Evidence for translational repression of the SOCS-1 major open reading frame by an upstream open reading frame

The suppressor of cytokine signalling 1 protein (SOCS-1) belongs to a novel family of cytokine inducible factors which function as inhibitors of the J AK/ STAT pathway. While SOCS-1 previously has been described as a single-ex on gene, here we present evidence for an additional 5' exon, separated by a 509 bp intron from exon 2. Exon 1 and part of exon 2 contain an open readi ng frame of 115 nt, ending one nucleotide upstream of the major reading fra me. Using SOCS-1-promoter/luciferase constructs, we investigated which sequ ences are involved in the regulation of SOCS-1 expression. Serial promoter deletion clones indicate the localization and functionality of SP1, interfe ron-stimulated responsive elements (ISRE), and interferon-gamma-activated s ites (GAS) promoter elements in the SOCS-1 5' flanking region. We present e vidence that the upstream open reading frame (uORF) represses the translati on of the downstream major open reading frame (mORF). Mutating the start co don of the uORF relieves this repression. Our data indicate that expression of the SOCS-1 protein is repressed on translational level by a mechanism, which bears similarities to that postulated for genes like retinoic acid re ceptor beta 2 (RAR beta 2), S-adenosylmethionine-decarboxylase (AdoMetDC), Bcl-2, and others. (C) 2000 Academic Press.