Tumour necrosis factor (TNF)-α mRNA contains an AU-rich element (ARE) in its 3′ untranslated region (3′UTR), which determines its half-life and translational efficiency. In unstimulated macrophages, TNF-α mRNA is repressed translationally, and becomes efficiently translated upon cell activation. Gel retardation experiments and screening of a macrophage cDNA expression library with the TNF-α ARE allowed the identification of TIA-1-related protein (TIAR), T-cell intracellular antigen-1 (TIA-1) and tristetraprolin (TTP) as TNF-α ARE-binding proteins. Whereas TIAR and TIA-1 bind the TNF-α ARE independently of the activation state of macrophages, the TTP-ARE complex is detectable upon stimulation with lipopolysaccharide (LPS). Moreover, treatment of LPS-induced macrophage extracts with phosphatase significantly abrogates TTP binding to the TNF-α ARE, indicating that TTP phosphorylation is required for ARE binding. Carballo, Lai and Blackshear [(1998) Science 281, 1001–1005] showed that TTP was a TNF-α mRNA destabilizer. In contrast, TIA-1, and most probably TIAR, acts as a TNF-α mRNA translational silencer. A two-hybrid screening with TIAR and TIA-1 revealed the capacity of these proteins to interact with other RNA-binding proteins. Interestingly, TIAR and TIA-1 are not engaged in the same interaction, indicating for the first time that TIAR and TIA-1 can be functionally distinct. These findings also suggest that ARE-binding proteins interact with RNA as multimeric complexes, which might define their function and their sequence specificity.
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Conference Article|
November 01 2002
AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors
T. Zhang;
T. Zhang
1Laboratory of Biological Chemistry, Institute of Molecular Biology and Medicine, Free University of Brussels, 12 rue des Profs Jeener et Brachet, 6041 Gosselies, Belgium
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V. Kruys;
V. Kruys
1Laboratory of Biological Chemistry, Institute of Molecular Biology and Medicine, Free University of Brussels, 12 rue des Profs Jeener et Brachet, 6041 Gosselies, Belgium
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G. Huez;
G. Huez
1Laboratory of Biological Chemistry, Institute of Molecular Biology and Medicine, Free University of Brussels, 12 rue des Profs Jeener et Brachet, 6041 Gosselies, Belgium
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C. Gueydan
C. Gueydan
1
1Laboratory of Biological Chemistry, Institute of Molecular Biology and Medicine, Free University of Brussels, 12 rue des Profs Jeener et Brachet, 6041 Gosselies, Belgium
1To whom correspondence should be addressed (e-mail cgueydan@ulb.ac.be)
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Publisher: Portland Press Ltd
Received:
June 19 2002
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2002 Biochemical Society
2002
Biochem Soc Trans (2002) 30 (6): 952–958.
Article history
Received:
June 19 2002
Citation
T. Zhang, V. Kruys, G. Huez, C. Gueydan; AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors. Biochem Soc Trans 1 November 2002; 30 (6): 952–958. doi: https://doi.org/10.1042/bst0300952
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