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.
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.
Kastelic
T
T
Sandoz Research Institute, Berne, Switzerland.
Schnyder
J
J
Leutwiler
A
A
Traber
R
R
Streit
B
B
Niggli
H
H
MacKenzie
A
A
Cheneval
D
D
D001483:Base Sequence; D003001:Cloning, Molecular; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D018942:Macrolides; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D007783:Lactones; D008070:Lipopolysaccharides; D018942:Macrolides; D012333:RNA, Messenger; D003609:Dactinomycin; D003513:Cycloheximide; C035359:monorden