Identification of novel mediators of NF-kappaB through genome-wide survey of monocyte adherence-induced genes.

Journal Article (Journal Article)

The transcription factor nuclear factor (NF)-kappaB controls the expression of genes involved in inflammation, cell proliferation, apoptosis, and differentiation. Impaired regulation of NF-kappaB has been associated with many diseases; thus, there is significant interest in therapeutic approaches based on modulation of this transcription factor. NF-kappaB activity is controlled by numerous signaling molecules, many of which are potentially to be identified. Monocytes are principal effectors of the immune system, and monocyte adherence is the first step leading to their activation and differentiation. Adherence induces activation of NF-kappaB, resulting in the induction of proinflammatory genes as well as anti-inflammatory genes, which counterbalance and limit the intensity and duration of NF-kappaB activation. Here, to identify novel mediators of NF-kappaB signaling, we used the model of monocyte adherence to perform a systematic, genome-wide survey of adherence-induced genes. Having isolated mRNAs from nonadherent and adherent primary human monocytes, we constructed suppressive subtraction hybridization libraries containing cDNAs, which were differentially regulated by adherence. Of 366 identified differentially expressed genes, most were found to be up-regulated by adherence. Having analyzed a subset of these genes, we found that the library was enriched with inhibitors of NF-kappaB. Three of those (an orphan nuclear receptor NUR77, a guanosine 5'-diphosphate/guanosine 5'-triphosphate exchange factor RABEX5, and a PRK1-associated protein AWP1) were particularly potent inhibitors of NF-kappaB activation. Thus, the collection of monocyte adherence-regulated genes represents a rich source for the identification of novel components of the machinery that controls NF-kappaB activation.

Full Text

Duke Authors

Cited Authors

  • Diatchenko, L; Romanov, S; Malinina, I; Clarke, J; Tchivilev, I; Li, X; Makarov, SS

Published Date

  • December 2005

Published In

Volume / Issue

  • 78 / 6

Start / End Page

  • 1366 - 1377

PubMed ID

  • 16204640

International Standard Serial Number (ISSN)

  • 0741-5400

Digital Object Identifier (DOI)

  • 10.1189/jlb.0405211

Language

  • eng

Conference Location

  • United States