1. Induction of rapid IL-1 beta mRNA degradation in THP-1 cells mediated through the AU-rich region in the 3'UTR by a radicicol analogue.
- Author
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Kastelic T, Schnyder J, Leutwiler A, Traber R, Streit B, Niggli H, MacKenzie A, and Cheneval D
- Subjects
- Base Sequence, Cloning, Molecular, Cycloheximide pharmacology, Dactinomycin pharmacology, Enzyme-Linked Immunosorbent Assay, Humans, Interleukin-1 metabolism, Lactones pharmacology, Lipopolysaccharides pharmacology, Macrolides, Molecular Sequence Data, Polymerase Chain Reaction, Structure-Activity Relationship, Tumor Cells, Cultured, Interleukin-1 genetics, Lactones chemistry, RNA, Messenger metabolism
- Abstract
A radicicol analogue (analogue A) was found to inhibit interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha) secretion from THP-1 cells. If added to cells activated by interferon gamma and lipopolysaccharide, radicicol analogue A not only inhibited the secretion of IL-1 beta but also induced an extremely rapid degradation of IL-1 beta, IL-6 and TNF-alpha mRNA to undetectable levels within 5-8 h. This degradation is independent of translation and of the signal inducing transcription. The common feature of these genes is the inclusion of one or more copies of the mRNA-instability sequence, AUUUA, in the 3' untranslated region. Indeed, no destabilizing effect of radicicol analogue A could be observed on mRNA derived from the expression of an IL-1 beta construct lacking the AUUUA motifs of the 3'UTR. The effect of radicicol analogue A on protein/mRNA interaction and on post-translational modifications of cytoplasmic proteins is described. This class of compound constitutes a valuable tool for the further elucidation of the mechanism of mRNA degradation of cytokines and proto-oncogenes.
- Published
- 1996
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