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Gene Review

HSPA5  -  heat shock 70kDa protein 5 (glucose...

Homo sapiens

Synonyms: 78 kDa glucose-regulated protein, BIP, BiP, Endoplasmic reticulum lumenal Ca(2+)-binding protein grp78, GRP-78, ...
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Disease relevance of HSPA5

  • Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells [1].
  • Activation of the grp78 and grp94 promoters by hepatitis C virus E2 envelope protein [2].
  • These cell lines express elevated levels of the transcription factor c-Myb due to genomic amplification of the c-myb locus and we hypothesized that c-Myb regulates GRP78 expression in colon cancer cells [3].
  • Interestingly, while the majority of the breast cancer cell lines can respond to tunicamycin- and thapsigargin-induced stress by increasing the steady state levels of grp94 and grp78 transcripts, the induction at the GRP protein level is variable and does not always correspond with the transcript level [4].
  • The M(r) 78,000 glucose-regulated protein (GRP78) can be induced by physiological stresses such as glucose deprivation and hypoxia [5].
  • Increased Grp78 expression was consistently associated with greater risk of prostate cancer recurrence and worse overall survival in patients who had not undergone prior hormonal manipulation [6].
  • For estrogen-dependent MCF-7/BUS breast cancer cells, overexpression of GRP78 inhibits estrogen starvation-induced BAX activation, mitochondrial permeability transition, and consequent apoptosis [7].
  • Our study indicates a molecular mechanism by which the sensitivity of thyroid cancer cells is regulated by the level of GRP78 as well as preferential induction of GRP78 or CHOP upon treatment with proteasome inhibitors [8].
  • Overexpression of GRP78 in glioma cells decreases caspase 7 activation and renders the cells resistant to etoposide- and cisplatin-induced apoptosis, whereas silencing of GRP78 decreases cell growth and sensitizes glioma cells to etoposide, cisplatin, and gamma-radiation [9].

Psychiatry related information on HSPA5

  • Functional polymorphisms of HSPA5: possible association with bipolar disorder [10].
  • Interestingly, GRP78 levels are reduced in the brains of Alzheimer's disease patients [11].
  • Regulation of ER stress proteins, such as the 78-kilodalton glucose regulated protein (GRP78) by chronic treatment with mood stabilizing drugs suggests that this family of proteins may be involved in the pathophysiology of mood disorders [12].
  • Our previous studies have demonstrated that a small number of genes exhibit increased expression in the cerebral cortex of the mouse and rat during recovery sleep after sleep deprivation: egr-3, fra-2, grp78, grp94, ngfi-b, and nr4a3 [13].

High impact information on HSPA5

  • The class I heavy chain and beta 2-microglobulin are cotranslationally translocated into the endoplasmic reticulum where their assembly may be facilitated by the sequential association of the heavy chain with chaperone proteins BiP and calnexin [14].
  • The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone [15].
  • However, the translocation of peptide across the endoplasmic reticulum (ER) membrane does not require ATP, and binding of biotinylated peptide to BiP, an ER luminal protein, occurs after ATP depletion [16].
  • We show that it is identical with two previously described proteins: GRP78, whose synthesis is induced by glucose starvation, and BiP, which is found bound to immunoglobulin heavy chains in pre-B cells [17].
  • These changes in functional state are accompanied by structural rearrangements that alter translocon conformation, composition, and interactions with ligands such as the ribosome and BiP [18].

Chemical compound and disease context of HSPA5


Biological context of HSPA5


Anatomical context of HSPA5

  • Endoplasmic reticulum stress induction of the Grp78/BiP promoter: activating mechanisms mediated by YY1 and its interactive chromatin modifiers [24].
  • Consistent with reports that prosurvival/physiologic UPR components are required for B-cell differentiation into antibody-secreting cells, we found that MM cells inherently expressed the ER chaperones GRP78/Bip and GRP94/gp96 [25].
  • Lastly, using stable cell lines with suppressed TFII-I levels, we show that TFII-I is required for optimal induction of Grp78 by ER stress [26].
  • Of 20 fibroblast cell strains from patients with osteogenesis imperfecta (OI), a disease caused by mutations in the genes encoding type I procollagen, three had increased synthesis of BiP (GRP78), an hsp70-related, endoplasmic reticulum-resident protein [27].
  • In the present study we show that the molecular chaperone Grp78/BiP co-immunoprecipitates with both the wild type and two different mutant (W556S and C646Y) LDL receptors in lysates obtained from human liver cells overexpressing wild type or mutant LDL receptors [28].

Associations of HSPA5 with chemical compounds

  • ER luminal sequences flanking the transmembrane domain are required for GRP78 interaction, and deletion of this portion of PEK led to its activation even in the absence of ER stress [29].
  • Previously, we reported that genistein, a general inhibitor of tyrosine kinase, could suppress ER stress induction of Grp78 by inhibiting complex formation on the ER stress element; however, the mechanism is not known [26].
  • Ascorbate, which increases procollagen synthesis, increases BiP synthesis and content in these three strains and not in the others [27].
  • These changes were accompanied by increased expression of UPR target genes, including immunoglobulin heavy chain-binding protein/glucose-regulated protein, 78 kDa and CCAAT/enhancer binding protein-homologous protein/growth arrest- and DNA damage-inducible gene (CHOP/GADD153) [1].
  • We report in the present study that the induction of endogenous grp78 mRNA by the amino acid analogue azetidine (AzC) requires the integrity of a signal transduction pathway mediated by p38 mitogen-activated protein kinase (p38 MAPK) [30].
  • The interaction was confirmed by colocalization studies and antibody competition experiments that also mapped the epitope recognized by Ab39 to the COOH terminus of GRP78 [31].

Physical interactions of HSPA5

  • However, calreticulin and BiP interacted preferentially with aggregates whereas calnexin preferentially associated with monomeric forms of HCV glycoproteins or noncovalent complexes [32].
  • K8/18-bound grp78 can be dissociated by Mg-ATP and the association can be reconstituted in vitro using purified grp78, then redissociated again by Mg-ATP [33].
  • Furthermore, hypoxia increased the transcriptional activity of a 12-O-tetradecanoylphorbol-13-acetate response element-like motif on the GRP78 promoter and increased the abundance and DNA binding activity of AP-1 complex composed of c-Jun and c-Fos [5].
  • These methods were used to investigate several key steps of ATF6 activation in the ER stress response including binding and dissociation of BiP to ATF6, translocation from the ER to the Golgi and cleavage in the Golgi [34].
  • We found that the molecular chaperone GRP78 in the endoplasmic reticulum formed a stable complex with the underglycosylated EGFR but did not with the mature form [35].

Regulatory relationships of HSPA5

  • Our results demonstrate a direct association of grp78 with K8 under conditions that induce grp78 expression [33].
  • Furthermore, E2 but not E1 protein induces the synthesis of GRP78 from the endogenous cellular gene [2].
  • In favor of an active dissociation model, one specific region within the ATF6 lumenal domain was identified as a specific ER stress-responsive sequence required for ER stress-triggered BiP release [36].
  • In cotransfection studies, YY1 specifically enhanced the transcriptional activation of the grp78 promoter under a variety of stress conditions: depletion of the endoplasmic reticulum calcium stores, protein glycosylation block, and formation of aberrant proteins by azetidine treatment [37].
  • Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress [38].

Other interactions of HSPA5

  • The blockade of ATF6 cleavage by BiP/grp78 reversed this inhibitory effect [39].
  • This sequence is homologous with previously determined regulatory sequences of the human GRP78 and GRP94 promoters [40].
  • In addition, the molecular chaperones BiP, ERp72, and ERp94, but not calnexin, were found in a complex with unglycosylated, unfolded hCG-beta and may be involved in the folding of this beta form [41].
  • These data indicate that CR, GRP78, GRP94, and protein disulfide isomerase may in part have similar transcriptional regulation and suggest that their gene products while structurally distinct may have similar functions or co-functions [40].
  • Role of extracellular molecular chaperones in the folding of oxidized proteins. Refolding of colloidal thyroglobulin by protein disulfide isomerase and immunoglobulin heavy chain-binding protein [42].

Analytical, diagnostic and therapeutic context of HSPA5


  1. Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. Zu, K., Bihani, T., Lin, A., Park, Y.M., Mori, K., Ip, C. Oncogene (2006) [Pubmed]
  2. Activation of the grp78 and grp94 promoters by hepatitis C virus E2 envelope protein. Liberman, E., Fong, Y.L., Selby, M.J., Choo, Q.L., Cousens, L., Houghton, M., Yen, T.S. J. Virol. (1999) [Pubmed]
  3. Expression of stress response protein glucose regulated protein-78 mediated by c-Myb. Ramsay, R.G., Ciznadija, D., Mantamadiotis, T., Anderson, R., Pearson, R. Int. J. Biochem. Cell Biol. (2005) [Pubmed]
  4. De-regulation of GRP stress protein expression in human breast cancer cell lines. Gazit, G., Lu, J., Lee, A.S. Breast Cancer Res. Treat. (1999) [Pubmed]
  5. Induction of glucose-regulated protein 78 by chronic hypoxia in human gastric tumor cells through a protein kinase C-epsilon/ERK/AP-1 signaling cascade. Song, M.S., Park, Y.K., Lee, J.H., Park, K. Cancer Res. (2001) [Pubmed]
  6. Expression of stress response protein Grp78 is associated with the development of castration-resistant prostate cancer. Pootrakul, L., Datar, R.H., Shi, S.R., Cai, J., Hawes, D., Groshen, S.G., Lee, A.S., Cote, R.J. Clin. Cancer Res. (2006) [Pubmed]
  7. GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Fu, Y., Li, J., Lee, A.S. Cancer Res. (2007) [Pubmed]
  8. Different induction of GRP78 and CHOP as a predictor of sensitivity to proteasome inhibitors in thyroid cancer cells. Wang, H.Q., Du, Z.X., Zhang, H.Y., Gao, D.X. Endocrinology (2007) [Pubmed]
  9. GRP78 is overexpressed in glioblastomas and regulates glioma cell growth and apoptosis. Lee, H.K., Xiang, C., Cazacu, S., Finniss, S., Kazimirsky, G., Lemke, N., Lehman, N.L., Rempel, S.A., Mikkelsen, T., Brodie, C. Neuro-oncology (2008) [Pubmed]
  10. Functional polymorphisms of HSPA5: possible association with bipolar disorder. Kakiuchi, C., Ishiwata, M., Nanko, S., Kunugi, H., Minabe, Y., Nakamura, K., Mori, N., Fujii, K., Umekage, T., Tochigi, M., Kohda, K., Sasaki, T., Yamada, K., Yoshikawa, T., Kato, T. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  11. Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Katayama, T., Imaizumi, K., Sato, N., Miyoshi, K., Kudo, T., Hitomi, J., Morihara, T., Yoneda, T., Gomi, F., Mori, Y., Nakano, Y., Takeda, J., Tsuda, T., Itoyama, Y., Murayama, O., Takashima, A., St George-Hyslop, P., Takeda, M., Tohyama, M. Nat. Cell Biol. (1999) [Pubmed]
  12. Increased temporal cortex ER stress proteins in depressed subjects who died by suicide. Bown, C., Wang, J.F., MacQueen, G., Young, L.T. Neuropsychopharmacology (2000) [Pubmed]
  13. Gene expression in the rat cerebral cortex: comparison of recovery sleep and hypnotic-induced sleep. Wisor, J.P., Morairty, S.R., Huynh, N.T., Steininger, T.L., Kilduff, T.S. Neuroscience (2006) [Pubmed]
  14. Antigen processing and presentation by the class I major histocompatibility complex. York, I.A., Rock, K.L. Annu. Rev. Immunol. (1996) [Pubmed]
  15. The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone. Anttonen, A.K., Mahjneh, I., Hämäläinen, R.H., Lagier-Tourenne, C., Kopra, O., Waris, L., Anttonen, M., Joensuu, T., Kalimo, H., Paetau, A., Tranebjaerg, L., Chaigne, D., Koenig, M., Eeg-Olofsson, O., Udd, B., Somer, M., Somer, H., Lehesjoki, A.E. Nat. Genet. (2005) [Pubmed]
  16. ATP is required for in vitro assembly of MHC class I antigens but not for transfer of peptides across the ER membrane. Lévy, F., Gabathuler, R., Larsson, R., Kvist, S. Cell (1991) [Pubmed]
  17. An Hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Munro, S., Pelham, H.R. Cell (1986) [Pubmed]
  18. The translocon: a dynamic gateway at the ER membrane. Johnson, A.E., van Waes, M.A. Annu. Rev. Cell Dev. Biol. (1999) [Pubmed]
  19. Stress protein GRP78 prevents apoptosis induced by calcium ionophore, ionomycin, but not by glycosylation inhibitor, tunicamycin, in human prostate cancer cells. Miyake, H., Hara, I., Arakawa, S., Kamidono, S. J. Cell. Biochem. (2000) [Pubmed]
  20. A stress-inducible rat liver endoplasmic reticulum protein, ERp29. Mkrtchian, S., Fang, C., Hellman, U., Ingelman-Sundberg, M. Eur. J. Biochem. (1998) [Pubmed]
  21. ER calcium discharge stimulates GDNF gene expression through MAPK-dependent and -independent pathways in rat C6 glioblastoma cells. Oh-hashi, K., Kaneyama, M., Hirata, Y., Kiuchi, K. Neurosci. Lett. (2006) [Pubmed]
  22. Detection of a serum DNA-binding protein associated with cancer. Galvan, L., Evans, J.E., Comis, R.L., Gottlieb, A., Gyorkey, F., Lane, M., Prestayko, A.W., Crooke, S.T. Cancer Res. (1982) [Pubmed]
  23. RXRA and HSPA5 map to the telomeric end of dog chromosome 9. Werner, P., Raducha, M.G., Prociuk, U., Lyons, L.A., Kehler, J.S., Henthorn, P.S., Patterson, D.F. Anim. Genet. (1998) [Pubmed]
  24. Endoplasmic reticulum stress induction of the Grp78/BiP promoter: activating mechanisms mediated by YY1 and its interactive chromatin modifiers. Baumeister, P., Luo, S., Skarnes, W.C., Sui, G., Seto, E., Shi, Y., Lee, A.S. Mol. Cell. Biol. (2005) [Pubmed]
  25. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Obeng, E.A., Carlson, L.M., Gutman, D.M., Harrington, W.J., Lee, K.P., Boise, L.H. Blood (2006) [Pubmed]
  26. Transcriptional regulation of the Grp78 promoter by endoplasmic reticulum stress: role of TFII-I and its tyrosine phosphorylation. Hong, M., Lin, M.Y., Huang, J.M., Baumeister, P., Hakre, S., Roy, A.L., Lee, A.S. J. Biol. Chem. (2005) [Pubmed]
  27. BiP binds type I procollagen pro alpha chains with mutations in the carboxyl-terminal propeptide synthesized by cells from patients with osteogenesis imperfecta. Chessler, S.D., Byers, P.H. J. Biol. Chem. (1993) [Pubmed]
  28. Grp78 is involved in retention of mutant low density lipoprotein receptor protein in the endoplasmic reticulum. Jørgensen, M.M., Jensen, O.N., Holst, H.U., Hansen, J.J., Corydon, T.J., Bross, P., Bolund, L., Gregersen, N. J. Biol. Chem. (2000) [Pubmed]
  29. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress. Ma, K., Vattem, K.M., Wek, R.C. J. Biol. Chem. (2002) [Pubmed]
  30. Requirement of the p38 mitogen-activated protein kinase signalling pathway for the induction of the 78 kDa glucose-regulated protein/immunoglobulin heavy-chain binding protein by azetidine stress: activating transcription factor 6 as a target for stress-induced phosphorylation. Luo, S., Lee, A.S. Biochem. J. (2002) [Pubmed]
  31. Phage display derived human monoclonal antibodies isolated by binding to the surface of live primary breast cancer cells recognize GRP78. Jakobsen, C.G., Rasmussen, N., Laenkholm, A.V., Ditzel, H.J. Cancer Res. (2007) [Pubmed]
  32. Involvement of endoplasmic reticulum chaperones in the folding of hepatitis C virus glycoproteins. Choukhi, A., Ung, S., Wychowski, C., Dubuisson, J. J. Virol. (1998) [Pubmed]
  33. Association of glucose-regulated protein (grp78) with human keratin 8. Liao, J., Price, D., Omary, M.B. FEBS Lett. (1997) [Pubmed]
  34. ER stress signaling by regulated proteolysis of ATF6. Shen, J., Prywes, R. Methods (2005) [Pubmed]
  35. Down-regulation of epidermal growth factor receptor-signaling pathway by binding of GRP78/BiP to the receptor under glucose-starved stress conditions. Cai, B., Tomida, A., Mikami, K., Nagata, K., Tsuruo, T. J. Cell. Physiol. (1998) [Pubmed]
  36. Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response. Shen, J., Snapp, E.L., Lippincott-Schwartz, J., Prywes, R. Mol. Cell. Biol. (2005) [Pubmed]
  37. Induction of the mammalian GRP78/BiP gene by Ca2+ depletion and formation of aberrant proteins: activation of the conserved stress-inducible grp core promoter element by the human nuclear factor YY1. Li, W.W., Hsiung, Y., Zhou, Y., Roy, B., Lee, A.S. Mol. Cell. Biol. (1997) [Pubmed]
  38. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Ye, J., Rawson, R.B., Komuro, R., Chen, X., Davé, U.P., Prywes, R., Brown, M.S., Goldstein, J.L. Mol. Cell (2000) [Pubmed]
  39. ATF6 modulates SREBP2-mediated lipogenesis. Zeng, L., Lu, M., Mori, K., Luo, S., Lee, A.S., Zhu, Y., Shyy, J.Y. EMBO J. (2004) [Pubmed]
  40. The 5'-flanking region of the human calreticulin gene shares homology with the human GRP78, GRP94, and protein disulfide isomerase promoters. McCauliffe, D.P., Yang, Y.S., Wilson, J., Sontheimer, R.D., Capra, J.D. J. Biol. Chem. (1992) [Pubmed]
  41. The asparagine-linked oligosaccharides of the human chorionic gonadotropin beta subunit facilitate correct disulfide bond pairing. Feng, W., Matzuk, M.M., Mountjoy, K., Bedows, E., Ruddon, R.W., Boime, I. J. Biol. Chem. (1995) [Pubmed]
  42. Role of extracellular molecular chaperones in the folding of oxidized proteins. Refolding of colloidal thyroglobulin by protein disulfide isomerase and immunoglobulin heavy chain-binding protein. Delom, F., Mallet, B., Carayon, P., Lejeune, P.J. J. Biol. Chem. (2001) [Pubmed]
  43. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. Shuda, M., Kondoh, N., Imazeki, N., Tanaka, K., Okada, T., Mori, K., Hada, A., Arai, M., Wakatsuki, T., Matsubara, O., Yamamoto, N., Yamamoto, M. J. Hepatol. (2003) [Pubmed]
  44. Selective cytotoxic activity of valinomycin against HT-29 Human colon carcinoma cells via down-regulation of GRP78. Ryoo, I.J., Park, H.R., Choo, S.J., Hwang, J.H., Park, Y.M., Bae, K.H., Shin-Ya, K., Yoo, I.D. Biol. Pharm. Bull. (2006) [Pubmed]
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