Inhibition of CHOP translation by a peptide encoded by an open reading frame localized in the chop 5 ' UTR

Chop is a ubiquitously expressed mammalian gene encoding a small nuclear pr otein related to the CCAAT/enhancer-binding protein (C/EBP) family of trans cription factors. CHOP protein plays an important role in various cellular processes such as growth, differentiation and programmed cell death. CHOP e xpression is strongly increased in response to a large variety of stresses including perturbation of the endoplasmic reticulum function, DNA damage an d nutrient deprivation. Multiple mechanisms including transcriptional and p ost-transcriptional controls are involved in the regulation of CHOP express ion. We show here that the 5'UTR of the Chop transcript plays an important role in controlling the synthesis of CHOP protein. In particular, the 5'UTR contains a conserved uORF which encodes a 31 amino acid peptide that inhib its the expression of the downstream ORF. Mutational analysis of the 5' lea der region and peptide coding sequences suggests that the peptide itself in hibits expression of the downstream ORF. Such results suggest a role for uO RF in limiting ribosomal access to downstream initiation sites. With respec t to the importance of CHOP protein in the regulation of cellular functions , the mechanisms that regulate its basal level are of considerable interest .