Posttranscriptional Regulation by NF-κB

Abstract

Nuclear factor κB (NF-κB) is well known for its activity as a transcription factor that contributes to stimulation of gene expression in response to various stimuli, including infection and inflammation. One of the genes stimulated by NF-κB appears to be involved in controlling mRNA stability, thus conferring a posttranscriptional mechanism of NF-κB-mediated inhibition of gene expression. Sitcheran et al. describe an RNA sequence that confers NF-κB-mediated mRNA destabilization. MyoD and Sox9 are two transcriptional regulators that contribute to mesenchymal differentiation to muscle and cartilage, respectively. The mRNA for Sox9 was found to be decreased after treatment of chondrocytic cells with tumor necrosis factor-α (TNF-α), and this effect was blocked by overexpression of an NF-κB signaling superrepressor (IκBα-SR). In nuclear run-on assays with samples from TNF-α-treated or control C2C12 cells, MyoD transcription was not inhibited by TNF-α despite a decrease in MyoD mRNA. Deletion analysis of the MyoD RNA sequence allowed a minimal region required for NF-κB-mediated destabilization to be identified, and within that region, a multiply occurring ACUACAG was responsible for NF-κB-mediated destabilization. This repeated motif was also present in Sox9 and conferred NF-κB-mediated mRNA destabilization to a transcript not normally regulated by NF-κB. NF-κB transcriptional activity is required for MyoD inhibition; thus, the authors propose that NF-κB stimulates the expression of factors that control mRNA stability, which allows NF-κB signals to lead to decreased expression of genes. R. Sitcheran, P. C. Cogswell, A. S. Baldwin Jr., NF-κB mediates inhibition of mesenchymal cell differentation through a posttranscriptional gene silencing mechanism. Genes Dev. 17 , 2368-2373 (2003). [Abstract] [Full Text]