title: Akt fine-tunes NF-κB-dependent gene expression during T cell activation.
abstract: Activation of the NF-κB 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-κB 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-κB-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-α 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-κB-dependent genes, controlled by the strength and/or duration of NF-κB signaling. More broadly, our results suggest that defining the more graded effects of signaling, such as those demonstrated here for Akt and the NF-κB pathway, is important to understanding how cells can fine-tune signaling responses for optimal sensitivity and specificity.
authors.affiliation: Dept. of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Dept. of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
authors.forename: Binh
authors.initials: B
authors.lastname: Phong
authors.affiliation: Division of Rheumatology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224.
authors.forename: David C
authors.initials: DC
authors.lastname: Wilson
authors.affiliation: Division of Rheumatology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224.
authors.forename: Raphael
authors.initials: R
authors.lastname: Hirsch
authors.affiliation: Dept. of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261. Electronic address: lkane@pitt.edu.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kane
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; C498143:RELA protein, human; D051996:Transcription Factor RelA; D051057:Proto-Oncogene Proteins c-akt; C426242:CARD11 protein, human; D006162:Guanylate Cyclase