NF-κB stimulates Akt phosphorylation and gene expression by distinct signaling mechanisms

摘要

While NF-κB may be a donwstream of Akt, Akt can also be regulated by NF-κB. Elevated expression of p65/RelA stimulates both phosphorylation and expression of Akt in NIH3T3 cells and primary endothelial cells. Booth effects of p65 on Akt are blocked by transcripational and translational inhibitors, suggesting the need for new gene expression. Elevated p65 expression leads to an activation of PI-3 kinase and PDK1. Treatment with antisense PDK1 oligonucleotides reduces PDK1 expression and inhibits the stimulation of Akt phosphorylation by p65. Pharmacological inhibition of PI-3 kinase blocks both PDK1 and Akt phosphorylation by p65, placing PI-3 kinase upstream of PDK1 in the singaling cascade leading to incrased Akt phosphorylation. However, neither inhibition of PI-3 kinase or of PDK1 affected the ability of p65 to stimulate Akt expression, sugesting that distinct mechanisms underlie the two stimulatory effects of p65 on Akt. Incresaed Akt expression by p65 is mediated at the transcriptional level.