Regulation and dysregulation of 3′UTR-mediated translational control

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Translational control provides numerous advantages in regulation of gene expression including rapid responsiveness, intracellular localization, nondestruction of template mRNA, and coordinated regulation of transcript ensembles. Transcript-selective, translational control is driven by the specific interaction of factor(s) with the 5′ or 3′ untranslated region (UTR), thereby influencing initiation, elongation, or termination of mRNA translation. The mean length of human 3′UTRs is greater than that of 5′UTR, indicating the expanded potential for motifs, structural elements, and binding sites for trans-acting factors that exert transcript-selective translation control. New and unexpected mechanisms of 3′UTR-mediated translational control and their contributions to disease have received increasing attention during the last decade. Here, we briefly review a few recent and representative discoveries of 3′UTR-mediated translational control, emphasizing the novel aspects of these regulatory mechanisms and their potential pathophysiological significance.

Section snippets

The GAIT system as archetype for 3′UTR-mediated translational control and its modulation

Recognition and binding of proteins or protein complexes to defined sequence or structural RNA elements in the mRNA 3′UTR is a common translational control mechanism (Figure 1). This mechanism is generally directed by stimulus-dependent posttranslational modifications that regulate protein–protein interactions and complex assembly, as well as the RNA-binding properties of these assemblages. Recent attention has focused on an additional layer of complexity in which the processes involved in

Translational control by 3′UTR-targeting miRNA

microRNAs (miRNAs) are 20-nt to 23-nt, noncoding RNAs that can target mRNA [12], DNA [13], and even protein [14], to regulate gene expression at both transcriptional and posttranscriptional levels. miRNAs bind complementary sequences, most often in the 3′UTR of target mRNAs, to alter expression by regulating either mRNA decay or translation. A ribosome profiling study pointed to mRNA decay, rather than translational silencing, as the dominant mechanism for miRNA-mediated inhibition of gene

3′UTR-mediated translational control in disease and therapeutics

Experimental and clinical studies have suggested that 3′UTR-mediated translational control has a critical role in regulating gene expression in cancer and other pathological states (Table 1). Phosphorylation of a 3′UTR-binding protein was recently shown to significantly impact transforming growth factor (TGF)-β-induced epithelial-mesenchymal transition (EMT), a critical early step in tumorigenesis. The newly recognized BAT (TGF-β-activated translation) complex, consisting of hnRNP E1 and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

P.L.F was supported by NIH grants P01 HL029582, P01 HL076491, and R01 GM086430, A.A. by a National Center Scientist Development Grant 10SDG3930003 from the American Heart Association, and P.Y. by a fellowship from the American Heart Association, Great Rivers Affiliate. Owing to space limitations, combined with remarkable growth in this burgeoning research area, we were not able to include all, or even most, recent discoveries about this topic; we apologize to the authors whose important work

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