Cyclosporin A Promotes Translational Silencing of Autocrine Interleukin-3 via Ribosome-Associated Deadenylation

Abstract

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.

ACKNOWLEDGMENTS

We thank George Thomas, Harold Jeffries, and Witold Filipowicz for advice; Adrian Wyss, Lyndall Brennan, and Corina Gyssler-Frey for technical assistance; members of the laboratory for their comments on the manuscript; and Nicole Vehlinger for secretarial assistance.