Epigenetic Activation of a Subset of mRNAs by eIF4E Explains Its Effects on Cell Proliferation

PLoS One. 2007 Feb 21;2(2):e242. doi: 10.1371/journal.pone.0000242.

Abstract

Background: Translation deregulation is an important mechanism that causes aberrant cell growth, proliferation and survival. eIF4E, the mRNA 5' cap-binding protein, plays a major role in translational control. To understand how eIF4E affects cell proliferation and survival, we studied mRNA targets that are translationally responsive to eIF4E.

Methodology/principal findings: Microarray analysis of polysomal mRNA from an eIF4E-inducible NIH 3T3 cell line was performed. Inducible expression of eIF4E resulted in increased translation of defined sets of mRNAs. Many of the mRNAs are novel targets, including those that encode large- and small-subunit ribosomal proteins and cell growth-related factors. In addition, there was augmented translation of mRNAs encoding anti-apoptotic proteins, which conferred resistance to endoplasmic reticulum-mediated apoptosis.

Conclusions/significance: Our results shed new light on the mechanisms by which eIF4E prevents apoptosis and transforms cells. Downregulation of eIF4E and its downstream targets is a potential therapeutic option for the development of novel anti-cancer drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics
  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics
  • Cell Division / genetics
  • Epigenesis, Genetic*
  • Eukaryotic Initiation Factor-4E / genetics
  • Eukaryotic Initiation Factor-4E / physiology*
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / genetics
  • Mice
  • NIH 3T3 Cells / cytology
  • Oligonucleotide Array Sequence Analysis
  • Polyribosomes / metabolism
  • Protein Biosynthesis
  • RNA, Messenger / biosynthesis*
  • RNA, Messenger / genetics
  • Recombinant Fusion Proteins / physiology
  • Regulatory Sequences, Ribonucleic Acid / genetics
  • Ribosomal Proteins / biosynthesis
  • Ribosomal Proteins / genetics

Substances

  • 5' Untranslated Regions
  • Apoptosis Regulatory Proteins
  • Eukaryotic Initiation Factor-4E
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Regulatory Sequences, Ribonucleic Acid
  • Ribosomal Proteins