Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators.

Abstract

Recently, cDNA sequences have been reported for both human and murine tumor necrosis factor (TNF; cachectin). The coding region of the TNF genes is highly conserved between man and mouse; 80% homology is apparent at the amino acid level. We now observe that a 33-nucleotide sequence, comprised entirely of A and T residues and located in the 3'-untranslated region, is conserved in toto in the murine and human TNF mRNAs. Since the 3'-untranslated region is normally not conserved, we reasoned that this sequence might play a regulatory role. We identified a consensus sequence (TTATTTAT) present in the 3'-untranslated region of both human and mouse TNF mRNAs, as well as the mRNAs encoding human lymphotoxin, human colony stimulating factor, human and mouse interleukin 1, human and rat fibronectin, and most of the sequenced human and mouse interferons. All of these mRNAs, except the lymphotoxin mRNA, lack homology to the TNF mRNAs in the coding region. The consensus sequence is uncommon among mammalian mRNAs in general, but it appears with a frequency greater than chance alone would dictate, suggesting that it may serve a specific regulatory function among the mRNAs in which it is found. It is particularly prevalent among mRNAs encoding proteins related to the inflammatory response.

Mechanisms of differential regulation of interleukin‐6 mRNA accumulation by tumor necrosis factor alpha and lymphotoxin during monocytic differentiation

“…Two AU-rich islands have been detected in its 3' untranslated region [4]. These se-quences largely contribute to the instability of the IL-6 mRNA [5] and have also been identified in many other cytokine genes or proto-oncogenes whose expression is transiently regulated by external stimuli [6]. Many different cell types such as monocytes, fibroblasts, keratinocytes, endothelial cells, T-cells and B-cells synthesize IL-6 either constitutively or following induction by a variety of stimuli [1].…”

Molecular characterization and expression profiles in response to bacterial infection of Chinese soft-shelled turtle interleukin-8 (IL-8), the first reptilian chemokine gene

“…Messenger RNAs containing AU-rich motifs have been shown to have reduced stability in comparison to those lacking AU-rich motifs. Some transiently expressed genes, such as inflammatory genes, often contain AU-rich sequences within the 3 0 -UTR of their mRNAs [22,23]. As shown in Fig.…”

Is there a future for TNF promoter polymorphisms?

“…Control at this point is important to the overall levels of TNF availability, but subsequent steps also play a significant role. The 3 0 UTR of the TNF gene contains a rapid decay motif 19 common to other cytokine genes, known as the AU-rich element (ARE), and results in rapid clearance of the mRNA transcript. Stabilization of transcripts is a major regulatory step.…”