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Gene Review

HSPA1A  -  heat shock 70kDa protein 1A

Homo sapiens

Synonyms: HEL-S-103, HSP70-1, HSP70-1A, HSP70I, HSP72, ...
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Disease relevance of HSPA1A

  • Treatment of human K562 erythroleukemia cells with the antiproliferative prostaglandin A1 results in the elevated transcription of two heat shock genes, HSP70 and HSP90 [1].
  • Here we show that constitutive overexpression of the major inducible heat shock protein, hsp70, in transfected human cells reduces the extent of HSF activation after a heat stress [2].
  • This demonstrates that the promoter of this human hsp70 gene interacts with at least two positive transcriptional activators, CTF, which is required for CCAAT-box-dependent transcription as in other promoters such as those of globin and herpes simplex virus thymidine kinase genes, and HSTF, which is involved in heat inducibility [3].
  • Western blotting analysis showed that treatment of K562 cells with HA tetrasaccharides up-regulated Hsp72 expression after exposure to hyperthermia [4].
  • Induction of Hsp70 by ALLN was dose-dependent and not related to cell toxicity [5].

Psychiatry related information on HSPA1A

  • Polypeptides belonging to the Hsp70 major stress protein family and to the NF-kB/Rel multi-functional regulatory complex are known to be involved in cellular defense mechanisms [6].
  • However, large individual differences were observed as 3 of the 6 subjects had a marked increase in the release of Hsp72, whereas exercise had little effect on the cerebral Hsp72 balance in the remaining 3 subjects [7].
  • In an investigation of heat shock proteins (HSPs) in the brains of Alzheimer's disease (AD) patients and cognitively intact control subjects, we found that 2 HSPs, termed "HSP72" and "GRP78," underwent major changes in expression in AD [8].
  • Therefore, we purified a preparation of HSP70/HSC70 from bovine muscle and used it in a model of Huntington's disease [9].
  • Baseline physical activity and 6-min walk distance correlated negatively with circulating IL-6 (p<0.05); except for a negative correlation between TGF-beta and Hsp70 37 degrees C L (p<0.05), no significant relationships were found between cytokines and Hsp70 [10].

High impact information on HSPA1A

  • Genetic and biochemical analysis shows that several distinct chaperone systems, including Hsp70 and the cylindrical chaperonins, assist the folding of proteins upon translation in the cytosol of both prokaryotic and eukaryotic cells [11].
  • Whereas the main role of the HSP70/HSP40 chaperone system is to minimize aggregation of newly synthesized proteins, the HSP60 chaperones also facilitate the actual folding process by providing a secluded environment for individual folding molecules and may also promote the unfolding and refolding of misfolded intermediates [12].
  • We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5 [13].
  • While both folding and degradation of VHL require Hsp70, the chaperonin TRiC is essential for folding but is dispensable for degradation [14].
  • The TPR1 domain of Hop specifically recognizes the C-terminal heptapeptide of Hsp70 while the TPR2A domain binds the C-terminal pentapeptide of Hsp90 [15].

Chemical compound and disease context of HSPA1A


Biological context of HSPA1A


Anatomical context of HSPA1A

  • We identified the molecular chaperone Hsp70 as an interacting partner of FANCC in lymphoblasts and HeLa cells using 'pull-down' and co-immunoprecipitation experiments [26].
  • To study further the functional significance of Ku/CHBF in the cellular response to heat shock, we established rodent cell lines that stably and constitutively overexpressed one or both subunits of the human Ku protein, and examined the thermal induction of hsp70 and other heat shock proteins in these Ku-overexpressing ing cells [27].
  • Here we investigated the mechanism of Hsp72-mediated protection from tumor necrosis factor (TNF)-induced apoptosis of primary culture of IMR90 human fibroblasts [28].
  • Hemin-induced transcriptional activation of the HSP70 gene during erythroid maturation in K562 cells is due to a heat shock factor-mediated stress response [29].
  • We observed that N-acetyl-leucyl-leucyl-norleucinal (ALLN), a synthetic aldehydic tripeptide that inhibits proteasomes, markedly induced Hsp70 levels (up to 30-fold above base line in HepG2 cells and human endothelial cells) [5].

Associations of HSPA1A with chemical compounds

  • Moreover, CHIP enhanced Parkin-mediated in vitro ubiquitination of Pael-R in the absence of Hsp70 [30].
  • L-glutamine potentiation of Hsp72 is associated with increased epithelial resistance to apoptotic injury [31].
  • HSF activation in response to treatment with sodium arsenite or the proline analog azetidine was also depressed in hsp70-expressing cells relative to that in the nontransfected control cells [2].
  • Quercetin was found to inhibit hsp70 synthesis for a period of 3-6 h after PGA1 treatment [32].
  • Because MAP/AbeAdo caused also an intracelluar accumulation of putrescine, we tested the effect of exogenous putrescine, which was found to stabilize the mRNAs for hsp70 and c-jun [33].

Physical interactions of HSPA1A

  • Inhibition of HSP70 expression by calcium ionophore A23187 in human cells. An effect independent of the acquisition of DNA-binding activity by the heat shock transcription factor [34].
  • HspBP1 prevented ATP binding to Hsp70, and therefore this is the likely mechanism of inhibition [35].
  • To further elucidate the role of the association of Hsp70 with the NQO1*1 protein, site-directed mutagenesis was used to modify a proposed Hsp70 binding site near the N terminus of the NQO1 protein [36].
  • Here, we demonstrate that, during the priming step, ATP-bound hsp70 is converted to GR-bound hsp70 that is approximately 1/3 in the ADP- and approximately 2/3 in the ATP-dependent conformation [37].
  • After translocation, p53 is freed from Hsp proteins for binding to DNA where Hsp70 and Hsp90 are no longer able to form a nuclear complex probably rendering Hsp's labile to proteolysis [38].

Enzymatic interactions of HSPA1A

  • An increase in the intracellular Ca2+ concentration ([Ca2+]i), externalization of Fas, and decrease in Hsp70 and phosphorylated HSF1 were observed following the combined treatment [39].
  • Thus, in erythroid precursors undergoing terminal differentiation, Hsp70 prevents active caspase-3 from cleaving GATA-1 and inducing apoptosis [40].

Co-localisations of HSPA1A

  • After insulin treatment, Hsp70 was mostly colocalized to the plasma membrane with dystrophin [41].
  • Hsp70 also colocalizes with RNA polymerase I, both being restricted to the DFC [42].
  • At the onset of caspase activation, Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation [40].

Regulatory relationships of HSPA1A


Other interactions of HSPA1A


Analytical, diagnostic and therapeutic context of HSPA1A


  1. Antiproliferative prostaglandins activate heat shock transcription factor. Amici, C., Sistonen, L., Santoro, M.G., Morimoto, R.I. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  2. The DNA-binding activity of the human heat shock transcription factor is regulated in vivo by hsp70. Mosser, D.D., Duchaine, J., Massie, B. Mol. Cell. Biol. (1993) [Pubmed]
  3. Two transcriptional activators, CCAAT-box-binding transcription factor and heat shock transcription factor, interact with a human hsp70 gene promoter. Morgan, W.D., Williams, G.T., Morimoto, R.I., Greene, J., Kingston, R.E., Tjian, R. Mol. Cell. Biol. (1987) [Pubmed]
  4. Effect of hyaluronan oligosaccharides on the expression of heat shock protein 72. Xu, H., Ito, T., Tawada, A., Maeda, H., Yamanokuchi, H., Isahara, K., Yoshida, K., Uchiyama, Y., Asari, A. J. Biol. Chem. (2002) [Pubmed]
  5. Evidence that a rapidly turning over protein, normally degraded by proteasomes, regulates hsp72 gene transcription in HepG2 cells. Zhou, M., Wu, X., Ginsberg, H.N. J. Biol. Chem. (1996) [Pubmed]
  6. Major stress protein Hsp70 interacts with NF-kB regulatory complex in human T-lymphoma cells. Guzhova, I.V., Darieva, Z.A., Melo, A.R., Margulis, B.A. Cell Stress Chaperones (1997) [Pubmed]
  7. Exercise induces the release of heat shock protein 72 from the human brain in vivo. Lancaster, G.I., Møller, K., Nielsen, B., Secher, N.H., Febbraio, M.A., Nybo, L. Cell Stress Chaperones (2004) [Pubmed]
  8. Expression of heat shock proteins in Alzheimer's disease. Hamos, J.E., Oblas, B., Pulaski-Salo, D., Welch, W.J., Bole, D.G., Drachman, D.A. Neurology (1991) [Pubmed]
  9. Treatment with extracellular HSP70/HSC70 protein can reduce polyglutamine toxicity and aggregation. Novoselova, T.V., Margulis, B.A., Novoselov, S.S., Sapozhnikov, A.M., van der Spuy, J., Cheetham, M.E., Guzhova, I.V. J. Neurochem. (2005) [Pubmed]
  10. Biochemical changes in response to intensive resistance exercise training in the elderly. Bautmans, I., Njemini, R., Vasseur, S., Chabert, H., Moens, L., Demanet, C., Mets, T. Gerontology. (2005) [Pubmed]
  11. Folding of newly translated proteins in vivo: the role of molecular chaperones. Frydman, J. Annu. Rev. Biochem. (2001) [Pubmed]
  12. Chaperone-mediated protein folding. Fink, A.L. Physiol. Rev. (1999) [Pubmed]
  13. 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]
  14. Folding and quality control of the VHL tumor suppressor proceed through distinct chaperone pathways. McClellan, A.J., Scott, M.D., Frydman, J. Cell (2005) [Pubmed]
  15. Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Scheufler, C., Brinker, A., Bourenkov, G., Pegoraro, S., Moroder, L., Bartunik, H., Hartl, F.U., Moarefi, I. Cell (2000) [Pubmed]
  16. Ectopic expression of Hsp70 confers resistance and silencing its expression sensitizes human colon cancer cells to curcumin-induced apoptosis. Rashmi, R., Kumar, S., Karunagaran, D. Carcinogenesis (2004) [Pubmed]
  17. Transactivation of hsp70-1/2 in geldanamycin-treated human non-small cell lung cancer H460 cells: involvement of intracellular calcium and protein kinase C. Shu, C.W., Cheng, N.L., Chang, W.M., Tseng, T.L., Lai, Y.K. J. Cell. Biochem. (2005) [Pubmed]
  18. Higher induction of heat shock protein 72 by heat stress in cisplatin-resistant than in cisplatin-sensitive cancer cells. Abe, T., Gotoh, S., Higashi, K. Biochim. Biophys. Acta (1999) [Pubmed]
  19. JNK phosphorylates the HSF1 transcriptional activation domain: role of JNK in the regulation of the heat shock response. Park, J., Liu, A.Y. J. Cell. Biochem. (2001) [Pubmed]
  20. Quercetin suppresses heat shock-induced nuclear translocation of Hsp72. Jakubowicz-Gil, J., Pawlikowska-Pawlega, B., Piersiak, T., Pawelec, J., Gawron, A. Folia Histochem. Cytobiol. (2005) [Pubmed]
  21. Gene conversion and GC-content evolution in mammalian Hsp70. Kudla, G., Helwak, A., Lipinski, L. Mol. Biol. Evol. (2004) [Pubmed]
  22. Comparison of gene expression profile between human chondrons and chondrocytes: a cDNA microarray study. Zhang, Z., Fan, J., Becker, K.G., Graff, R.D., Lee, G.M., Francomano, C.A. Osteoarthr. Cartil. (2006) [Pubmed]
  23. The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression. Abravaya, K., Myers, M.P., Murphy, S.P., Morimoto, R.I. Genes Dev. (1992) [Pubmed]
  24. Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue. Differential regulation of hsp70 expression and hsf1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs. Schett, G., Redlich, K., Xu, Q., Bizan, P., Gröger, M., Tohidast-Akrad, M., Kiener, H., Smolen, J., Steiner, G. J. Clin. Invest. (1998) [Pubmed]
  25. Heat shock factor-1 protein in heat shock factor-1 gene-transfected human epidermoid A431 cells requires phosphorylation before inducing heat shock protein-70 production. Ding, X.Z., Tsokos, G.C., Kiang, J.G. J. Clin. Invest. (1997) [Pubmed]
  26. FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity. Pang, Q., Keeble, W., Christianson, T.A., Faulkner, G.R., Bagby, G.C. EMBO J. (2001) [Pubmed]
  27. Modulation of thermal induction of hsp70 expression by Ku autoantigen or its individual subunits. Yang, S.H., Nussenzweig, A., Li, L., Kim, D., Ouyang, H., Burgman, P., Li, G.C. Mol. Cell. Biol. (1996) [Pubmed]
  28. Hsp72 and stress kinase c-jun N-terminal kinase regulate the bid-dependent pathway in tumor necrosis factor-induced apoptosis. Gabai, V.L., Mabuchi, K., Mosser, D.D., Sherman, M.Y. Mol. Cell. Biol. (2002) [Pubmed]
  29. Hemin-induced transcriptional activation of the HSP70 gene during erythroid maturation in K562 cells is due to a heat shock factor-mediated stress response. Theodorakis, N.G., Zand, D.J., Kotzbauer, P.T., Williams, G.T., Morimoto, R.I. Mol. Cell. Biol. (1989) [Pubmed]
  30. CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Imai, Y., Soda, M., Hatakeyama, S., Akagi, T., Hashikawa, T., Nakayama, K.I., Takahashi, R. Mol. Cell (2002) [Pubmed]
  31. Anti-apoptotic effects of L-glutamine-mediated transcriptional modulation of the heat shock protein 72 during heat shock. Ropeleski, M.J., Riehm, J., Baer, K.A., Musch, M.W., Chang, E.B. Gastroenterology (2005) [Pubmed]
  32. Modulation of prostaglandin A1-induced thermotolerance by quercetin in human leukemic cells: role of heat shock protein 70. Elia, G., Amici, C., Rossi, A., Santoro, M.G. Cancer Res. (1996) [Pubmed]
  33. Effects of polyamine imbalance on the induction of stress genes in hepatocarcinoma cells exposed to heat shock. Desiderio, M.A., Tacchini, L., Anzon, E., Pogliaghi, G., Radice, L., Bernelli-Zazzera, A. Hepatology (1996) [Pubmed]
  34. Inhibition of HSP70 expression by calcium ionophore A23187 in human cells. An effect independent of the acquisition of DNA-binding activity by the heat shock transcription factor. Elia, G., De Marco, A., Rossi, A., Santoro, M.G. J. Biol. Chem. (1996) [Pubmed]
  35. Inhibition of Hsp70 ATPase activity and protein renaturation by a novel Hsp70-binding protein. Raynes, D.A., Guerriero, V. J. Biol. Chem. (1998) [Pubmed]
  36. Interaction of the molecular chaperone Hsp70 with human NAD(P)H:quinone oxidoreductase 1. Anwar, A., Siegel, D., Kepa, J.K., Ross, D. J. Biol. Chem. (2002) [Pubmed]
  37. Evidence for iterative ratcheting of receptor-bound hsp70 between its ATP and ADP conformations during assembly of glucocorticoid receptor.hsp90 heterocomplexes. Morishima, Y., Kanelakis, K.C., Murphy, P.J., Shewach, D.S., Pratt, W.B. Biochemistry (2001) [Pubmed]
  38. Multiple p53 protein isoforms and formation of oligomeric complexes with heat shock proteins Hsp70 and Hsp90 in the human mammary tumor, T47D, cell line. Selkirk, J.K., Merrick, B.A., Stackhouse, B.L., He, C. Appl. Theor. Electrophor. (1994) [Pubmed]
  39. Enhancement of apoptosis by nitric oxide released from alpha-phenyl-tert-butyl nitrone under hyperthermic conditions. Cui, Z.G., Kondo, T., Matsumoto, H. J. Cell. Physiol. (2006) [Pubmed]
  40. Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1. Ribeil, J.A., Zermati, Y., Vandekerckhove, J., Cathelin, S., Kersual, J., Dussiot, M., Coulon, S., Moura, I.C., Zeuner, A., Kirkegaard-S??rensen, T., Varet, B., Solary, E., Garrido, C., Hermine, O. Nature (2007) [Pubmed]
  41. Insulin induces myocardial protection and Hsp70 localization to plasma membranes in rat hearts. Li, G., Ali, I.S., Currie, R.W. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  42. Specific intranucleolar distribution of Hsp70 during heat shock in polytene cells. Morcillo, G., Gorab, E., Tanguay, R.M., Díez, J.L. Exp. Cell Res. (1997) [Pubmed]
  43. Bag1 functions in vivo as a negative regulator of Hsp70 chaperone activity. Nollen, E.A., Brunsting, J.F., Song, J., Kampinga, H.H., Morimoto, R.I. Mol. Cell. Biol. (2000) [Pubmed]
  44. Metabolic oxidative stress-induced HSP70 gene expression is mediated through SAPK pathway. Role of Bcl-2 and c-Jun NH2-terminal kinase. Lee, Y.J., Corry, P.M. J. Biol. Chem. (1998) [Pubmed]
  45. Chaperone hsp27 inhibits translation during heat shock by binding eIF4G and facilitating dissociation of cap-initiation complexes. Cuesta, R., Laroia, G., Schneider, R.J. Genes Dev. (2000) [Pubmed]
  46. GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1. Höhfeld, J., Jentsch, S. EMBO J. (1997) [Pubmed]
  47. Is preeclampsia associated with higher frequency of HSP70 gene polymorphisms? Fekete, A., Vér, A., Bögi, K., Treszl, A., Rigó, J. Eur. J. Obstet. Gynecol. Reprod. Biol. (2006) [Pubmed]
  48. Activation of heat shock factor 2 during hemin-induced differentiation of human erythroleukemia cells. Sistonen, L., Sarge, K.D., Phillips, B., Abravaya, K., Morimoto, R.I. Mol. Cell. Biol. (1992) [Pubmed]
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