Regulation of SOCS-1 expression by translational repression

Accumulating evidence demonstrates that cytokine receptor signaling is nega tively regulated by a family of Src homology 2 domain-containing adaptor mo lecules termed SOCS (Suppressor of cytokine signaling). Previous studies ha ve indicated that the expression of SOCS-related molecules is tightly contr olled at the level of transcription. Furthermore, it has been reported that SOCS polypeptides are relatively unstable in cells, unless they are associ ated with elongins B and C. Herein, we document the existence of a third me chanism of regulation of SOCS function. Our data showed that expression of SOCS-1, a member of the SOCS family, is strongly repressed at the level of translation initiation. Structure-function analyses indicated that this eff ect is mediated by the 5' untranslated region of socs-1 and that it relates to the presence of two upstream AUGs in this region. Further studies revea led that socs-1 translation is cap-dependent and that it is modulated by eI F4E-binding proteins. In combination, these results uncover a novel level o f regulation of SOCS-related molecules. Moreover, coupled with previous fin dings, they suggest that SOCS expression is tightly regulated through multi ple mechanisms, in order to avoid inappropriate interference with cytokine- mediated effects.