MINIREVIEW
The heat shock factor family and adaptation to
proteotoxic stress
Mitsuaki Fujimoto and Akira Nakai
Yamaguchi University School of Medicine, Ube, Japan
Introduction
All living organisms respond to elevated temperatures
by producing a set of highly conserved proteins,
known as heat shock proteins (HSP) [1]. This response
is called the heat shock response, and is a universal
mechanism of protection against proteotoxic stress,
including heat shock and oxidative stress. In Escheri-
chia coli, heat shock genes are under the control of a
specific transcription factor, r32, which directs the
core RNA polymerase to promoters [2]. In eukaryotes,
the heat shock response is regulated mainly at the level
of transcription by heat shock factors (HSFs) [3]. Heat
shock genes, such as HSP110, HSP90, HSP70, HSP40
and HSP27, contain heat shock elements (HSEs) com-
posed of at least three inverted repeats of the highly
conserved consensus sequence nGAAn in the proximal
promoter region [4]. Here we call them ‘classical heat
shock genes’, which encode major HSPs or molecular
chaperones. Heat shock triggers the conversion of an
HSF1 monomer in a metazoan species that is nega-
tively regulated by HSPs into a trimer that binds to
Keywords
evolution; heat shock; protein homeostasis;
protein-misfolding disorder; transcription
factor; vertebrate
Correspondence

induction of classical as well as of nonclassical heat shock genes, both of
which might be required to maintain protein homeostasis.
Abbreviations
BRG1, brahma-related gene 1; DAF-16, abnormal dauer formation 16; HR, hydrophobic heptad repeat; HSE, heat shock element; HSF, heat
shock factor; HSP, heat shock protein; MEF, mouse embryonic fibroblast; polyQ, polyglutamine.
4112 FEBS Journal 277 (2010) 4112–4125 ª 2010 The Authors Journal compilation ª 2010 FEBS
the HSE with high affinity, and the bound HSF1 rap-
idly induces a robust activation of the classical heat
shock genes [5,6].
There is a single gene encoding HSF in yeast, in
Caenorhabditis elegans and in Drosophila. HSF is
required not only for the heat shock response, but also
for cell growth and differentiation in yeast [7]. In verte-
brates, there are multiple HSF genes, which encode
members of the HSF family (HSF1–4). In mammals,
as in yeast and Drosophila, the HSF1 is required for
the heat shock response, whereas HSF3 is required for
this response in avian species [8,9]. Both mouse HSF1
and chicken HSF3 are necessary for thermotolerance,
at least through the expression of classical heat shock
genes [10,11]. In addition to their role in the heat
shock response, mouse HSFs are critical in develop-
mental processes such as gametogenesis and neuro-
genesis, in the maintenance of sensory and ciliated
tissues, and in immune responses [12–14]. HSF1- and
HSF3-mediated mechanisms of cellular adaptation to
heat shock have been analyzed in detail in chicken
cells, and were considered specific to chicken cells as it
was believed until recently that HSF3 was an avian-
specific factor. In this minireview, we summarize the

identified. Therefore, HSF3 was considered specific to
avian species, and HSF4 was considered specific to
mammalian species [5,8,9,12].
Although human and mouse genome sequences have
become available [26,27], no HSF3-related sequence
was identified in silico from the genome database [28].
However, analysis of the chicken genome enabled com-
parison of the syntenic regions [29], where the same
genes occur in a similar order along the chromosomes
of different organisms [30]. For example, HSF2 was
flanked by the SERINCI gene in human, mouse and
chicken orthologous segments (Fig. 1) [31]. Likewise,
the chicken HSF3 gene was located between Vsig4 and
HEPH on chromosome 4, and orthologous segments
containing the two genes were found on the human
and mouse X chromosome. Sequencing of a region
between the two genes revealed the mouse HSF3 gene.
Although sequences related to HSF3 were also
observed in an orthologous region of the human gen-
ome, this genomic segment is likely to be an HSF3
pseudogene as no transcript was identified [31]. Fur-
thermore, HSF4 was located in a region between the
TRADD–FBXL8 genes and the NoL3 gene in the
human and mouse genomes, and chicken HSF4 was
identified in an orthologous segment [31].
Comparison of the predicted amino acids of four
members of the vertebrate HSF family revealed that
sequences of the DNA-binding and trimerization
[hydrophobic heptad repeat (HR)-A ⁄ B] domains are
well conserved (Fig. 2) [31]. The identity of the amino

ons are well conserved, whereas those of introns are
not [31], suggesting that four duplicated HSF genes
have been conserved during evolution under selective
pressure, except for human HSF3.
Expression of classical heat shock
genes induced by two heat-responsive
HSFs
After the identification of mammalian HSF1 and
HSF2 [20–22], and of chicken HSF1, HSF2 and HSF3
[23], research was conducted to reveal the factors
responsible for the heat-inducible HSE-binding activ-
ity. In mammalian cells, HSF1 remains an inert mono-
mer in unstressed cells and forms a trimer that binds
to the HSE in response to heat shock [35,36], whereas
the HSE-binding activity of HSF2 is induced during
hemin-induced differentiation of erythroleukemia
cells and is constitutively high during early mouse
development [37–39]. In chicken cells, both an HSF1
monomer and an HSF3 dimer were converted to
homotrimers that bind to the HSE under heat shock
[40]. The disruption of HSF genes in mouse embryonic
fibroblasts (MEFs) clearly demonstrated that mouse
HSF1 is required for the expression of classical heat
shock genes [10], whereas mouse HSF2 is not [41].
Unexpectedly, disruption of chicken HSF3 in chicken
B-lymphocyte DT40 cells resulted in a severe reduction
in the inducible expression of HSP70, and the expres-
sion of HSP110, HSP90a, HSP90b and HSP40 were
not induced at all in chicken HSF3-null cells [11].
These observations imply that duplicated HSF genes

10 kb
20 kb
HSF2 SERINC1
Human Chr.
6
HSF3
Human Chr.X
HEPH
Vsig4
Mouse Chr.X
HSF3
Vsig4
100 kb
100 kb
HSF3
HEPH
Chicken Chr.11
TRADD FBXL8
HSF4
NL3
HSF4
Mouse Chr.8
NoL3TRADD FBXL8
HSF4
Human Chr.16
N
o
L3
HSF4
10 kb

expression of the classical heat shock genes [28].
Thus, chicken HSF1 lacks the ability to induce the
expression of classical heat shock genes, whereas
mouse HSF1 is a master regulator of these genes.
Interestingly, the amino-terminal region of chicken
HSF1 containing an alanine-rich sequence and the
DNA-binding domain is sufficient to cause the func-
tional difference between the two orthologues [28]. As
chicken HSF1 can bind to the HSE, its amino-terminal
domain might inhibit exposure of the activation
domain to basal transcriptional machinery. Alterna-
tively, the corresponding domain of mouse HSF1, but
not that of chicken HSF1, could recruit components
required for gene activation.
Recent identification of mouse HSF3 enabled us to
examine the functional difference of HSF3 in mouse
and chicken cells [31]. In cells exposed to heat shock,
mouse HSF3 fused to green fluorescent protein moved
into the nucleus, similarly to chicken HSF3 [40], indi-
cating that both chicken and mouse HSF3 are heat-
responsive factors. Furthermore, overexpression of
DBD HR-A/B HR-
C
DHR
hHSF1
hHSF2
5291 16 120 130 203 384 409
415
446
5361 8 112 119 192 360 385

cHSF3
58 678592
92
82
1342
4647 7
2
76
25 193849 2206
Chicken
cHSF4
30 23
285384
CeHSF1
DmHSF
53
59
58
31
30
hHSFY1
31
ScHSF
CeHSF1
53
31
46
32
hHSFX1
20

276 347
424
1 80 198 401
1 37 155 423
1 14 129 596
Fig. 2. Members of the HSF superfamily. Diagrammatic representation of vertebrate and nonvertebrate HSF family members and of human
HSF-related gene products. The percentage identity between human HSF1 and each HSF was established using the computer program
GENETYX-MAC. The number of amino acids of each HSF is shown at the amino-terminal end. c, chicken; Ce, Caenorhabditis elegans ; DHR,
downstream of HR-C; DBD, DNA-binding domain; DHR, downstream of HR-C; Dm, Drosophila melanogaster; h, human; HR, hydrophobic
heptad repeat; m, mouse; Region X, a region upstream of the HR-C domain; Region Y, a C-terminal region downstream of the HR-C-like
domain; Sc, Saccharomyces cerevisiae. hHSF1 (hHSF1-a) [20]; hHSF2 (hHSF2-a) [21]; hHSF4 (hHSF4b) [24]; mHSF1 (hHSF1-a) and mHSF2
(hHSF2-a) [35]; mHSF3 (mHSF3a) [31]; mHSF4 (mHSF4b) [25]; cHSF1, cHSF2 and cHSF3 [23]; cHSF4 (cHSF4b) [31]; DmHSF [Wu 1990];
CeHSF1 (Swiss-P accession no. Q9XW45); ScHSF [Pelham; Parker 1988]; hHSFY1 (SP accession no. Q96LI6) [106,107]; hHSFX1 ⁄ LW-1 (SP
accession no. Q9UBD0); hHSF5 (SP accession no. Q4G112). The hatched box indicates an HR-C-like domain, in which hydrophobic amino
acids are not well conserved. The DBD domain of HSF family members is conserved with one region in hHSFY1, hHSFX1 and hHSF5 that
may not bind to the HSE.
M. Fujimoto and A. Nakai Evolution and function of the HSF family
FEBS Journal 277 (2010) 4112–4125 ª 2010 The Authors Journal compilation ª 2010 FEBS 4115
chicken HSF3 in HSF1-null MEF cells induced the
constitutive and heat-induced expression of classical
heat shock genes. In marked contrast, overexpression
of mouse HSF3 in the same cells did not affect the
expression of classical heat shock genes at all, even
after heat shock. Therefore, mouse HSF3 lacks the
ability to induce the expression of classical heat shock
genes, whereas chicken HSF3 is a master regulator.
Why does mouse HSF3 fail to induce the expression
of classical heat shock genes? It was revealed, by exam-
ining a DNA-binding transcription factor required for
the activation of the GAL genes in response to galac-

HSP70 mRNA expression in HSF1-null MEF cells
during heat shock [47,48]. It was revealed that mouse
HSF3 does not bind to BRG1, or recruit BRG1 to the
HSP70 promoter [31], whereas chicken HSF3 does
bind to and recruit BRG1. These observations indicate
that mouse HSF3 does not induce the expression of
the classical heat shock genes, at least in part because
of its inability to interact with BRG1.
HSF-mediated adaptation to thermal
stress
Heat shock induces both apoptotic and necrotic cell
death, but the pathways of cell death and the factors
hHSF5
hHSFY1
hHSFX1
mHSF3
cHSF3
mHSF2
cHSF2
674
991
1000
1000
1000
1000
602
1000
1000
1000
1000

ous targets of extremely high temperatures that induce
cell death. Therefore, HSPs should not be the only
proteins that protect against cell death. Nevertheless,
HSPs are recognized as major players in the protec-
tion of cells from heat shock, especially from proteo-
toxic stress [1,2]. As the expression of a set of HSPs is
regulated by HSFs, HSFs should be involved in the
protection of cells from heat shock or proteotoxic
stress [49].
It is well established that cells pretreated with suble-
thal heat shock can survive lethal heat shock. This
phenomenon is called induced thermotolerance, and is
regulated by mouse HSF1 and chicken HSF3 through
the activation of the heat shock genes [10,11]. HSPs
prevent the denaturation and aggregation of cellular
proteins, and support their renaturation when the cells
are recovering [1]. At the same time, HSPs inhibit sev-
eral molecules, such as apoptotic peptidase activating
factor 1 (Apaf-1) and cytochrome c, which are
involved in mitochondria-mediated apoptotic pathways
[50].
Both HSF1 and HSF3 complementarily regulate the
constitutive expression of some HSPs in normally
growing chicken DT40 cells [11,42]. In these cells, a
lack of the two factors resulted in increased sensitivity
to a single exposure to high temperature because of
reduced Hsp90a expression, and the cell cycle is
blocked at the G
2
phase [42]. A similar phenotype was

in the lens
Polyploid
Chicken cell
HSF3
HSF4
HSF4
HSF2
HSF1
HSF1
> 310 Myr ago
High expression
in the lens
HSF3
HSP induction
HSF2
Fig. 4. A model to explain the evolution of HSF genes. Two rounds of whole-genome duplication (WGD) may have occurred in vertebrate
ancestral cells more than 440 million years ago (Ma) [110,111], which resulted in polyploidization. Thereafter, avian and mammalian cells
evolved differently from an ancestral cell 310 Ma. The expression and function of the four HSF genes were conserved or diverged during
evolution [112]. For example, during mammalian evolution, HSF1 retained the ability to induce the expression of heat shock proteins,
whereas it lost this function during avian evolution. Instead, avian HSF3 retained the function. Expression of the HSF4 gene increased in the
lens during both avian and mammalian evolutions (M. Fujimoto and A. Nakai, unpublished). Diamonds, circles and triangles represent regula-
tory regions driving expression in different tissues.
M. Fujimoto and A. Nakai Evolution and function of the HSF family
FEBS Journal 277 (2010) 4112–4125 ª 2010 The Authors Journal compilation ª 2010 FEBS 4117
was able to protect HSF1-null MEF cells from heat
shock without inducing the expression of the classical
heat shock genes [31]. These observations indicate that
chicken HSF1 and mouse HSF3 protect cells from
thermal stress by regulating the expression of heat-
inducible genes other than classical heat shock genes.

repeat protein-interacting protein) [61], decreased, but
was still observed in HSF1-null MEF cells during heat
shock [31]. Overexpression of mouse HSF3 or chicken
HSF1 in the HSF1-null MEF cells restored the marked
induction of expression of PDZK3, whereas knock-
down of mouse HSF3 completely abolished the induc-
tion. Induction of another nonclassical heat shock
gene, that for a membrane glycoprotein, prominin-2
(PROM2) [62], was abolished in HSF1-null MEF cells,
but was restored when mouse HSF3 or chicken HSF1
was overexpressed [31]. These observations clearly
demonstrated that evolutionally conserved mouse
HSF3 and chicken HSF1 uniquely regulate only non-
classical genes, suggesting importance of the regulation
of the nonclassical heat shock genes.
It is worth noting that HSF4 also regulates nonclas-
sical heat shock genes in lens cells although it is not a
heat-responsive factor. A set of HSF4-binding regions
was identified in lens cells, and the expression of genes
located in and near these regions was examined [63].
Interestingly, a great number of the genes (33%) were
expressed in response to heat shock, and, unexpect-
edly, the expression of these genes was not induced in
HSF1-null lens cells. Surprisingly, HSF4 was required
for the expression of half of the genes, in part by facil-
itating the binding of HSF1 to the promoters [63].
Moreover, the expression of satellite III repeat
sequences during heat shock was extensively studied
[64,65]. HSF1 is required for expression of the satellite
III gene during heat shock, but HSF2 also greatly

expression of HSPs. HSF2 may modulate this process by interact-
ing with HSF1 [6,113]. Members of the HSF family coordinately
bind to the less-conserved HSE located on and near numerous non-
classical heat shock genes, and greatly affect heat-induced expres-
sion of the genes including PDZK3, PROM2 and satellite III
[31,63,66]. HSF3 is not expressed in human cells.
Evolution and function of the HSF family M. Fujimoto and A. Nakai
4118 FEBS Journal 277 (2010) 4112–4125 ª 2010 The Authors Journal compilation ª 2010 FEBS
a trimer that binds to the HSE. However, the binding
of HSF to the promoter of a heat shock gene markedly
increased during heat shock in S. cerevisiae in vivo [67].
Furthermore, HSF was essential even in the fission
yeast S. pombe, in which HSF forms a trimer only
under stress, similar that observed for vertebrate HSF1
[19]. These observations implied that a balance of the
monomer and trimer HSF affects the amount of HSF
bound to the HSE in vivo, but even a small amount of
the trimer could regulate the gene expression, which is
required for survival under normal growth conditions
in unicellular yeasts. In fact, HSF binds to many target
genes in vivo, and their products have a broad range of
biological functions, including protein folding and deg-
radation, energy generation and protein trafficking
[57]. Human HSF2, but not HSF1, forms a trimer and
functionally complements the viability defect of yeast
cells lacking HSF, and both human HSF1 and HSF2
partially rescue the induction of heat-inducible genes,
which is associated with acquired thermotolerance [68].
These observations suggest that the roles of HSF
under normal growth conditions can be distinguished

cal epithelial HeLa cells stably expressing short hairpin
RNA for HSF1 were generated (these cells show >
95% reduction in the HSF1 level), and were highly
sensitive to combined treatment with both elevated
temperature and anticancer reagents [83]. Then,
decreased lymphomagenesis in a p53-deficient mouse
model was shown in the absence of HSF1 [84]. Unex-
pectedly, in addition to being required for carcinogene-
sis in mice, HSF1 is required for proliferation and
survival in various human cancer cell lines, including
HeLa cells, but not in normal or immortalized cells
[85]. This observation suggests the possibility of com-
mon HSF-mediated mechanisms for cell proliferation
and survival in cancer cells and in yeast cells.
Is the HSF1 in cancer cells activated? As HSF1
expression, which is correlated with HSE-binding
activity [35], is elevated in human cancer cells [81,82],
the HSE-binding activity of HSF1 might be higher in
cancer cells than in normal cells. Even so, the HSE-
binding activity is robustly induced in response to heat
shock in cancer cells, such as HeLa cells, compared
with normal cells [35,36] or in fission yeast cells [19].
HSF1 is involved in regulating translation, ribosome
biogenesis and glucose metabolism in cancer cells [85],
and is also required for the expression of numerous
genes, including those for inflammatory cytokines,
chemokine-related genes and interferon-related genes,
even in normally growing primary cultures of MEF
cells [86]. Furthermore, the ability of HSF1 to form a
trimer is required for the gene expression [87]. Taken

[49,88]. Interestingly, a forkhead box (FOXO) family
transcription factor, DAF-16 (abnormal dauer forma-
tion 16), which is a component of the insulin-like signal-
ling pathway that regulates life span, also inhibits polyQ
aggregates, indicating that aging and protein homeosta-
sis are highly related [89,90]. In a C. elegans model of
Alzheimer’s disease, HSF1 inhibited the formation of
toxic aggregates of an aggregation-prone peptide Ab
(1–42) whereas DAF-16 promoted the formation of less-
toxic high-molecular-weight aggregates [91]. Thus,
HSF1 and DAF-16 regulate distinct pathways that
reduce the toxicity of aggregation-prone proteins.
Among mouse polyQ models, the R6 ⁄ 2 polyQ model
has been extensively studied as it is transgenic only for
the 5¢ end of the human huntingtin gene carrying 115–
150 CAG repeat expansions [92]. The formation of
polyQ aggregates is observed not only in the brain but
also in nonneuronal tissues, including the skeletal mus-
cle, heart, liver and pancreas, in mice [93]. Ubiquitous
overexpression of HSP70 in the R6 ⁄ 2 Huntington’s
model had no effect on the life span or neuronal phe-
notypes of the mice and delayed aggregation only
slightly [94,95]. There is only one HSF1 transgenic
mouse model, in which an actively mutated HSF1 is
expressed in tissues such as the testis, skeletal muscle,
heart and stomach, but not in the brain [75]. Remark-
ably, overexpression of an active HSF1 in nonneuronal
tissues in R6 ⁄ 2 mice crossed with HSF1 transgenic
mice suppressed polyQ aggregates, at least in skeletal
muscle, and markedly extended the life span [96].

is actually a promising therapeutic approach for pro-
tein-misfolding disorders.
Conclusions and perspectives
We have learned from the identification and character-
ization of HSF1 and HSF3 in chicken and mouse cells
that the function of these two heat-responsive factors
has diverged greatly during the evolution of vertebrates,
even though the nucleic acid sequence of each has been
well conserved. Importantly, chicken HSF1 and mouse
HSF3 are involved in protecting cells from heat shock
and in maintaining protein homeostasis without induc-
ing the expression of the classical heat shock genes. It
was revealed recently that there are numerous nonclas-
sical heat shock genes, whose expression is induced dur-
ing heat shock in various organisms. Remarkably,
chicken HSF1 and mouse HSF3, as well as mammalian
HSF2 and HSF4, play a role in inducing the expression
of only nonclassical heat shock genes. These observa-
tions suggest the importance of the regulation and func-
tion of the nonclassical heat shock genes. Analysis of
these new findings will help us to understand why the
activation of HSF1 suppresses the progression of pro-
tein-misfolding disorders more than HSPs and should
be beneficial in identifying pathways involved in adap-
tation to proteotoxic stress. Furthermore, these analy-
ses would develop our understanding of the biological
significance of the heat shock response.
Acknowledgements
We thank members of our laboratory for discussions
and Naoki Hayashida for comments on the manu-

¨
rk JK & Sistonen L (2010) Regulation of the mem-
bers of the mammalian heat shock factor family. FEBS
J 277, 4126–4139.
7 Morano KA & Thiele DJ (1999) Heat shock factor
function and regulation in response to cellular stress,
growth, and differentiation signals. Gene Expr 7, 271–
282.
8 Nakai A (1999) New aspects in the vertebrate heat
shock factor system: Hsf3 and Hsf4. Cell Stress Chap-
erones 4, 86–93.
9 Pirkkala L, Nykanen P & Sistonen L (2001) Roles of the
heat shock transcription factors in regulation of the heat
shock response and beyond. FASEB J 15, 1118–1131.
10 McMillan DR, Xiao X, Shao L, Graves K &
Benjamin IJ (1998) Targeted disruption of heat shock
transcription factor 1 abolishes thermotolerance and
protection against heat-inducible apoptosis. J Biol
Chem 273, 7523–7528.
11 Tanabe M, Kawazoe Y, Takeda S, Morimoto RI,
Nagata K & Nakai A (1998) Disruption of the HSF3
gene results in the severe reduction of heat shock gene
expression and loss of thermotolerance. EMBO J 17,
1750–1758.
12 Akerfelt M, Trouillet D, Mezger V & Sistonen L
(2007) Heat shock factors at a crossroad between stress
and development. Ann NY Acad Sci 1113, 15–27.
13 Nakai A (2009) Heat shock transcription factors and
sensory placode development. BMB Rep 42, 631–635.
14 Abane R & Mezger V (2010) Roles of heat shock fac-

heat shock factors with distinct inducible and constitu-
tive DNA-binding ability. Genes Dev 5, 1902–1911.
23 Nakai A & Morimoto RI (1993) Characterization of a
novel chicken heat shock transcription factor, heat
shock factor 3, suggests a new regulatory pathway.
Mol Cell Biol 13, 1983–1997.
24 Nakai A, Tanabe M, Kawazoe Y, Inazawa J, Morimoto
RI & Nagata K (1997) HSF4, a new member of the
human heat shock factor family which lacks properties
of a transcriptional activator. Mol Cell Biol 17, 469–481.
25 Tanabe M, Sasai N, Nagata K, Liu XD, Liu PC, Thi-
ele DJ & Nakai A (1999) The mammalian HSF4 gene
generates both an activator and a repressor of heat
shock genes by alternative splicing. J Biol Chem 274,
27845–27856.
26 International Human Genome Sequencing Consortium
(2001) Initial sequencing and analysis of the human
genome. Nature 409, 860–921.
27 Mouse Genome Sequencing Consortium (2002) Initial
sequencing and comparative analysis of the mouse gen-
ome. Nature 420, 520–562.
28 Inouye S, Katsuki K, Izu H, Fujimoto M, Sugahara
K, Yamada S, Shinkai Y, Oka Y, Katoh Y & Nakai A
(2003) Activation of heat shock genes is not necessary
for protection by heat shock transcription factor 1
against cell death due to a single exposure to high tem-
peratures. Mol Cell Biol 23, 5882–5895.
29 International Chicken Genome Sequencing Consortium
(2004) Sequence and comparative analysis of the
M. Fujimoto and A. Nakai Evolution and function of the HSF family

36 Baler R, Dahl G & Voellmy R (1993) Activation of
human heat shock genes is accompanied by oligomeri-
zation, modification, and rapid translocation of heat
shock transcription factor HSF1. Mol Cell Biol 13,
2486–2496.
37 Sistonen L, Sarge KD, Phillips B, Abravaya K &
Morimoto RI (1992) Activation of heat shock factor 2
during hemin-induced differentiation of human
erythroleukemia cells. Mol Cell Biol 12, 4104–4111.
38 Sistonen L, Sarge KD & Morimoto RI (1994) Human
heat shock factors 1 and 2 are differentially activated
and can synergistically induce hsp70 gene transcription.
Mol Cell Biol 14, 2087–2099.
39 Murphy SP, Gorzowski JJ, Sarge KD & Phillips B
(1994) Characterization of constitutive HSF2 DNA-
binding activity in mouse embryonal carcinoma cells.
Mol Cell Biol 8, 5309–5317.
40 Nakai A, Kawazoe Y, Tanabe M, Nagata K &
Morimoto RI (1995) The DNA-binding properties of
two heat shock factors, HSF1 and HSF3 are induced
in the avian erythroblast cell line HD6. Mol Cell Biol
15, 5168–5178.
41 McMillan DR, Christians E, Forster M, Xiao X,
Connell P, Plumier JC, Zuo X, Richardson J, Morgan
S & Benjamin IJ (2002) Heat shock transcription factor
2 is not essential for embryonic development, fertility,
or adult cognitive and psychomotor function in mice.
Mol Cell Biol 22, 8005–8014.
42 Nakai A & Ishikawa T (2001) Cell cycle transition
under stress conditions controlled by vertebrate heat

shock transcription factor (Hsf1) mutant is defective in
both Hsc82 ⁄ Hsp82 synthesis and spindle pole body
duplication. J Cell Sci 110, 1879–1891.
52 Morano KA, Santoro N, Koch KA & Thiele DJ
(1999) A trans-activation domain in yeast heat shock
transcription factor is essential for cell cycle progres-
sion during stress. Mol Cell Biol 19, 402–411.
53 Metchat A, Akerfelt M, Bierkamp C, Delsinne V,
Sistonen L, Alexandre H & Christians ES (2009)
Mammalian heat shock factor 1 is essential for oocyte
meiosis and directly regulates Hsp90alpha expression.
J Biol Chem 284, 9521–9528.
54 Takaki E, Fujimoto M, Sugahara K, Nakahari T,
Yonemura S, Tanaka Y, Hayashida N, Inouye S,
Takemoto T, Yamashita H et al. (2006) Maintenance
of olfactory neurogenesis requires HSF1, a major heat
shock transcription factor in mice. J Biol Chem 281,
4931–4937.
55 Yan LJ, Christians ES, Liu L, Xiao X, Sohal RS &
Benjamin IJ (2002) Mouse heat shock transcription
factor 1 deficiency alters cardiac redox homeostasis
and increases mitochondrial oxidative damage. EMBO
J 21, 5164–5172.
Evolution and function of the HSF family M. Fujimoto and A. Nakai
4122 FEBS Journal 277 (2010) 4112–4125 ª 2010 The Authors Journal compilation ª 2010 FEBS
56 Takaki E, Fujimoto M, Nakahari T, Yonemura S,
Miyata Y, Hayashida N, Yamamoto K, Vallee RB,
Mikuriya T, Sugahara K et al. (2007) Heat shock tran-
scription factor 1 is required for maintenance of ciliary
beating in mice. J Biol Chem 282, 37285–37292.

regulation during development and heat shock
response in mouse lenses. J Biol Chem 283, 29961–
29970.
64 Jolly C, Metz A, Govin J, Vigneron M, Turner BM,
Khochbin S & Vourc’h C (2004) Stress-induced tran-
scription of satellite III repeats. J Cell Biol 164, 25–33.
65 Rizzi N, Denegri M, Chiodi I, Corioni M, Valgards-
dottir R, Cobianchi F, Riva S & Biamonti G (2004)
Transcriptional activation of a constitutive heterochro-
matic domain of the human genome in response to
heat shock. Mol Cell Biol 15, 543–551.
66 Sandqvist A, Bjo
¨
rk JK, Akerfelt M, Chitikova Z,
Grichine A, Vourc’h C, Jolly C, Salminen TA,
Nymalm Y & Sistonen L (2009) Heterotrimerization of
heat-shock factors 1 and 2 provides a transcriptional
switch in response to distinct stimuli. Mol Biol Cell 20,
1340–1347.
67 Giardina C & Lis JT (1995) Dynamic protein-DNA
architecture of a yeast heat shock promoter. Mol Cell
Biol 15, 2737–2744.
68 Liu XD, Liu PC, Santoro N & Thiele DJ (1997) Con-
servation of a stress response: human heat shock tran-
scription factors functionally substitute for yeast HSF.
EMBO J 16, 6466–6477.
69 Jedlicka P, Mortin MA & Wu C (1997) Multiple func-
tions of Drosophila heat shock transcription factor in
vivo. EMBO J 16, 2452–2462.
70 Xiao X, Zuo X, Davis AA, McMillan DR, Curry BB,

Moskophidis D & Mivechi NF (2004) Essential
requirement for both hsf1 and hsf2 transcriptional
activity in spermatogenesis and male fertility. Genesis
38, 66–80.
78 Chang Y, Ostling P, Akerfelt M, Trouillet D, Rallu M,
Gitton Y, Fatimy EI, Fardeau V, Le Crom S, Mor-
ange M et al. (2006) Role of heat-shock factor 2 in
cerebral cortex formation and as a regulator of p35
expression. Genes Dev 20, 836–847.
79 Whitesell L & Lindquist SL (2005) HSP90 and the
chaperoning of cancer. Nat Rev Cancer 5, 761–772.
80 Calderwood SK, Khaleque MA, Sawyer DB &
Ciocca DR (2006) Heat shock proteins in cancer:
chaperones of tumorigenesis. Trends Biochem Sci 31,
164–172.
81 Hoang AT, Huang J, Rudra-Ganguly N, Zheng J,
Powell WC, Rabindran SK, Wu C & Roy-Burman P
(2000) A novel association between the human heat
M. Fujimoto and A. Nakai Evolution and function of the HSF family
FEBS Journal 277 (2010) 4112–4125 ª 2010 The Authors Journal compilation ª 2010 FEBS 4123
shock transcription factor 1 (HSF1) and prostate ade-
nocarcinoma. Am J Pathol 156, 857–864.
82 Tang D, Khaleque MA, Jones EL, Theriault JR, Li C,
Wong WH, Stevenson MA & Calderwood SK (2005)
Expression of heat shock proteins and heat shock pro-
tein messenger ribonucleic acid in human prostate car-
cinoma in vitro and in tumors in vivo. Cell Stress
Chaperones 10, 46–58.
83 Rossi A, Ciafre
`

90 Morley JF & Morimoto RI (2004) Regulation of lon-
gevity in Caenorhabditis elegans by heat shock factor
and molecular chaperones. Mol Biol Cell 15, 657–664.
91 Cohen E, Bieschke J, Perciavalle RM, Kelly JW &
Dillin A (2006) Opposing activities protect against
age-onset proteotoxicity. Science 313, 1604–1610.
92 Mangiarini L, Sathasivam K, Seller M, Cozens B,
Harper A, Hetherington C, Lawton M, Trottier Y,
Lehrach H, Davies SW et al. (1996) Exon 1 of the HD
gene with an expanded CAG repeat is sufficient to
cause a progressive neurological phenotype in trans-
genic mice. Cell 87, 493–506.
93 Sathasivam K, Hobbs C, Turmaine M, Mangiarini L,
Mahal A, Bertaux F, Wanker EE, Doherty P, Davies
SW & Bates GP (1999) Formation of polyglutamine
inclusions in non-CNS tissue. Hum Mol Genet 8, 813–
822.
94 Hansson O, Nylandsted J, Castilho RF, Leist M,
Ja
¨
a
¨
ttela
¨
M & Brundin P (2003) Overexpression of heat
shock protein 70 in R6 ⁄ 2 Huntington’s disease mice
has only modest effects on disease progression. Brain
Res 970, 47–57.
95 Hay DG, Sathasivam K, Tobaben S, Stahl B,
Marber M, Mestril R, Mahal A, Smith DL,

Yamaguchi M & Toda T (2008) Heat shock transcrip-
tion factor 1-activating compounds suppress polygluta-
mine-induced neurodegeneration through induction of
multiple molecular chaperones. J Biol Chem 283,
26188–26197.
102 Waza M, Adachi H, Katsuno M, Minamiyama M,
Sang C, Tanaka F, Inukai A, Doyu M & Sobue G
(2005) 17-AAG, an Hsp90 inhibitor, ameliorates
polyglutamine-mediated motor neuron degeneration.
Nat Med 11, 1088–1095.
103 Katsuno M, Sang C, Adachi H, Minamiyama M,
Waza M, Tanaka F, Doyu M & Sobue G (2005)
Pharmacological induction of heat-shock proteins
alleviates polyglutamine-mediated motor neuron
disease. Proc Natl Acad Sci USA 102, 16801–16806.
104 Westerheide SD, Bosman JD, Mbadugha BN,
Kawahara TL, Matsumoto G, Kim S, Gu W,
Devlin JP, Silverman RB & Morimoto RI (2004)
Evolution and function of the HSF family M. Fujimoto and A. Nakai
4124 FEBS Journal 277 (2010) 4112–4125 ª 2010 The Authors Journal compilation ª 2010 FEBS
Celastrols as inducers of the heat shock response and
cytoprotection. J Biol Chem 279, 56053–56060.
105 Neef DW, Turski ML & Thiele DJ (2010) Modulation
of heat shock transcription factor 1 as a therapeutic
target for small molecule intervention in neurodegener-
ative disease. PLoS Biol 8, e1000291.
106 Shinka T, Sato Y, Chen G, Naroda T, Kinoshita K,
Unemi Y, Tsuji K, Toida K, Iwamoto T &
Nakahori Y (2004) Molecular characterization of heat
shock-like factor encoded on the human Y

tributes to inducible expression of hsp genes through
interplay with HSF1. J Biol Chem 282, 7077–7086.
M. Fujimoto and A. Nakai Evolution and function of the HSF family
FEBS Journal 277 (2010) 4112–4125 ª 2010 The Authors Journal compilation ª 2010 FEBS 4125