Role of 3'UTRs in the translation of mRNAs regulated by oncogenic eIF4E--a computational inference.
Eukaryotic cap-dependent mRNA translation is mediated by the initiation factor eIF4E, which binds mRNAs and stimulates efficient translation initiation. eIF4E is often overexpressed in human cancers. To elucidate the molecular signature of eIF4E target mRNAs, we analyzed sequence and structural properties of two independently derived polyribosome recruited mRNA datasets. These datasets originate from studies of mRNAs that are actively being translated in response to cells over-expressing eIF4E or cells with an activated oncogenic AKT: eIF4E signaling pathway, respectively. Comparison of eIF4E target mRNAs to mRNAs insensitive to eIF4E-regulation has revealed surprising features in mRNA secondary structure, length and microRNA-binding properties. Fold-changes (the relative change in recruitment of an mRNA to actively translating polyribosomal complexes in response to eIF4E overexpression or AKT upregulation) are positively correlated with mRNA G+C content and negatively correlated with total and 3'UTR length of the mRNAs. A machine learning approach for predicting the fold change was created. Interesting tendencies of secondary structure stability are found near the start codon and at the beginning of the 3'UTR region. Highly upregulated mRNAs show negative selection (site avoidance) for binding sites of several microRNAs. These results are consistent with the emerging model of regulation of mRNA translation through a dynamic balance between translation initiation at the 5'UTR and microRNA binding at the 3'UTR.
Santhanam
Arti N
AN
Gene Regulation Section, Laboratory of Cancer Prevention, National Cancer Institute, Frederick, Maryland, United States of America.
Bindewald
Eckart
E
Rajasekhar
Vinagolu K
VK
Larsson
Ola
O
Sonenberg
Nahum
N
Colburn
Nancy H
NH
Shapiro
Bruce A
BA
D020413:3' Untranslated Regions; D018387:Codon, Initiator; D018388:Codon, Terminator; D039561:Eukaryotic Initiation Factor-4E / Q000502:physiology*; D035683:MicroRNAs / Q000235:genetics; D009690:Nucleic Acid Conformation; D015513:Oncogene Proteins / Q000502:physiology*; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics*
D020413:3' Untranslated Regions; D018387:Codon, Initiator; D018388:Codon, Terminator; D039561:Eukaryotic Initiation Factor-4E; D035683:MicroRNAs; D015513:Oncogene Proteins; D012333:RNA, Messenger