Role of 3′UTRs in the translation of mRNAs regulated by oncogenic eIF4E - A computational inference Journal Article

Authors: Santhanam, A. N.; Bindewald, E.; Rajasekhar, V. K.; Larsson, O.; Soneberg, N.; Colburn, N. H.; Shapiro, B. A.
Article Title: Role of 3′UTRs in the translation of mRNAs regulated by oncogenic eIF4E - A computational inference
Abstract: 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 overexpressing 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 39UTR 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.
Keywords: signal transduction; protein kinase b; controlled study; oncoprotein; gene sequence; human cell; sequence analysis; genetics; stop codon; gene overexpression; microrna; physiology; oncogene; chemistry; messenger rna; protein synthesis; rna, messenger; eukaryota; oncogene proteins; initiation factor 4e; rna translation; protein biosynthesis; polysome; binding site; 3' untranslated region; conformation; nucleic acid conformation; codon; protein secondary structure; micrornas; cysteine; glycine; gene structure; 3' untranslated regions; genetic database; start codon; codon, initiator; codon, terminator; eukaryotic initiation factor-4e
Journal Title: PLoS ONE
Volume: 4
Issue: 3
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2009-03-17
Start Page: e4868
Language: English
DOI: 10.1371/journal.pone.0004868
PUBMED: 19290046
PROVIDER: scopus
PMCID: PMC2654073
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "Art. No.: e4868" - "Source: Scopus"
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