Akt fine-tunes NF-?B-dependent gene expression during T cell activation.

ABSTRACT: Activation of the NF-?B signaling pathway is critical for leukocyte activation and development. Although previous studies suggested a role for the Akt kinase in coupling the T cell antigen receptor and CD28 to NF-?B activation in T cells, the nature of the role of Akt in this pathway is still unclear. Using a targeted gene profiling approach, we found that a subset of NF-?B-dependent genes required Akt for optimal up-regulation during T cell activation. The selective effects of Akt were manifest at the level of mRNA transcription and p65/RelA binding to upstream promoters and appear to be due to altered formation of the Carma1-Bcl10 complex. The proinflammatory cytokine TNF-? was found to be particularly sensitive to Akt inhibition or knockdown, including in primary human blood T cells and a murine model of rheumatoid arthritis. Our findings are consistent with a hierarchy in the expression of NF-?B-dependent genes, controlled by the strength and/or duration of NF-?B signaling. More broadly, our results suggest that defining the more graded effects of signaling, such as those demonstrated here for Akt and the NF-?B pathway, is important to understanding how cells can fine-tune signaling responses for optimal sensitivity and specificity.

SUBMITTER: Cheng J 

PROVIDER: S-EPMC3195567 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature