Cyclosporin A promotes translational silencing of autocrine interleukin-3 via ribosome-associated deadenylation.
Translation is regulated predominantly by an interplay between cis elements at the 3' and 5' ends of mRNAs and trans-acting proteins. Cyclosporin A (CsA), a calcineurin antagonist and blocker of interleukin-2 (IL-2) transcription in T cells, was found to inhibit translation of IL-3 mRNA in autocrine mast cell tumor lines. The mechanism involved ribosome-associated poly(A) shortening and required an intact AU-rich element in the 3' untranslated region. FK506, another calcineurin inhibitor, shared the effect. The translational inhibition by CsA was specific to oncogenically induced lymphokines IL-3 and IL-4 but not to IL-6, c-jun, and c-myc, which are expressed in the nonmalignant precursor cells. Furthermore, no translational down-regulation of the mRNA was observed in IL-3-transfected precursor cells. These data suggest that translational silencing is associated with the tumor phenotype.
Nair
A P
AP
Institute for Medical Microbiology, University of Basel, Basel, Switzerland.
Hirsch
H H
HH
Colombi
M
M
Moroni
C
C
D000818:Animals; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D015536:Down-Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007377:Interleukin-3 / Q000235:genetics*; D007425:Intracellular Membranes / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008811:Mice, Inbred DBA; D010641:Phenotype; D011061:Poly A; D011132:Polyribosomes; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D012270:Ribosomes / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D007166:Immunosuppressive Agents; D007377:Interleukin-3; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D011061:Poly A; D016572:Cyclosporine