TIA-1 is a translational silencer that selectively regulates the expression of TNF-α
- 1 August 2000
- journal article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 19 (15), 4154-4163
- https://doi.org/10.1093/emboj/19.15.4154
Abstract
TIA‐1 and TIAR are related proteins that bind to an AU‐rich element (ARE) in the 3′ untranslated region of tumor necrosis factor alpha (TNF‐α) transcripts. To determine the functional significance of this interaction, we used homologous recombination to produce mutant mice lacking TIA‐1. Although lipopolysaccharide (LPS)‐stimulated macrophages derived from wild‐type and TIA‐1−/− mice express similar amounts of TNF‐α transcripts, macrophages lacking TIA‐1 produce significantly more TNF‐α protein than wild‐type controls. The half‐life of TNF‐α transcripts is similar in wild‐type and TIA‐1−/− macrophages, indicating that TIA‐1 does not regulate transcript stability. Rather, the absence of TIA‐1 significantly increases the proportion of TNF‐α transcripts that associate with polysomes, suggesting that TIA‐1 normally functions as a translational silencer. TIA‐1 does not appear to regulate the production of interleukin 1β, granulocyte–macrophage colony‐stimulating factor or interferon γ, indicating that its effects are, at least partially, transcript specific. Mice lacking TIA‐1 are hypersensitive to the toxic effects of LPS, indicating that this translational control pathway may regulate the organismal response to microbial stress.Keywords
This publication has 67 references indexed in Scilit:
- Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization directed by the AU-rich elementGenes & Development, 1999
- Impaired On/Off Regulation of TNF Biosynthesis in Mice Lacking TNF AU-Rich Elements: Implications for Joint and Gut-Associated ImmunopathologiesImmunity, 1999
- Binding of neuronal ELAV‐like proteins to the uridine‐rich sequence in the 3′‐untranslated region of tumor necrosis factor‐α messenger RNAFEBS Letters, 1999
- RNA stabilization by the AU-rich element binding protein, HuR, an ELAV proteinThe EMBO Journal, 1998
- Mapping of a Minimal AU-rich Sequence Required for Lipopolysaccharide-induced Binding of a 55-kDa Protein on Tumor Necrosis Factor-α mRNAPublished by Elsevier BV ,1998
- The Role of 3′ Poly(A) Tail Metabolism in Tumor Necrosis Factor-α RegulationJournal of Biological Chemistry, 1997
- Identification of HuR as a protein implicated in AUUUA-mediated mRNA decayThe EMBO Journal, 1997
- AUF1 Binding Affinity to A+U-rich Elements Correlates with Rapid mRNA DegradationPublished by Elsevier BV ,1996
- A Pathogenetic Role for TNFα in the Syndrome of Cachexia, Arthritis, and Autoimmunity Resulting from Tristetraprolin (TTP) DeficiencyImmunity, 1996
- Individual RNA Recognition Motifs of TIA-1 and TIAR Have Different RNA Binding SpecificitiesPublished by Elsevier BV ,1996