Meng Fanyin, D'Mello Santosh R
Department of Molecular and Cell Biology, University of Texas at Dallas, 2601 N. Floyd Road, Richardson, TX 75083, USA.
Biochim Biophys Acta. 2003 Oct 20;1630(1):35-40. doi: 10.1016/j.bbaexp.2003.09.001.
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.
虽然核因子-κB（NF-κB）可能是Akt的下游靶点，但Akt也可受NF-κB调控。p65/RelA的表达升高可刺激NIH3T3细胞和原代内皮细胞中Akt的磷酸化及表达。p65对Akt的这两种作用均被转录和翻译抑制剂阻断，提示需要新的基因表达。p65表达升高导致磷脂酰肌醇-3激酶（PI-3激酶）和丙酮酸脱氢酶激酶1（PDK1）激活。用反义PDK1寡核苷酸处理可降低PDK1表达，并抑制p65对Akt磷酸化的刺激作用。PI-3激酶的药理学抑制可阻断p65对PDK1和Akt的磷酸化，在导致Akt磷酸化增加的信号级联反应中，将PI-3激酶置于PDK1的上游。然而，抑制PI-3激酶或PDK1均不影响p65刺激Akt表达的能力，提示p65对Akt的两种刺激作用存在不同机制。p65增加Akt表达是在转录水平介导的。
