Upstream open reading frames: molecular switches in (patho)physiology.
Bottom Line: Conserved upstream open reading frames (uORFs) are found within many eukaryotic transcripts and are known to regulate protein translation.Evidence from genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of human diseases.The high prevalence of uORFs in the human transcriptome suggests that intensified search for mutations within 5' RNA leader regions may reveal a multitude of alterations affecting uORFs, causing pathogenic deregulation of protein expression.
Affiliation: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.Show MeSH
Related in: MedlinePlus
Mentions: The recent validation of the (patho)physiological importance of uORF translation in mice added a new level of significance to this cis-regulatory mechanism of translational control. C/EBPα and β transcription factors represent well-established examples of how translational control by uORFs may affect cell fate decisions. Accumulating evidence suggests that deregulated uORF function might be a widespread mechanism underlying the development of human diseases. The rapid progress in advanced sequencing technologies will permit screening approaches to identify causative uORF mutations in primary material derived from patients. Malignancies of the blood might be among the most suitable types of diseases to start such an analysis, as cell samples are readily accessible. One would, e.g. expect to uncover mutations resulting in a “loss of uORF function” in proto-oncogenes, causing their ectopic and transformation-inducing overexpression. In turn, mutations yielding a “gain of uORF function” in tumor suppressor genes may result in malignant transformation due to a decreased production of protective proteins (Fig. 5). Given the high number of human transcripts carrying at least one uORF, the in-depth analysis of 5′ leader sequence mutations has the potential to substantially widen the spectrum of diseases with molecularly resolved etiology. Uncovering disease-related uORF mutations will inspire extensive subsequent research aiming to target the misexpressed proteins for therapeutic intervention.
Affiliation: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.