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Gene Review

HSF1  -  heat shock transcription factor 1

Homo sapiens

Synonyms: HSF 1, HSTF 1, HSTF1, Heat shock factor protein 1, Heat shock transcription factor 1
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Disease relevance of HSF1

  • Gel mobility shift analysis revealed increased HSF1 activation, and Western blotting and immunohistochemistry revealed increased hsp70 expression in RA synovial tissue, but not in synovial tissue derived from patients with osteoarthritis [1].
  • Like its counterpart in Drosophila, human HSF1 produced in Escherichia coli in the absence of heat shock is active as a DNA binding transcription factor, suggesting that the intrinsic activity of HSF is under negative control in human cells [2].
  • HSF1 is activated by heat shock and other forms of stress, whereas HSF2 is activated during hemin-induced differentiation of human K562 erythroleukemia cells, suggesting a role for HSF2 in regulating heat shock gene expression under nonstress conditions such as differentiation and development [3].
  • Furthermore, inhibition of HSF1/hsp70 was accompanied by an increase in apoptosis rates from 20% to 50% in response to heat stress [4].
  • Thus, disrupting HSF1 in combination with hyperthermia may open new possibilities for treatment of cancers that have acquired resistance to heat treatment [5].
  • We observed that the Hsp70 co-chaperone, BAG3 (Bcl-2-associated athanogene domain 3), is strongly induced by HNE in control but not in HSF1-silenced colon cancer cells [6].

Psychiatry related information on HSF1

  • Subsequent to the stressful event, hHSF1 is deactivated and eventually returned to its unactivated form [7].
  • Alzheimer's disease (AD) and control cybrid cells (SH-SY5Y cells in which the mitochondria were replaced with platelet mitochondria from AD or matched control subjects) were used to test the effects of the chronic oxidative stress caused by the excessive production of reactive oxygen intermediates (ROIs) in AD cybrids on HSF-1 activity [8].

High impact information on HSF1


Chemical compound and disease context of HSF1


Biological context of HSF1

  • The rapid yet transient transcriptional activation of heat shock genes is mediated by the reversible conversion of HSF1 from an inert negatively regulated monomer to a transcriptionally active DNA-binding trimer [19].
  • During attenuation of the heat shock response, transcription of heat shock genes returns to basal levels and HSF1 reverts to an inert monomer [19].
  • Activation of PKC can cause phosphorylation of HSF1, which leads to an enhanced but transient increase in HSP-70 production [20].
  • The HSF1 gene was inserted into pCDNA3 plasmid and then transfected into human epidermoid A431 cells using the CaOP3 method [20].
  • Heat shock factor-1 (HSF1) is a transcriptional factor that binds to heat shock elements located on the promoter region of heat shock protein genes [20].

Anatomical context of HSF1


Associations of HSF1 with chemical compounds

  • This finding is further supported by phosphopeptide mapping and analysis with S303/7 phosphospecific antibodies, which demonstrate that serine 303 is a target for strong heat-inducible phosphorylation, corresponding to the inducible HSF1 sumoylation [24].
  • Sumoylation is rapidly and transiently enhanced on lysine 298, located in the regulatory domain of HSF1, adjacent to several critical phosphorylation sites [24].
  • Upon activation, HSF1 trimerizes, binds to DNA, concentrates in the nuclear stress granules, and undergoes a marked multisite phosphorylation, which correlates with its transcriptional activity [24].
  • Inhibition of HSP70 expression is correlated with alterations in HSF1 phosphorylation in heat-shocked cells, but not in sodium arsenite-treated cells, indicating that different mechanisms may be involved in mediating A23187 inhibitory activity [25].
  • The effects of ALLN appeared to require de novo protein synthesis, since the induction of both HSF1 trimerization and hsp72 transcription was blocked by co-treatment with cycloheximide [26].

Physical interactions of HSF1

  • In this study, we demonstrate that the less-well characterized HSF2 interacts physically with HSF1 and is a novel stress-responsive component of the stress granules [27].
  • The negative regulatory region (NR) of HSF1 did not interact with any general factors tested in vitro but did bind TFIID in nuclear extracts through contacts that probably involve TATA associated proteins (TAFs) [28].
  • At least in the case of the IL1B promoter, repression did not seem to involve another factor whose activity is affected by the NSAIDs, NFkappaB as the IL1B promoter fragment used in our studies is not NFkappaB responsive and binds specifically to HSF1 [29].
  • Here, we show that the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the transactivation domain of HSF1 and repress heat shock gene transcription [19].
  • We show for the first time that HSF1 binds directly to NF-IL6 in vivo and antagonizes its activity [30].

Enzymatic interactions of HSF1

  • We previously showed that ERK1 phosphorylates HSF1 on serine 307 and leads to secondary phosphorylation by glycogen synthase kinase 3 (GSK3) on serine 303 within the regulatory domain and that these phosphorylation events repress HSF1 [31].
  • We have shown that MK2 directly phosphorylates HSF1 and inhibits activity by decreasing its ability to bind the heat shock elements (HSE) found in the promoters of target genes encoding the HSP molecular chaperones and cytokine genes [32].
  • JNK phosphorylates the HSF1 transcriptional activation domain: role of JNK in the regulation of the heat shock response [33].
  • We showed that treatment of HeLa cells with MG132, a proteasome inhibitor and known INK activator, caused the transcriptional activation domain of HSF1 to be targeted and phosphorylated by JNK2 in vivo [33].
  • 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 [34].

Co-localisations of HSF1

  • HSF1 colocalizes with SUMO-1 in nuclear stress granules, which is prevented by mutation of lysine 298 [35].

Regulatory relationships of HSF1

  • Based on analysis of our deletion mutants, HSF2 influences to the localization of HSF1 in stress granules [27].
  • Sumoylation analyses of HSF1 phosphorylation site mutants reveal that specifically the phosphorylation-deficient S303 mutant remains devoid of SUMO modification in vivo and the mutant mimicking phosphorylation of S303 promotes HSF1 sumoylation in vitro, indicating that S303 phosphorylation is required for K298 sumoylation [24].
  • Elevated expression of heat shock factor (HSF) 2A stimulates HSF1-induced transcription during stress [36].
  • HSF1 has little effect on IL-1beta promoter activity stimulated by the essential monocytic transcription factor Spi.1 but is strongly inhibitory to transcriptional activation by NF-IL6 and to the synergistic activation by NF-IL6 and Spi [30].
  • Here we show, for the first time, that HSF1 is regulated by the proinflammatory protein kinase MAPKAP kinase 2 (MK2) [32].

Other interactions of HSF1

  • We demonstrate that human HSF2, but not HSF1, homotrimerizes and functionally complements the viability defect associated with a deletion of the yeast HSF gene [37].
  • We showed that RET expression leads to increased HSF1 activation, which correlates with increased expression of stress response genes [38].
  • The possibility that activation of the MAPK signaling cascade, notably JNK, may contribute to the hyperphosphorylation of human HSF1 (hHSF1) is discussed [39].
  • Pharmacological inhibitors of the ERK1/2 kinase pathway or the p38 kinase had little or no effect on the pervanadate-induced hyperphosphorylation of HSF1 [39].
  • These results suggest a model for transcriptional regulation by HSF1 that involves a shift between formation of dysfunctional TFIID complexes with the NR and transcriptionally competent complexes with the C-terminal activation domains [28].

Analytical, diagnostic and therapeutic context of HSF1


  1. 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]
  2. Molecular cloning and expression of a human heat shock factor, HSF1. Rabindran, S.K., Giorgi, G., Clos, J., Wu, C. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  3. Human heat shock factors 1 and 2 are differentially activated and can synergistically induce hsp70 gene transcription. Sistonen, L., Sarge, K.D., Morimoto, R.I. Mol. Cell. Biol. (1994) [Pubmed]
  4. Activation of Fas inhibits heat-induced activation of HSF1 and up-regulation of hsp70. Schett, G., Steiner, C.W., Gröger, M., Winkler, S., Graninger, W., Smolen, J., Xu, Q., Steiner, G. FASEB J. (1999) [Pubmed]
  5. Blocking HSF1 by dominant-negative mutant to sensitize tumor cells to hyperthermia. Wang, J.H., Yao, M.Z., Gu, J.F., Sun, L.Y., Shen, Y.F., Liu, X.Y. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  6. HSF1-mediated BAG3 expression attenuates apoptosis in 4-hydroxynonenal-treated colon cancer cells via stabilization of anti-apoptotic Bcl-2 proteins. Jacobs, A.T., Marnett, L.J. J. Biol. Chem. (2009) [Pubmed]
  7. Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex. Guo, Y., Guettouche, T., Fenna, M., Boellmann, F., Pratt, W.B., Toft, D.O., Smith, D.F., Voellmy, R. J. Biol. Chem. (2001) [Pubmed]
  8. Rapid activation of heat shock factor-1 DNA binding by H2O2 and modulation by glutathione in human neuroblastoma and Alzheimer's disease cybrid cells. Bijur, G.N., Davis, R.E., Jope, R.S. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  9. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Zou, J., Guo, Y., Guettouche, T., Smith, D.F., Voellmy, R. Cell (1998) [Pubmed]
  10. Activation of heat shock transcription factor 3 by c-Myb in the absence of cellular stress. Kanei-Ishii, C., Tanikawa, J., Nakai, A., Morimoto, R.I., Ishii, S. Science (1997) [Pubmed]
  11. Crystal structure of the DNA binding domain of the heat shock transcription factor. Harrison, C.J., Bohm, A.A., Nelson, H.C. Science (1994) [Pubmed]
  12. Competitive inhibition of hsp70 gene expression causes thermosensitivity. Johnston, R.N., Kucey, B.L. Science (1988) [Pubmed]
  13. Localized recruitment of a chromatin-remodeling activity by an activator in vivo drives transcriptional elongation. Corey, L.L., Weirich, C.S., Benjamin, I.J., Kingston, R.E. Genes Dev. (2003) [Pubmed]
  14. Polo-like kinase 1 phosphorylates heat shock transcription factor 1 and mediates its nuclear translocation during heat stress. Kim, S.A., Yoon, J.H., Lee, S.H., Ahn, S.G. J. Biol. Chem. (2005) [Pubmed]
  15. Quercetin inhibits heat shock protein induction but not heat shock factor DNA-binding in human breast carcinoma cells. Hansen, R.K., Oesterreich, S., Lemieux, P., Sarge, K.D., Fuqua, S.A. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  16. Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. Fujimoto, M., Takaki, E., Hayashi, T., Kitaura, Y., Tanaka, Y., Inouye, S., Nakai, A. J. Biol. Chem. (2005) [Pubmed]
  17. Targeting the heat shock factor 1 by RNA interference: a potent tool to enhance hyperthermochemotherapy efficacy in cervical cancer. Rossi, A., Ciafrè, S., Balsamo, M., Pierimarchi, P., Santoro, M.G. Cancer Res. (2006) [Pubmed]
  18. Formation of nuclear HSF1 granules varies depending on stress stimuli. Holmberg, C.I., Illman, S.A., Kallio, M., Mikhailov, A., Sistonen, L. Cell Stress Chaperones (2000) [Pubmed]
  19. Molecular chaperones as HSF1-specific transcriptional repressors. Shi, Y., Mosser, D.D., Morimoto, R.I. Genes Dev. (1998) [Pubmed]
  20. 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]
  21. 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]
  22. Distinct stress-inducible and developmentally regulated heat shock transcription factors in Xenopus oocytes. Gordon, S., Bharadwaj, S., Hnatov, A., Ali, A., Ovsenek, N. Dev. Biol. (1997) [Pubmed]
  23. Activation of heat shock factor 1 by hyperosmotic or hypo-osmotic stress is drastically attenuated in normal human fibroblasts during senescence. Lu, J., Park, J.H., Liu, A.Y., Chen, K.Y. J. Cell. Physiol. (2000) [Pubmed]
  24. Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Hietakangas, V., Ahlskog, J.K., Jakobsson, A.M., Hellesuo, M., Sahlberg, N.M., Holmberg, C.I., Mikhailov, A., Palvimo, J.J., Pirkkala, L., Sistonen, L. Mol. Cell. Biol. (2003) [Pubmed]
  25. 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]
  26. 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]
  27. Formation of nuclear stress granules involves HSF2 and coincides with the nucleolar localization of Hsp70. Alastalo, T.P., Hellesuo, M., Sandqvist, A., Hietakangas, V., Kallio, M., Sistonen, L. J. Cell. Sci. (2003) [Pubmed]
  28. Potential targets for HSF1 within the preinitiation complex. Yuan, C.X., Gurley, W.B. Cell Stress Chaperones (2000) [Pubmed]
  29. Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Housby, J.N., Cahill, C.M., Chu, B., Prevelige, R., Bickford, K., Stevenson, M.A., Calderwood, S.K. Cytokine (1999) [Pubmed]
  30. Heat shock factor 1 represses transcription of the IL-1beta gene through physical interaction with the nuclear factor of interleukin 6. Xie, Y., Chen, C., Stevenson, M.A., Auron, P.E., Calderwood, S.K. J. Biol. Chem. (2002) [Pubmed]
  31. Regulation of molecular chaperone gene transcription involves the serine phosphorylation, 14-3-3 epsilon binding, and cytoplasmic sequestration of heat shock factor 1. Wang, X., Grammatikakis, N., Siganou, A., Calderwood, S.K. Mol. Cell. Biol. (2003) [Pubmed]
  32. Phosphorylation of HSF1 by MAPK-activated protein kinase 2 on serine 121, inhibits transcriptional activity and promotes HSP90 binding. Wang, X., Khaleque, M.A., Zhao, M.J., Zhong, R., Gaestel, M., Calderwood, S.K. J. Biol. Chem. (2006) [Pubmed]
  33. 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]
  34. 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]
  35. Regulation of heat shock transcription factor 1 by stress-induced SUMO-1 modification. Hong, Y., Rogers, R., Matunis, M.J., Mayhew, C.N., Goodson, M.L., Park-Sarge, O.K., Sarge, K.D., Goodson, M. J. Biol. Chem. (2001) [Pubmed]
  36. Elevated expression of heat shock factor (HSF) 2A stimulates HSF1-induced transcription during stress. He, H., Soncin, F., Grammatikakis, N., Li, Y., Siganou, A., Gong, J., Brown, S.A., Kingston, R.E., Calderwood, S.K. J. Biol. Chem. (2003) [Pubmed]
  37. Conservation of a stress response: human heat shock transcription factors functionally substitute for yeast HSF. Liu, X.D., Liu, P.C., Santoro, N., Thiele, D.J. EMBO J. (1997) [Pubmed]
  38. The RET receptor is linked to stress response pathways. Myers, S.M., Mulligan, L.M. Cancer Res. (2004) [Pubmed]
  39. Pervanadate induces the hyperphosphorylation but not the activation of human heat shock factor 1. Park, J., Liu, A.Y. J. Cell. Physiol. (2000) [Pubmed]
  40. Developmentally dictated expression of heat shock factors: exclusive expression of HSF4 in the postnatal lens and its specific interaction with alphaB-crystallin heat shock promoter. Somasundaram, T., Bhat, S.P. J. Biol. Chem. (2004) [Pubmed]
  41. Activation of heat-shock transcription factor 1 in heated Chinese hamster ovary cells is dependent on the cell cycle and is inhibited by sodium vanadate. He, L., Fox, M.H. Radiat. Res. (1999) [Pubmed]
  42. 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]
  43. Functional role for heat shock factors in the transcriptional regulation of human RANK ligand gene expression in stromal/osteoblast cells. Roccisana, J.L., Kawanabe, N., Kajiya, H., Koide, M., Roodman, G.D., Reddy, S.V. J. Biol. Chem. (2004) [Pubmed]
  44. Regulation of the HIV1 long terminal repeat by mutant heat shock factor. Ignatenko, N.A., Gerner, E.W. Exp. Cell Res. (2003) [Pubmed]
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