AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors.
Tumour necrosis factor (TNF)-alpha 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-alpha 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-alpha ARE allowed the identification of TIA-1-related protein (TIAR), T-cell intracellular antigen-1 (TIA-1) and tristetraprolin (TTP) as TNF-alpha ARE-binding proteins. Whereas TIAR and TIA-1 bind the TNF-alpha 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-alpha 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-alpha mRNA destabilizer. In contrast, TIA-1, and most probably TIAR, acts as a TNF-alpha 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.
Zhang
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Laboratory of Biological Chemistry, Institute of Molecular Biology and Medicine, Free University of Brussels, 12 rue des Profs Jeener et Brachet, 6041 Gosselies, Belgium.
Kruys
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V
Huez
G
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Gueydan
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C
D020413:3' Untranslated Regions; D000818:Animals; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D017874:Immediate-Early Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D014176:Protein Biosynthesis; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse