Skip to main content
Article thumbnail
Location of Repository

Role of 3′UTRs in the Translation of mRNAs Regulated by Oncogenic eIF4E—A Computational Inference

By Arti N. Santhanam, Eckart Bindewald, Vinagolu K. Rajasekhar, Ola Larsson, Nahum Sonenberg, Nancy H. Colburn and Bruce A. Shapiro

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 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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:2654073
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles

    Citations

    1. (2006). A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors.
    2. (2005). A microRNA polycistron as a potential human oncogene.
    3. (2003). A Model Based Background Adjustement for Oligonucleotide ExpressionArrays.
    4. (2006). A periodic pattern of mRNA secondary structure created by the genetic code.
    5. (2005). Animal MicroRNAs confer robustness to gene expression and have a significant impact on 39UTR evolution.
    6. (2006). Apoptosis resistance downstream of eIF4E: posttranscriptional activation of an antiapoptotic transcript carrying a consensus hairpin structure.
    7. (2004). Bioconductor: open software development for computational biology and bioinformatics.
    8. (2004). Borkhardt A
    9. (1998). Control of translation initiation in animals.
    10. (1999). eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation.
    11. (2007). Epigenetic activation of a subset of mRNAs by eIF4E explains its effects on cell proliferation.
    12. (2007). Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors.
    13. (1997). Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
    14. (2008). Getting to the Root of miRNAMediated Gene Silencing.
    15. (2006). Human let-7a miRNA blocks protein production on actively translating polyribosomes.
    16. (1986). Influence of 59 proximal secondary structure on the translational efficiency of eukaryotic mRNAs and on their interaction with initiation factors.
    17. (1995). Intuitive Biostatistics.
    18. (2006). let-7 microRNA functions as a potential growth suppressor in human colon cancer cells.
    19. (2001). LIBSVM : a library for support vector machines.
    20. (2006). Local RNA base pairing probabilities in large sequences.
    21. (2008). Mechanisms of posttranscriptionalregulationbymicroRNAs:aretheanswersinsight?NatRevGenet.
    22. (2007). MicroRNA inhibition of translation initiation in vitro by targeting the capbinding complex eIF4F.
    23. (2006). MicroRNA regulates the expression of human cytochrome P450 1B1.
    24. (2007). MicroRNAs and cancer.
    25. (2006). miRBase: microRNA sequences, targets and gene nomenclature.
    26. (2006). miRBase: the microRNA sequence database.
    27. (1992). mRNAs containing extensive secondary structure in their 59 non-coding region translate efficiently in cells overexpressing initiation factor eIF-4E.
    28. (2003). Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes.
    29. (1999). Predicting oligonucleotide affinity to nucleic acid targets.
    30. (2004). Prediction of locally stable RNA secondary structures for genome-wide surveys.
    31. (2004). Preprocessing of oligonucleotide array data. Nat Biotechnol 22: 656–658; author reply 658.
    32. (2008). Proliferating cells express mRNAs with shortened 39 untranslated regions and fewer microRNA target sites.
    33. (1996). Regulation of ornithine decarboxylase in a transformed cell line that overexpresses translation initiation factor eIF-4E.
    34. (2001). Regulation of translation initiation by FRAP/mTOR.
    35. (1989). RNA helicase activity associated with the human p68 protein.
    36. (2006). RNA secondary structure prediction from sequence alignments using a network of k-nearest neighbor classifiers.
    37. (2001). RNAMotif, an RNA secondary structure definition and search algorithm.
    38. (2008). Suppression of non-small cell lung tumor development by the let-7 microRNA family.
    39. (2000). Synthesis of the translational apparatus is regulated at the translational level.
    40. (2008). Targeting the eukaryotic translation initiation factor 4E for cancer therapy.
    41. (2006). The cap-dependent translation apparatus integrates and amplifies cancer pathways.
    42. (2007). The role of site accessibility in microRNA target recognition.
    43. (2007). The roles of binding site arrangement and combinatorial targeting in microRNA repression of gene expression.
    44. (1991). Translational control in mammalian cells.
    45. (2000). Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis.
    46. (1952). Use of ranks in one-criterion variance analysis.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.