Alternative titles; symbols
HGNC Approved Gene Symbol: HSF1
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38) : 8:144,291,604-144,314,720 (from NCBI)
HSF1 plays a crucial role in inducing heat shock proteins (e.g., HSPA1A; 140550), which is required for thermotolerance. In addition, HSF1 is involved in oogenesis, spermatogenesis, and placental development (summary by Inouye et al., 2004).
Heat-shock transcription factors (HSFs) activate heat-shock response genes under conditions of heat or other stresses. By screening cDNA libraries with a human cDNA fragment produced by PCR with primers deduced from conserved amino acids in the Drosophila and yeast HSF sequences, Rabindran et al. (1991) isolated a cDNA for a human HSF, referred to as HSF1. The deduced full-length 529-amino acid protein is rich in prolines and serines and contains 4 putative leucine zipper motifs. Northern blot analysis of HeLa cells detected a 2.0- to 2.2-kb HSF1 transcript that was expressed at similar levels before and after heat shock.
By immunohistochemical analysis of mouse testis, Akerfelt et al. (2010) found that Hsf1 was highly and specifically expressed in nuclei of spermatocytes and round spermatids.
Zhang et al. (1998) determined that the mouse Hsf1 gene contains 13 exons. The first exon of the Bop1 gene (610596) lies on the opposite strand and just upstream of the Hsf1 translation initiation site. Functional analysis showed that the region of overlap behaves as a bidirectional promoter for transcription of both genes.
Gross (2012) mapped the HSF1 gene to chromosome 8q24.3 based on an alignment of the HSF1 sequence (GenBank BC014638) with the genomic sequence (GRCh37).
Using recombinant human protein, Rabindran et al. (1991) found that HSF1 specifically bound to heat shock elements (HSEs) and stimulated transcription from HSEs in a Drosophila embryo cell-free transcription system.
In a novel in vitro system in which human HSF1 can be activated by nonnative protein, heat, and geldanamycin, Zou et al. (1998) found that addition of Hsp90 (140571) inhibited activation. Reduction of the level of Hsp90 dramatically activated HSF1. Hsp90-containing HSF1 complex is present in the unstressed cell and dissociates during stress. Zou et al. (1998) concluded that Hsp90, by itself and/or associated with multichaperone complexes, is a major repressor of HSF1.
In ECGs of transgenic mouse hearts overexpressing a constitutively active form of Hsf1, Zou et al. (2003) found faster recovery from ST segment elevation induced by ischemia/reperfusion injury. There was a smaller area of infarction and less cardiomyocyte death compared to wildtype mice. Protein kinase B/Akt (see AKT1; 164730) was more strongly activated, whereas Jun N-terminal kinase (see JNK1; 601158) and caspase-3 (CASP3; 600636) were less active in transgenic hearts than wildtype hearts. Zou et al. (2003) concluded that HSF1 protects cardiomyocytes from death, at least in part, through activation of AKT and inactivation of JNK and CASP3.
The heat-shock transcription factor HSF1 is present in unstressed cells in an inactive monomeric form and becomes activated by heat and other stress stimuli. HSF1 activation involves trimerization and acquisition of a site-specific DNA-binding activity, which is negatively regulated by interaction with certain heat-shock proteins. Shamovsky et al. (2006) showed that HSF1 activation by heat shock is an active process that is mediated by a ribonucleoprotein complex containing translation elongation factor eEF1A (130590) and a previously unknown noncoding RNA that they termed heat-shock RNA-1 (HSR1; 610157). HSR1 is constitutively expressed in human and rodent cells and its homologs are functionally interchangeable. Both HSR1 and eEF1A are required for HSF1 activation in vitro; antisense oligonucleotides or short interfering RNA against HSR1 impaired the heat-shock response in vivo, rendering cells thermosensitive. Shamovsky et al. (2006) suggested that the central role of HSR1 during heat shock implies that targeting this RNA could serve as a new therapeutic model for cancer, inflammation, and other conditions associated with HSF1 deregulation.
Using differential display of DNA-binding proteins to screen mouse liver extracts collected throughout the light/dark cycle, Reinke et al. (2008) found that Hsf1 exhibited highly circadian DNA-binding activity. Hsf1 drove expression of heat-shock proteins at the onset of the dark phase, when the animals became behaviorally active. Furthermore, Hsf1-deficient mice had a longer free-running period than wildtype littermates.
Westerheide et al. (2009) demonstrated that human HSF1 is inducibly acetylated at a critical residue (lysine-80, K80) that negatively regulates DNA-binding activity. Activation of the deacetylase and longevity factor SIRT1 (604479) prolonged HSF1 binding to the heat-shock promoter HSP70 (140550) by maintaining HSF1 in a deacetylated, DNA binding-competent state. Conversely, downregulation of SIRT1 accelerated the attenuation of the heat-shock response and release of HSF1 from its cognate promoter elements. Westerheide et al. (2009) concluded that their results provided a mechanistic basis for the requirement of HSF1 in the regulation of life span and established a role for SIRT1 in protein homeostasis and the heat-shock response.
Using chromatin immunoprecipitation on promoter microarray (ChIP-chip) analysis, Akerfelt et al. (2010) discovered that Hsf1 bound 742 putative target genes in mouse testis. Hsf1 predominantly bound genes associated with transcription and nucleic acid binding, and it showed prominent association with multicopy genes of the sex chromosomes. ChIP analysis confirmed specific binding of Hsf1 to multicopy genes on the Y and X chromosomes. Hsf1 localized to sex chromatin both prior to and after meiotic divisions in a repressed chromatin environment.
Kourtis et al. (2012) demonstrated that heat stroke triggers pervasive necrotic cell death and neurodegeneration in C. elegans. Preconditioning of animals at a mildly elevated temperature strongly protected from heat-induced necrosis. The heat-shock transcription factor HSF1 and the small heat-shock protein HSP-16.1 mediate cytoprotection by preconditioning. HSP-16.1 localizes to the Golgi, where it functions with the calcium- and magnesium-transporting ATPase PMR1 (604384) to maintain calcium homeostasis under heat stroke. Preconditioning also suppresses cell death inflicted by diverse insults, and protects mammalian neurons from heat cytotoxicity. Kourtis et al. (2012) concluded that their findings revealed an evolutionarily conserved mechanism that defends against diverse necrotic stimuli. In mouse cortical neurons and striatal cells, Kourtis et al. (2012) found that overexpression of crystallin alpha-A (123580), which colocalizes with the Golgi marker alpha-mannosidase-II (154582) and the PMR1 ATPase, was sufficient to protect mammalian neurons from heat stroke-induced death, even in the absence of preconditioning. Heat stroke caused massive necrotic death and axonal degeneration in neurons expressing short hairpin RNAs against Pmr1, even after preconditioning.
Through integrated chemical-genetic analyses, Santagata et al. (2013) found that a dominant transcriptional effect of blocking protein translation in cancer cells was inactivation of HSF1, a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for anabolic metabolism, cellular proliferation, and tumorigenesis. These analyses linked translational flux to the regulation of HSF1 transcriptional activity and to the modulation of energy metabolism. Targeting this link with translation initiation inhibitors such as rocaglates deprived cancer cells of their energy and chaperone armamentarium and selectively impaired the proliferation of both malignant and premalignant cells with early-stage oncogenic lesions.
Baird et al. (2014) engineered a modified hsf1 strain in C. elegans that increased stress resistance and longevity without enhanced chaperone induction. This health assurance acted through the regulation of the calcium-binding protein pat10. Loss of pat10 caused a collapse of the actin cytoskeleton, stress resistance, and life span. Furthermore, overexpression of pat10 increased actin filament stability, thermotolerance, and longevity, indicating that in addition to chaperone regulation, HSF1 has a prominent role in cytoskeletal integrity, ensuring cellular function during stress and aging. To test for conservation, Baird et al. (2014) disrupted the actin cytoskeleton in HEK293T cells using cytochalasin D, which blocks the addition of actin monomers to filaments, or latrunculin A, which binds actin monomers and prevents polymerization. Inhibiting filamentous actin formation with either agent significantly reduced thermotolerance in human cells without causing death at permissive temperatures. Baird et al. (2014) concluded that their findings reiterated the importance of the actin cytoskeleton during times of cellular stress.
Christians et al. (2000) demonstrated that mouse embryos from Hsf1 -/- females are unable to develop properly beyond the zygotic stage, although oocytes were ovulated and fertilized normally. Wildtype spermatozoa did not save zygotes from lethality, indicating that the reproductive failure of females deficient in this factor is caused by a 'maternal effect' mutation, and that HSF1 from the mother normally controls early postfertilization development. Female mice lacking the gene encoding HSF1 have normal ovaries and reproductive tracts, indicating that folliculogenesis and oogenesis do not require HSF1 expression, by contrast with the Drosophila HSF mutation and others affecting fertility in mammals. Ovulated eggs of Hsf1 -/- females remained properly arrested at metaphase 2 until fertilization, after which zygotes formed with 2 pronuclei and a second polar body. Although mutant embryos produced by Hsf1 -/- females can initiate early development, they do not survive after transplantation into the oviduct of the Hsf1 wildtype mice, indicating that the causes of Hsf1 -/- infertility are intrinsic rather than extrinsic. Hsf1-mutant zygotes were able to express heat-shock proteins, demonstrating that zygotic transcriptional activity can begin without HSF1. Ultrastructural analysis indicated that abnormalities affect mainly the nuclei of embryos from null females at the 2-cell stage.
The C. elegans transcription factor hsf1 regulates the heat-shock response and influences aging. Reducing hsf1 activity accelerates tissue aging and shortens life span; Hsu et al. (2003) showed that hsf1 overexpression extends life span. Hsu et al. (2003) found that hsf1, like the transcription factor daf16, whose human homologs include FOXO1 (136533), FOXO3 (602681), and FOXO4 (300033), is required for daf2-insulin (176730)/Igf1 receptor (147370) mutations to extend life span. Hsu et al. (2003) concluded that this is because hsf1 and daf16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity. The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease.
Steele et al. (2008) found that Hsf1-knockout mice died significantly faster after inoculation with prion proteins (176640) compared to wildtype mice with intact Hsf1 genes. However, both Hsf1-knockout and wildtype mice showed a similar timing in onset of behavioral abnormalities and pathologic changes after inoculation. The findings suggested a protective role for HSF1 in prion pathogenesis and establish that it is specific to disease progression as distinct from disease onset.
Akerfelt et al. (2010) found that Hsf1 -/- male mice displayed regions of seminiferous tubules containing only spermatogonia and increased morphologic abnormalities of sperm heads. Hsf1 -/- epididymis showed defects in chromatin packing and placement of chromatin-packing proteins.
Inouye et al. (2004) found that Hsf1 -/- mice immunized with sheep red blood cells exhibited a significant decrease in T cell-dependent B-cell responses, with diminished production of IgG, particularly IgG2a, and normal production of IgM. ELISA and microarray analysis in stimulated splenocytes and peritoneal macrophages showed significantly lower Il6 (147620) and Ccl5 (187011) in Hsf1 -/- cells compared with wildtype cells. ChIP analysis identified IL6 as a direct target of Hsf1. Inouye et al. (2004) concluded that HSF1 is linked molecularly to IL6, which is involved in immunity and inflammation.
Schuetz (1991) pointed out that although the names HSF1 and HSF2 (140581) were chosen for historical reasons, these peptides should be referred to as heat-shock transcription factors.
Akerfelt, M., Vihervaara, A., Laiho, A., Conter, A., Christians, E. S., Sistonen, L., Henriksson, E. Heat shock transcription factor 1 localizes to sex chromatin during meiotic repression. J. Biol. Chem. 285: 34469-34476, 2010. [PubMed: 20802198] [Full Text: https://doi.org/10.1074/jbc.M110.157552]
Baird, N. A., Douglas, P. M., Simic, M. S., Grant, A. R., Moresco, J. J., Wolff, S. C., Yates, J. R., III, Manning, G., Dillin, A. HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span. Science 346: 360-363, 2014. [PubMed: 25324391] [Full Text: https://doi.org/10.1126/science.1253168]
Christians, E., Davis, A. A., Thomas, S. D., Benjamin, I. J. Maternal effect of Hsf1 on reproductive success. Nature 407: 693-694, 2000. [PubMed: 11048707] [Full Text: https://doi.org/10.1038/35037669]
Gross, M. B. Personal Communication. Baltimore, Md. 4/10/2012.
Hsu, A.-L., Murphy, C. T., Kenyon, C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300: 1142-1145, 2003. Note: Erratum: Science 300: 2033 only, 2003. [PubMed: 12750521] [Full Text: https://doi.org/10.1126/science.1083701]
Inouye, S., Izu, H., Takaki, E., Suzuki, H., Shirai, M., Yokota, Y., Ichikawa, H., Fujimoto, M., Nakai, A. Impaired IgG production in mice deficient for heat shock transcription factor 1. J. Biol. Chem. 279: 38701-38709, 2004. [PubMed: 15226319] [Full Text: https://doi.org/10.1074/jbc.M405986200]
Kourtis, N., Nikoletopoulou, V., Tavernarakis, N. Small heat-shock proteins protect from heat-stroke-associated neurodegeneration. Nature 490: 213-218, 2012. [PubMed: 22972192] [Full Text: https://doi.org/10.1038/nature11417]
Rabindran, S. K., Giorgi, G., Clos, J., Wu, C. Molecular cloning and expression of a human heat shock factor, HSF1. Proc. Nat. Acad. Sci. 88: 6906-6910, 1991. [PubMed: 1871105] [Full Text: https://doi.org/10.1073/pnas.88.16.6906]
Reinke, H., Saini, C., Fleury-Olela, F., Dibner, C., Benjamin, I. J., Schibler, U. Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor. Genes Dev. 22: 331-345, 2008. [PubMed: 18245447] [Full Text: https://doi.org/10.1101/gad.453808]
Santagata, S., Mendillo, M. L., Tang, Y., Subramanian, A., Perley, C. C., Roche, S. P., Wong, B., Narayan, R., Kwon, H., Koeva, M., Amon, A., Golub, T. R., Porco, J. A., Jr., Whitesell, L., Lindquist, S. Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science 341: 1238303, 2013. Note: Electronic Article. [PubMed: 23869022] [Full Text: https://doi.org/10.1126/science.1238303]
Schuetz, T. J. Personal Communication. Boston, Mass. 10/3/1991.
Shamovsky, I., Ivannikov, M., Kandel, E. S., Gershon, D., Nudler, E. RNA-mediated response to heat shock in mammalian cells. Nature 440: 556-560, 2006. [PubMed: 16554823] [Full Text: https://doi.org/10.1038/nature04518]
Steele, A. D., Hutter, G., Jackson, W. S., Heppner, F. L., Borkowski, A. W., King, O. D., Raymond, G. J., Aguzzi, A., Lindquist, S. Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease. Proc. Nat. Acad. Sci. 105: 13626-13631, 2008. [PubMed: 18757733] [Full Text: https://doi.org/10.1073/pnas.0806319105]
Westerheide, S. D., Anckar, J., Stevens, S. M., Jr., Sistonen, L., Morimoto, R. I. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323: 1063-1066, 2009. Note: Erratum: Science 342: 931 only, 2013. [PubMed: 19229036] [Full Text: https://doi.org/10.1126/science.1165946]
Zhang, Y., Koushik, S., Dai, R., Mivechi, N. F. Structural organization and promoter analysis of murine heat shock transcription factor-1 gene. J. Biol. Chem. 273: 32514-32521, 1998. [PubMed: 9829985] [Full Text: https://doi.org/10.1074/jbc.273.49.32514]
Zou, J., Guo, Y., Guettouche, T., Smith, D. F., Voellmy, R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94: 471-480, 1998. [PubMed: 9727490] [Full Text: https://doi.org/10.1016/s0092-8674(00)81588-3]
Zou, Y., Zhu, W., Sakamoto, M., Qin, Y., Akazawa, H., Toko, H., Mizukami, M., Takeda, N., Minamino, T., Takano, H., Nagai, T., Nakai, A., Komuro, I. Heat shock transcription factor 1 protects cardiomyocytes from ischemia/reperfusion injury. Circulation 108: 3024-3030, 2003. [PubMed: 14623809] [Full Text: https://doi.org/10.1161/01.CIR.0000101923.54751.77]