Derepression of the Her-2 uORF is mediated by a novel post-transcriptional control mechanism in cancer cells

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Abstract
Transcripts harboring 5′ upstream open reading frames (uORFs) are often found in genes controlling cell growth including receptors, oncogenes, or growth factors. uORFs can modulate translation or RNA stability and mediate inefficient translation of these potent proteins under normal conditions. In dysregulated cancer cells, where the gene product, for example Her-2 receptor, is overexpressed, post-transcriptional processes must exist that serve to override the inhibitory effects of the uORFs. The 5′ untranslated region (UTR) of Her-2 mRNA contains a short uORF that represses translation of the downstream coding region. We demonstrate that in Her-2 overexpressing breast cancer cells, the 3′ UTR of the Her-2 mRNA can override translational inhibition mediated by the Her-2 uORF. Within this 3′ UTR, a translational derepression element (TDE) that binds to a 38-kDa protein was identified. These results define a novel biological mechanism in which translational control of genes harboring a 5′ uORF can be modulated by elements in their 3′ UTRs.