Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules

Nucleic Acids Res. 2012 Sep;40(16):8099-110. doi: 10.1093/nar/gks566. Epub 2012 Jun 20.

Abstract

Stress granules (SGs) are large cytoplasmic ribonucleoprotein complexes that are assembled when cells are exposed to stress. SGs promote the survival of stressed cells by contributing to the reprogramming of protein expression as well as by blocking pro-apoptotic signaling cascades. These cytoprotective effects implicated SGs in the resistance of cancer cells to radiation and chemotherapy. We have found that sodium selenite, a selenium compound with chemotherapeutic potential, is a potent inducer of SG assembly. Selenite-induced SGs differ from canonical mammalian SGs in their morphology, composition and mechanism of assembly. Their assembly is induced primarily by eIF4E-binding protein1 (4EBP1)-mediated inhibition of translation initiation, which is reinforced by concurrent phosphorylation of eIF2α. Selenite-induced SGs lack several classical SG components, including proteins that contribute to pro-survival functions of canonical SGs. Our results reveal a new mechanism of mammalian SG assembly and provide insights into how selenite cytotoxicity may be exploited as an anti-neoplastic therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cells, Cultured
  • Cytoplasmic Granules / chemistry
  • Cytoplasmic Granules / metabolism*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Eukaryotic Initiation Factor-4F / metabolism
  • Humans
  • Mice
  • Peptide Chain Initiation, Translational / drug effects*
  • Peptide Initiation Factors / metabolism
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Reactive Oxygen Species / metabolism
  • Ribonucleoproteins / metabolism
  • Sodium Selenite / pharmacology*
  • Stress, Physiological*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • EIF4EBP1 protein, human
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factor-4F
  • Peptide Initiation Factors
  • Phosphoproteins
  • Reactive Oxygen Species
  • Ribonucleoproteins
  • Sodium Selenite