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 (C sA), a calcineurin antagonist and blocker of interleukin-2 (IL-2) transcrip tion 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 re gion. FK506, another calcineurin inhibitor, shared the effect. The translat ional inhibition by CsA was specific to oncogenically induced lymphokines I L-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 do cvn-regulati on of the mRNA was observed in IL-3-transfected precursor cells. These data suggest that translational silencing is associated with the tumor phenotyp e.