Trends in Biochemical Sciences
ReviewThe glucose-regulated proteins: stress induction and clinical applications
Section snippets
Unique inducers for the mammalian Grp genes
The Grps were discovered in 1977 by Ira Pastan through the observation that two proteins of molecular size 78 and 94 kDa were strongly induced in chicken embryo fibroblasts cultured in glucose-free medium 5. These proteins were subsequently identified as Grp78 (also referred to as the immunoglobulin binding protein BiP) and Grp94 (alias gp96). Grp94 is the most abundant glycoprotein in the ER. In addition, whereas Grp78 is evolutionarily conserved from yeast to humans, Grp94 has only been
Conservation and divergence of the induction mechanism of yeast and mammalian Grp genes
Stress induction of both yeast and mammalian Grp genes is primarily regulated at the level of transcription (Fig. 2). The promoter of KAR2, the yeast homolog of Grp78, contains one copy of the unfolded protein response element (UPRE). This element, CAGCGTG, serves as the binding site for an activator Hac1, which undergoes ER stress-induced mRNA splicing catalyzed by an ER membrane protein, Ire1p, using an unconventional mechanism 4. The yeast UPR is negatively regulated by the phosphatase
Complex regulatory network for induction of Grp transcription
An unusual feature shared by mammalian Grp promoters is that they contain multiple copies of the CCAAT element flanked by GC-rich sequences. These turn out to be repetitive units of the ER stress response element (ERSE) 20, 21, which is an evolutionarily conserved tripartite structure CCAAT(N9)CCACG (N represents a 9-bp region) (Fig. 2). This sequence is notably more complex than the UPRE. Recently, another sequence motif, ATTGG(N)CCACG, referred to as ERSE-II, has been identified in the
Multiple functions of the Grps
A list of proteins encoded by mammalian genes that exhibit induction profiles similar to Grp78 and Grp94 in response to ER stress is summarized in Table 1. The majority of the Grps [Grp78, Grp94, Grp170, ERp72, PDI, calreticulin and GRP58 (alias ERp57)] are ER molecular chaperones that assist in protein folding and assembly. Grp78, Grp94, ERp72 and calreticulin are also Ca2+-binding proteins. Newly identified ER proteins that are inducible by ER stress include SERCA-2β, Herp, oxidoreductin 1-Lβ
Role of Grps in cell survival following ER stress
Overexpression, antisense and ribozyme approaches in tissue culture systems directly showed that Grp78, Grp94 and adapt78 can protect cells against cell death 3, 37, 38, 39, 40, 41, 42, 43 (Fig. 3). Interestingly, two independent studies suggest that Grp protects more against stress incurred by depletion of ER Ca2+ than by a block in protein glycosylation 37, 43. Although the mechanism for the anti-apoptotic effect of the Grps is not understood, a Grp78 mutant that is defective in ATP
Grps as targets for cancer chemotherapy
Whereas Grp overexpression could limit damage in organs exposed to ER stress, the anti-apoptotic function of the Grps also predicts that their induction in neoplastic cells could lead to cancer progression and drug resistance (Fig. 3). In a variety of cancer cell lines, solid tumors and human cancer biopsies, the levels of Grp78 and Grp94 are elevated, correlating with malignancy 3, 48. In addition, induction of Grp78 has been shown to protect cancer cells from immune surveillance, whereas
Role of Grp in immunotherapy
Grp94 has been shown to chaperone a broad array of peptides, including those derived from normal proteins as well as from foreign and altered proteins present in cancer or virus-infected cells 52. Thus, tumor-derived Grp94 carries tumor antigenic peptides, and Grp94 preparations from virus-infected cells carry viral epitopes. Although Grp94 is normally intracellular, necrotic cells release Grp94–peptide complexes, which are taken up by scavenging antigen-presenting cells. Presentation of the
Use of the stress-inducible Grp78 promoter in cancer gene therapy
Aggressive tumors often suffer from insufficient blood supply resulting in areas of acidosis, nutrient deprivation and hypoxia. Such adverse conditions specifically activate the Grp78 promoter. The use of the stress-inducible Grp78 promoter to drive therapeutic gene expression offers a novel approach for gene therapy of poorly perfused tumors and ischemic diseases. The Grp78 promoter confers higher efficacy than viral promoters in eradication of sizable tumors in mouse models bearing
Conclusion
Since the discovery of Grp78 and Grp94 20 years ago, there has been an explosion of new knowledge regarding the function and regulation of Grp in cell culture. Future experiments addressing the physiological roles played by Grp in vivo will further enhance our understanding of the importance of these proteins in human development and in diseases associated with the disturbance of ER homeostasis.
Acknowledgements
I thank my colleagues for privileged communication of the most updated research results. I apologize to the authors whose work is not cited owing to space limitations. This work is supported by a grant from the National Cancer Institute CA27607 to A.S.L.
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