Translational control by mTOR-independent routes: how eIF6 organizes metabolism

Biochem Soc Trans. 2016 Dec 15;44(6):1667-1673. doi: 10.1042/BST20160179.

Abstract

Over the past few years, there has been a growing interest in the interconnection between translation and metabolism. Important oncogenic pathways, like those elicited by c-Myc transcription factor and mTOR kinase, couple the activation of the translational machinery with glycolysis and fatty acid synthesis. Eukaryotic initiation factor 6 (eIF6) is a factor necessary for 60S ribosome maturation. eIF6 acts also as a cytoplasmic translation initiation factor, downstream of growth factor stimulation. eIF6 is up-regulated in several tumor types. Data on mice models have demonstrated that eIF6 cytoplasmic activity is rate-limiting for Myc-induced lymphomagenesis. In spite of this, eIF6 is neither transcriptionally regulated by Myc, nor post-transcriptionally regulated by mTOR. eIF6 stimulates a glycolytic and fatty acid synthesis program necessary for tumor growth. eIF6 increases the translation of transcription factors necessary for lipogenesis, such as CEBP/β, ATF4 and CEBP/δ. Insulin stimulation leads to an increase in translation and fat synthesis blunted by eIF6 deficiency. Paradoxycally, long-term inhibition of eIF6 activity increases insulin sensitivity, suggesting that the translational activation observed upon insulin and growth factors stimulation acts as a feed-forward mechanism regulating lipid synthesis. The data on the role that eIF6 plays in cancer and in insulin sensitivity make it a tempting pharmacological target for cancers and metabolic diseases. We speculate that eIF6 inhibition will be particularly effective especially when mTOR sensitivity to rapamycin is abrogated by RAS mutations.

Keywords: Myc; fatty acid synthesis; glycolysis; mechanistic target of rapamycin; translation factors.

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Insulin / pharmacology
  • Lipogenesis / drug effects
  • Lipogenesis / genetics
  • Metabolic Diseases / genetics
  • Metabolic Diseases / metabolism
  • Mice
  • Models, Genetic
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Peptide Initiation Factors / genetics*
  • Peptide Initiation Factors / metabolism
  • Protein Biosynthesis*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • ATF4 protein, human
  • CCAAT-Enhancer-Binding Protein-beta
  • Hypoglycemic Agents
  • Insulin
  • Peptide Initiation Factors
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors
  • eIF-6
  • Activating Transcription Factor 4
  • MTOR protein, human
  • TOR Serine-Threonine Kinases