An mRNA-specific tRNAi carrier eIF2A plays a pivotal role in cell proliferation under stress conditions: stress-resistant translation of c-Src mRNA is mediated by eIF2A

Nucleic Acids Res. 2017 Jan 9;45(1):296-310. doi: 10.1093/nar/gkw1117. Epub 2016 Nov 28.


c-Src, a non-receptor protein tyrosine kinase, activates NF-κB and STAT3, which in turn triggers the transcription of anti-apoptosis- and cell cycle-related genes. c-Src protein regulates cell proliferation, cell motility and programmed cell death. And the elevated level of activated c-Src protein is related with solid tumor generation. Translation of c-Src mRNA is directed by an IRES element which mediates persistent translation under stress conditions when translation of most mRNAs is inhibited by a phosphorylation of the alpha subunit of eIF2 carrying the initiator tRNA (tRNAi) to 40S ribosomal subunit under normal conditions. The molecular basis of the stress-resistant translation of c-Src mRNA remained to be elucidated. Here, we report that eIF2A, an alternative tRNAi carrier, is responsible for the stress-resistant translation of c-Src mRNA. eIF2A facilitates tRNAi loading onto the 40S ribosomal subunit in a c-Src mRNA-dependent manner. And a direct interaction between eIF2A and a stem-loop structure (SL I) in the c-Src IRES is required for the c-Src IRES-dependent translation under stress conditions but not under normal conditions. Finally, we showed that the eIF2A-dependent translation of c-Src mRNA plays a pivotal role in cell proliferation under stress conditions.

MeSH terms

  • Biotinylation
  • CSK Tyrosine-Protein Kinase
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Eukaryotic Initiation Factor-2 / genetics*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Gene Expression Regulation
  • HEK293 Cells
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nucleic Acid Conformation
  • Phosphorylation
  • Protein Biosynthesis*
  • RNA / genetics*
  • RNA / metabolism
  • RNA, Transfer, Met / genetics*
  • RNA, Transfer, Met / metabolism
  • Response Elements
  • Ribosome Subunits, Small, Eukaryotic / chemistry
  • Ribosome Subunits, Small, Eukaryotic / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Stress, Physiological
  • Tunicamycin / pharmacology
  • src-Family Kinases / genetics*
  • src-Family Kinases / metabolism


  • Eukaryotic Initiation Factor-2
  • NF-kappa B
  • RNA, Transfer, Met
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tunicamycin
  • RNA
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human