NF-kappaB stimulates Akt phosphorylation and gene expression by distinct signaling mechanisms.
While NF-kappaB may be a downstream target of Akt, Akt can also be regulated by NF-kappaB. Elevated expression of p65/RelA stimulates both phosphorylation and expression of Akt in NIH3T3 cells and primary endothelial cells. Both effects of p65 on Akt are blocked by transcriptional 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 signaling cascade leading to increased Akt phosphorylation. However, neither inhibition of PI-3 kinase or of PDK1 affected the ability of p65 to stimulate Akt expression, suggesting that distinct mechanisms underlie the two stimulatory effects of p65 on Akt. Increased Akt expression by p65 is mediated at the transcriptional level.
Department of Molecular and Cell Biology, University of Texas at Dallas, 2601 N. Floyd Road, Richardson, TX 75083, USA.
Fanyin
F
Meng
Santosh R
SR
D'Mello
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D015870:Gene Expression; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D064413:3-Phosphoinositide-Dependent Protein Kinases; D016328:NF-kappa B; D020319:Oligodeoxyribonucleotides, Antisense; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; C578564:Pdpk1 protein, mouse