numerous protein targets that control cell survival, proliferation and motility. Previous studies suggest that Akt regulates transcriptional activity of the nuclear factor-kappa B (NF kappa B) by inducing phosphorylation and subsequent degradation of inhibitor Of kappa B (I kappa B). We show here that NF kappa B-driven transcription increases in chicken embryonic fibroblasts (CEF) transformed by myristylated Akt (myrAkt). Accordingly, both a dominant negative mutant of Akt and Akt inhibitors repress NF kappa B-dependent transcription. The degradation of the I kappa B protein is strongly enhanced in Akt-transformed cells, and the loss of NF kappa B activity by introduction of a super-repressor of NF kappa B, I kappa BSR, interferes with PI3K- and Akt-induced oncogenic transformation of CEF. The phosphorylation of the p65 subunit of NF kappa B at serine 534 is also upregulated in Akt-transformed cells. Our data suggest that the stimulation of NF kappa B by Akt is dependent on the phosphorylation of p65 at S534, mediated by IKK (I kappa B kinase) a and P. Akt phosphorylates IKK alpha on T23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at S534 by IKKa and P. Our results demonstrate two separate functions of the IKK complex in NF kappa B activation in cells with constitutive Akt activity: the phosphorylation and consequent degradation of I kappa B and the phosphorylation of p65. The data further support the conclusion that NF kappa B activity is essential for PI3K- and Akt-induced oncogenic transformation. (C) 2009 UICC