Regulation of translational initiation during cellular responses to stress

Prog Nucleic Acid Res Mol Biol. 1998;58:79-125. doi: 10.1016/s0079-6603(08)60034-3.


Chemicals and conditions that damage proteins, promote protein misfolding, or inhibit protein processing trigger the onset of protective homeostatic mechanisms resulting in "stress responses" in mammalian cells. Included in these responses are an acute inhibition of mRNA translation at the initiation step, a subsequent induction of various protein chaperones, and the recovery of mRNA translation. Separate, but closely related, stress response systems exist for the endoplasmic reticulum (ER), relating to the induction of specific "glucose-regulated proteins" (GRPs), and for the cytoplasm, pertaining to the induction of the "heat shock proteins" (HSPs). Activators of the ER stress response system, including Ca(2+)-mobilizing and thiol-reducing agents, are discussed and compared to activators of the cytoplasmic stress system, such as arsenite, heavy metal cations, and oxidants. An emerging integrative literature is reviewed that relates protein chaperones associated with cellular stress response systems to the coordinate regulation of translational initiation and protein processing. Background information is presented describing the roles of protein chaperones in the ER and cytoplasmic stress response systems and the relationships of chaperones and protein processing to the regulation of mRNA translation. The role of chaperones in regulating eIF-2 alpha kinase activities, eIF-2 cycling, and ribosomal loading on mRNA is emphasized. The putative role of GRP78 in coupling rates of translation to processing is modeled, and functional relationships between the HSP and GRP chaperone systems are discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cytoplasm / metabolism
  • Endoplasmic Reticulum / metabolism
  • Eukaryotic Initiation Factor-2 / metabolism
  • Heat-Shock Proteins / biosynthesis
  • Heat-Shock Proteins / genetics
  • Humans
  • Peptide Chain Initiation, Translational*
  • Protein Processing, Post-Translational
  • Reticulocytes / metabolism
  • Stress, Physiological / genetics*
  • Stress, Physiological / metabolism*


  • Eukaryotic Initiation Factor-2
  • Heat-Shock Proteins