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Gene Review

HSF1  -  Hsf1p

Saccharomyces cerevisiae S288c

Synonyms: EXA3, HSF, HSTF, Heat shock factor protein, Heat shock transcription factor, ...
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Disease relevance of HSF1

  • A HSF1 mutant (hsf1-m3) which does not induce the expression of some heat shock proteins at heat stress (37-40 degrees C) is defective in recovery after heat shock at 50-52 degrees C compared to a corresponding wild-type strain in both stationary and exponentially growing cells [1].
  • In response to hyperthermia, heat shock transcription factor (HSF) activates transcription of a set of genes encoding heat shock proteins (HSPs) [2].
  • In an effort to elucidate the mechanism of this regulation, we constructed a series of HSF-VP16 fusions that join the HSF DNA-binding domain to the strong transcriptional activation domain from the VP16 gene of herpes simplex virus [3].
  • Here we show that E. coli HtpG immobilized to Affi-Gel beads selectively retains sigma 32 while the yeast hsp90 and rat hsp90 retain HSF [4].
  • Our findings establish the importance of HSF in prion initiation and strain determination and imply a similar regulatory role of mammalian HSFs in the complex etiology of prion disease [5].

High impact information on HSF1

  • Using a yeast heat shock gene flanked by mating-type silencers as a model system, we find that repressive, SIR-generated heterochromatin is permissive to the constitutive binding of an activator, HSF, and two components of the preinitiation complex (PIC), TBP and Pol II [6].
  • Heat shock factor and the heat shock response [7].
  • The yeast heat shock transcription factor contains a transcriptional activation domain whose activity is repressed under nonshock conditions [8].
  • These sustained and transient activities are regulated over different temperature ranges, and increases in both are associated with rises in the level of HSF phosphorylation [9].
  • Trimerization is mediated by a region of HSF that, like the leucine zipper, is characterized by the occurrence of hydrophobic amino acids every 7 residues [10].

Chemical compound and disease context of HSF1


Biological context of HSF1

  • These characteristics of the HSF1 loop region are transposable to HSF2 and sufficient to confer DNA-binding specificity, heat shock inducible HSP gene expression and protection from heat-induced apoptosis in vivo [12].
  • We have isolated mutations in the HSF1 gene from Saccharomyces cerevisiae that severely compromise the ability of HSF to bind to its normal binding site, repeats of the module nGAAn [13].
  • A double, semidominant HSF1 mutant with substitutions at codons 206 and 256 within the DNA-binding domain of the heat shock factor (HSF) confers two phenotypes [14].
  • Fine mapping by functional analysis of HSF1-HSF2 chimeras and point mutagenesis revealed that a small region in the amino-terminal portion of the HSF1 linker is required for maintenance of HSF1 in the monomeric state in both yeast and in transfected human 293 cells [15].
  • Using a plasmid shuffle screen, we isolated mutations in the HSF1 gene after in vitro mutagenesis of plasmid DNA with hydroxylamine [16].

Anatomical context of HSF1

  • Deletion analysis of HSF1 largely confirmed the mapping and expression pattern of activation domain 2 (AD2) previously reported by Green et al (1995) with the exception of the contribution of the oligomerization domain (hydrophobic region A) to basal repression in yeast, but not in HeLa cells [17].
  • The results have revealed that Hsf1 is necessary for heat-induced transcription of not only HSP but also genes encoding proteins involved in diverse cellular processes such as protein degradation, detoxification, energy generation, carbohydrate metabolism, and maintenance of cell wall integrity [2].
  • HSF mediates the transcriptional response of eukaryotic cells to heat, infection and inflammation, pharmacological agents, and other stresses [18].
  • Our studies suggest that Ssb is regulated like a core component of the ribosome and that HSF is required for proper regulation of SSB and ribosomal mRNA after a temperature upshift [19].
  • They also show that overexpression of HSF-1 in neurons or body-wall muscle cells is sufficient to extend longevity [20].

Associations of HSF1 with chemical compounds

  • We have introduced cysteine substitutions into the yeast HSF1 gene at a variety of locations [21].
  • Interestingly, approximately 30% of the HSF direct target genes are also induced by the diauxic shift, in which glucose levels begin to be depleted [11].
  • Our results suggest that the dramatic changes in S. cerevisiae HSF1 transcriptional activity in response to stress might be linked to the combined effects of trehalose and elevated temperatures in modifying the overall structure of HSF1's C-terminal activation domain [22].
  • Heat shock transcription factor Hsf1 activates ERO1 in response to heat, ethanol, and oxidative stresses [23].
  • Here we report that a short conserved element is involved in returning yeast HSF to the inactive state after heat shock and show that deactivation can be enhanced by phosphorylation of adjacent serine residues [24].

Physical interactions of HSF1

  • In addition, the N-terminal region of the SFL1 gene product shows extensive homology to the DNA-binding domain of HSTF [25].
  • Here we investigate the structural and functional effects of mutating HSE1, the preferred heat shock factor (HSF) binding site upstream of the yeast HSP82 gene [26].
  • The Skn7 response regulator of Saccharomyces cerevisiae interacts with Hsf1 in vivo and is required for the induction of heat shock genes by oxidative stress [27].
  • Our recent genomic footprinting experiments demonstrate that HSF binds constitutively to perfect and imperfect heat shock elements (HSEs) in the HSP26 gene in yeast [28].
  • Binding to these promoters is rapidly induced by heat stress at 39 degrees . HSF binds to ScSSA1 and HSP104 promoters under non-stress conditions, but at a low level [29].

Enzymatic interactions of HSF1

  • We then focused on the contribution of the activation domains of Hsf1 to the expression profile and extended our analysis to include msn2/4Delta strains deleted for the N-terminal or C-terminal activation domain of Hsf1 [30].

Regulatory relationships of HSF1

  • These data imply a critical role for HSF in displacing stably positioned nucleosomes in Saccharomyces cerevisiae and suggest that HSF transcriptionally activates HSP82 at least partly through its ability to alleviate nucleosome repression of the core promoter [26].
  • Here we show that the expression of Saccharomyces cerevisiae MDJ1 encoding a mitochondrial DnaJ homolog is regulated by HSF via a novel non-consensus HSE (ncHSE(MDJ1)), which consists of three separated pentameric nGAAn motifs, nTTCn-(11 bp)-nGAAn-(5 bp)-nGAAn [31].
  • Transcription from constructs designed to create steric competition between binding of HSF and histone H2A-H2B dimers was generally poor, suggesting that nucleosome assembly precedes and inhibits HSF binding [32].
  • Heat shock factor-independent heat control of transcription of the CTT1 gene encoding the cytosolic catalase T of Saccharomyces cerevisiae [33].

Other interactions of HSF1

  • Sse1 is required for function of the glucocorticoid receptor, a model substrate of the Hsp90 chaperone machinery, and Hsp90-based repression of HSF under nonstress conditions [34].
  • To address this question, we constructed an msn2/4 double mutant and used microarrays to elucidate the genome-wide expression program of Hsf1 [30].
  • Heat shock induction of SSE1, encoding a member of the Hsp110 family of heat shock proteins, was also dependent on the HSF CTA [34].
  • We describe here our phenotypic analysis of two such mutants, hsf1-82 and ydj1-10, that affect the heat shock transcription factor and a yeast dnaj-like protein chaperone, respectively. hsf1-82 and ydj1-10 temperature-sensitive mutants arrest the cell division cycle at several stages [35].
  • Consistent with this hypothesis, EXA3-1 is tightly linked to HSF1, the gene encoding the transcriptional regulatory protein known as "heat shock factor." All of the genes identified in this study seem to be involved in regulating the expression of SSA3 and SSA4 or the activity of their protein products [36].

Analytical, diagnostic and therapeutic context of HSF1


  1. The heat shock factor and mitochondrial Hsp70 are necessary for survival of heat shock in Saccharomyces cerevisiae. Nwaka, S., Mechler, B., von Ahsen, O., Holzer, H. FEBS Lett. (1996) [Pubmed]
  2. Identification of a novel class of target genes and a novel type of binding sequence of heat shock transcription factor in Saccharomyces cerevisiae. Yamamoto, A., Mizukami, Y., Sakurai, H. J. Biol. Chem. (2005) [Pubmed]
  3. Temperature-dependent regulation of a heterologous transcriptional activation domain fused to yeast heat shock transcription factor. Bonner, J.J., Heyward, S., Fackenthal, D.L. Mol. Cell. Biol. (1992) [Pubmed]
  4. Hsp90 chaperonins possess ATPase activity and bind heat shock transcription factors and peptidyl prolyl isomerases. Nadeau, K., Das, A., Walsh, C.T. J. Biol. Chem. (1993) [Pubmed]
  5. De novo appearance and "strain" formation of yeast prion [PSI+] are regulated by the heat-shock transcription factor. Park, K.W., Hahn, J.S., Fan, Q., Thiele, D.J., Li, L. Genetics (2006) [Pubmed]
  6. Silenced chromatin is permissive to activator binding and PIC recruitment. Sekinger, E.A., Gross, D.S. Cell (2001) [Pubmed]
  7. Heat shock factor and the heat shock response. Sorger, P.K. Cell (1991) [Pubmed]
  8. The yeast heat shock transcription factor contains a transcriptional activation domain whose activity is repressed under nonshock conditions. Nieto-Sotelo, J., Wiederrecht, G., Okuda, A., Parker, C.S. Cell (1990) [Pubmed]
  9. Yeast heat shock factor contains separable transient and sustained response transcriptional activators. Sorger, P.K. Cell (1990) [Pubmed]
  10. Trimerization of a yeast transcriptional activator via a coiled-coil motif. Sorger, P.K., Nelson, H.C. Cell (1989) [Pubmed]
  11. Activation of the Saccharomyces cerevisiae heat shock transcription factor under glucose starvation conditions by Snf1 protein kinase. Hahn, J.S., Thiele, D.J. J. Biol. Chem. (2004) [Pubmed]
  12. The loop domain of heat shock transcription factor 1 dictates DNA-binding specificity and responses to heat stress. Ahn, S.G., Liu, P.C., Klyachko, K., Morimoto, R.I., Thiele, D.J. Genes Dev. (2001) [Pubmed]
  13. Genetic identification of the site of DNA contact in the yeast heat shock transcription factor. Torres, F.A., Bonner, J.J. Mol. Cell. Biol. (1995) [Pubmed]
  14. Mutated yeast heat shock transcription factor exhibits elevated basal transcriptional activation and confers metal resistance. Sewell, A.K., Yokoya, F., Yu, W., Miyagawa, T., Murayama, T., Winge, D.R. J. Biol. Chem. (1995) [Pubmed]
  15. Modulation of human heat shock factor trimerization by the linker domain. Liu, P.C., Thiele, D.J. J. Biol. Chem. (1999) [Pubmed]
  16. Translational readthrough at nonsense mutations in the HSF1 gene of Saccharomyces cerevisiae. Kopczynski, J.B., Raff, A.C., Bonner, J.J. Mol. Gen. Genet. (1992) [Pubmed]
  17. Expression of human heat shock transcription factors 1 and 2 in HeLa cells and yeast. Yuan, C.X., Czarnecka-Verner, E., Gurley, W.B. Cell Stress Chaperones (1997) [Pubmed]
  18. Genome-wide analysis of the biology of stress responses through heat shock transcription factor. Hahn, J.S., Hu, Z., Thiele, D.J., Iyer, V.R. Mol. Cell. Biol. (2004) [Pubmed]
  19. SSB, encoding a ribosome-associated chaperone, is coordinately regulated with ribosomal protein genes. Lopez, N., Halladay, J., Walter, W., Craig, E.A. J. Bacteriol. (1999) [Pubmed]
  20. Search for methuselah genes heats up. Longo, V.D. Science of aging knowledge environment [electronic resource] : SAGE KE (2004) [Pubmed]
  21. Structural analysis of yeast HSF by site-specific crosslinking. Bonner, J.J., Chen, D., Storey, K., Tushan, M., Lea, K. J. Mol. Biol. (2000) [Pubmed]
  22. Role of trehalose and heat in the structure of the C-terminal activation domain of the heat shock transcription factor. Bulman, A.L., Nelson, H.C. Proteins (2005) [Pubmed]
  23. Stress-induced transcription of the endoplasmic reticulum oxidoreductin gene ERO1 in the yeast Saccharomyces cerevisiae. Takemori, Y., Sakaguchi, A., Matsuda, S., Mizukami, Y., Sakurai, H. Mol. Genet. Genomics (2006) [Pubmed]
  24. A short element required for turning off heat shock transcription factor: evidence that phosphorylation enhances deactivation. Høj, A., Jakobsen, B.K. EMBO J. (1994) [Pubmed]
  25. Domains of the SFL1 protein of yeasts are homologous to Myc oncoproteins or yeast heat-shock transcription factor. Fujita, A., Kikuchi, Y., Kuhara, S., Misumi, Y., Matsumoto, S., Kobayashi, H. Gene (1989) [Pubmed]
  26. A critical role for heat shock transcription factor in establishing a nucleosome-free region over the TATA-initiation site of the yeast HSP82 heat shock gene. Gross, D.S., Adams, C.C., Lee, S., Stentz, B. EMBO J. (1993) [Pubmed]
  27. The Skn7 response regulator of Saccharomyces cerevisiae interacts with Hsf1 in vivo and is required for the induction of heat shock genes by oxidative stress. Raitt, D.C., Johnson, A.L., Erkine, A.M., Makino, K., Morgan, B., Gross, D.S., Johnston, L.H. Mol. Biol. Cell (2000) [Pubmed]
  28. A distal heat shock element promotes the rapid response to heat shock of the HSP26 gene in the yeast Saccharomyces cerevisiae. Chen, J., Pederson, D.S. J. Biol. Chem. (1993) [Pubmed]
  29. Effects of heat stress on yeast heat shock factor-promoter binding in vivo. Li, N., Zhang, L.M., Zhang, K.Q., Deng, J.S., Prandl, R., Schoffl, F. Acta Biochim. Biophys. Sin. (Shanghai) (2006) [Pubmed]
  30. Genome-wide Analysis Reveals New Roles for the Activation Domains of the Saccharomyces cerevisiae Heat Shock Transcription Factor (Hsf1) during the Transient Heat Shock Response. Eastmond, D.L., Nelson, H.C. J. Biol. Chem. (2006) [Pubmed]
  31. A novel non-conventional heat shock element regulates expression of MDJ1 encoding a DnaJ homolog in Saccharomyces cerevisiae. Tachibana, T., Astumi, S., Shioda, R., Ueno, M., Uritani, M., Ushimaru, T. J. Biol. Chem. (2002) [Pubmed]
  32. Evidence that partial unwrapping of DNA from nucleosomes facilitates the binding of heat shock factor following DNA replication in yeast. Geraghty, D.S., Sucic, H.B., Chen, J., Pederson, D.S. J. Biol. Chem. (1998) [Pubmed]
  33. Heat shock factor-independent heat control of transcription of the CTT1 gene encoding the cytosolic catalase T of Saccharomyces cerevisiae. Wieser, R., Adam, G., Wagner, A., Schüller, C., Marchler, G., Ruis, H., Krawiec, Z., Bilinski, T. J. Biol. Chem. (1991) [Pubmed]
  34. The yeast Hsp110 family member, Sse1, is an Hsp90 cochaperone. Liu, X.D., Morano, K.A., Thiele, D.J. J. Biol. Chem. (1999) [Pubmed]
  35. A yeast heat shock transcription factor (Hsf1) mutant is defective in both Hsc82/Hsp82 synthesis and spindle pole body duplication. Zarzov, P., Boucherie, H., Mann, C. J. Cell. Sci. (1997) [Pubmed]
  36. Isolation and characterization of extragenic suppressors of mutations in the SSA hsp70 genes of Saccharomyces cerevisiae. Nelson, R.J., Heschl, M.F., Craig, E.A. Genetics (1992) [Pubmed]
  37. Mutational analysis of the DNA-binding domain of yeast heat shock transcription factor. Hubl, S.T., Owens, J.C., Nelson, H.C. Nat. Struct. Biol. (1994) [Pubmed]
  38. 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]
  39. Interaction of the Neurospora crassa heat shock factor with the heat shock element during heat shock and different developmental stages. Meyer, U., Monnerjahn, C., Techel, D., Rensing, L. FEMS Microbiol. Lett. (2000) [Pubmed]
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