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EMBO J ; 19(15): 4154-63, 2000 Aug 01.
Article in English | MEDLINE | ID: mdl-10921895

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-alpha) 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-alpha transcripts, macrophages lacking TIA-1 produce significantly more TNF-alpha protein than wild-type controls. The half-life of TNF-alpha 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-alpha 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 1 beta, granulocyte-macrophage colony-stimulating factor or interferon gamma, 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.


Subject(s)
Membrane Proteins/metabolism , Protein Biosynthesis , Proteins , RNA-Binding Proteins/metabolism , Tumor Necrosis Factor-alpha/genetics , 3' Untranslated Regions , Animals , Cytokines/biosynthesis , Gene Expression Regulation , Macrophages, Peritoneal/immunology , Membrane Proteins/genetics , Mice , Mice, Mutant Strains , RNA-Binding Proteins/genetics , Shock, Septic/mortality , T-Cell Intracellular Antigen-1
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