The glucose-regulated proteins (GRP78 and GRP94): functions, gene regulation, and applications

Crit Rev Eukaryot Gene Expr. 1994;4(1):1-18. doi: 10.1615/critreveukargeneexpr.v4.i1.10.

Abstract

The knowledge of GRPs as molecular chaperones is rapidly evolving. It is anticipated that the GRPs will make special contributions in the areas of basic cell biology, biotechnology, and cancer biology. In particular, they may play a role as the prototype of a class of genes that are regulated by signal transduction pathways originating in the ER and traveling to the nucleus. GRP78 and GRP94 function as molecular chaperones and can bind to malfolded proteins and unassembled complexes. They are induced in response to stress, but once the stress is removed the GRPs are posttranscriptionally modified into biologically inactive forms. The promoters of the grp genes are highly conserved, with several CCAAT-like motifs and GC-rich regions. The high level of redundancy that exists in the mammalian grp promoters may act to ensure that the expression of the genes, both of which are single copy, is unlikely to be significantly lowered in the event of mutation. These genes are thought to be controlled by several transcription factors whose complex interactions with the grp promoters allow variable patterns of grp induction. The promoters of the grp genes constitutively express their gene products, and their promoter activities can be further enhanced in cellular environments of low glucose or oxygen. The grp78 promoter is known to retain its strong activity in differentiated and undifferentiated tissues. These features make it an attractive alternative to viral promoters for use in gene therapy. Gene therapy may also be useful in treating cancer in some cases, especially solid tumors. In these instances, GRP levels are already likely to be quite high. These high levels of GRPs may inhibit the efficacy of several anti-cancer treatments. Suppression of GRP induction, perhaps by anti-sense or ribozyme technology, may prove to be useful in conjunction with anti-cancer drugs to treat tumors.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Biological Transport
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Survival
  • Endoplasmic Reticulum / metabolism*
  • Gene Expression Regulation / drug effects*
  • Genetic Therapy
  • Glucose / pharmacology*
  • HSP70 Heat-Shock Proteins / biosynthesis
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / physiology*
  • Heat-Shock Proteins*
  • Mammals / metabolism
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Molecular Chaperones / biosynthesis
  • Molecular Chaperones / genetics
  • Molecular Chaperones / physiology*
  • Multigene Family
  • Neoplasms / therapy
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Biosynthesis
  • Protein Folding
  • Protein Processing, Post-Translational*
  • Proteins / metabolism
  • Signal Transduction
  • Stress, Physiological / metabolism
  • Transcription Factors / physiology
  • Transcription, Genetic

Substances

  • Carrier Proteins
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Membrane Proteins
  • Molecular Chaperones
  • Proteins
  • Transcription Factors
  • glucose-regulated proteins
  • Glucose
  • molecular chaperone GRP78