HSF1Base: A Comprehensive Database of HSF1 (Heat Shock Factor 1) Target Genes

: HSF1 (heat shock factor 1) is an evolutionarily conserved master transcriptional regulator of the heat shock response (HSR) in eukaryotic cells. In response to high temperatures, HSF1 upregulates genes encoding molecular chaperones, also called heat shock proteins, which assist the refolding or degradation of damaged intracellular proteins. Accumulating evidence reveals however that HSF1 participates in several other physiological and pathological processes such as differentiation, immune response, and multidrug resistance, as well as in ageing, neurodegenerative demise, and cancer. To address how HSF1 controls these processes one should systematically analyze its target genes. Here we present a novel database called HSF1Base (hsf1base.org) that contains a nearly comprehensive list of HSF1 target genes identified so far. The list was obtained by manually curating publications on individual HSF1 targets and analyzing relevant high throughput transcriptomic and chromatin immunoprecipitation data derived from the literature and the Yeastract database. To support the biological relevance of HSF1 targets identified by high throughput methods, we performed an enrichment analysis of (potential) HSF1 targets across different tissues/cell types and organisms. We found that general HSF1 functions (targets are expressed in all tissues/cell types) are mostly related to cellular proteostasis. Furthermore, HSF1 targets that are conserved across various animal taxa operate mostly in cellular stress pathways (e.g., autophagy), chromatin remodeling, ribosome biogenesis, and ageing. Together, these data highlight diverse roles for HSF1, expanding far beyond the HSR.

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Acute Pancreatitis Results in Induction of Heat Shock Proteins 70 and 27 and Heat Shock Factor-1

Pancreas ◽

10.1097/00006676-200010000-00005 ◽

2000 ◽

Vol 21 (3) ◽

pp. 248-256 ◽

Cited By ~ 48

Author(s):

Richard T. Ethridge ◽

Richard A. Ehlers ◽

Mark R. Hellmich ◽

Srinivasan Rajaraman ◽

B. Mark Evers

Keyword(s):

Acute Pancreatitis ◽

Heat Shock ◽

Heat Shock Proteins ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Shock Proteins

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Heat-shock factor-1, steroid hormones, and regulation of heat-shock protein expression in the heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.280.1.h455 ◽

2001 ◽

Vol 280 (1) ◽

pp. H455-H464 ◽

Cited By ~ 75

Author(s):

A. A. Knowlton ◽

Limin Sun

Keyword(s):

Heat Shock ◽

Steroid Hormones ◽

Cardiac Myocytes ◽

Hormone Receptors ◽

Cardiac Injury ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Adult Cardiac Myocytes ◽

Heat Shock Protein Expression ◽

Shock Proteins

Heat-shock proteins (HSPs) are an important family of endogenous, protective proteins. Overexpression of HSPs is protective against cardiac injury. Previously, we observed that dexamethasone activated heat-shock factor-1 (HSF-1) and induced a 60% increase in HSP72 in adult cardiac myocytes. The mechanism responsible for this effect of dexamethasone is unknown. Because HSP90 is known to bind the intracellular hormone receptors, we postulated that the interaction between HSP90, the receptors, and HSF was an important element in activation of HSF-1 by hormones. We hypothesized that there is an equilibrium between HSP90 and the various receptors/enzymes that it binds and that alteration in levels of certain hormones will alter the intracellular distribution of HSP90 and activate HSF-1. We report that, in adult cardiac myocytes, HSF-1 coimmunoprecipitates with HSP90. HSP90 redistributes in cardiac myocytes after treatment with 17β-estradiol or progesterone. Estrogen and progesterone activate HSF-1 in adult male isolated cardiac myocytes, and this is followed by an increase in HSP72 protein. Testosterone had no effect on HSP levels; however, no androgen receptor was found in cardiac myocytes; therefore, testosterone would not be expected to effect binding of HSP90 to HSF. Geldanamycin, which inactivates HSP90 and prevents it from binding to receptors, activates HSF-1 and stimulates HSP72 synthesis. Activation of HSF-1 by steroid hormones, resulting from a change in the interaction of HSP90 and HSF-1, represents a novel pathway for regulating expression of HSPs. These findings may explain some of the gender differences in cardiovascular disease.

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Role of heat shock factor-1 activation in the doxorubicin-induced heart failure in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01047.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. H1832-H1841 ◽

Cited By ~ 39

Author(s):

Kaushik Vedam ◽

Yoshinori Nishijima ◽

Lawrence J. Druhan ◽

Mahmood Khan ◽

Nicanor I. Moldovan ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Heat Shock ◽

Mrna Level ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Knock Out ◽

Apoptotic Protein ◽

Shock Proteins

Treating cancer patients with chemotherapeutics, such as doxorubicin (Dox), cause dilated cardiomyopathy and congestive heart failure because of oxidative stress. On the other hand, heat shock factor-1 (HSF-1), a transcription factor for heat shock proteins (Hsps), is also known to be activated in response to oxidative stress. However, the possible role of HSF-1 activation and the resultant Hsp25 in chemotherapeutic-induced heart failure has not been investigated. Using HSF-1 wild-type (HSF-1+/+) and knock-out (HSF-1−/−) mice, we tested the hypothesis that activation of HSF-1 plays a role in the development of Dox-induced heart failure. Higher levels of Hsp25 and its phosphorylated forms were found in the failing hearts of Dox-treated HSF-1+/+ mice. More than twofold increase in Hsp25 mRNA level was found in Dox-treated hearts. Proteomic analysis showed that there is accumulation and aggregation of Hsp25 in Dox-treated failing hearts. Additionally, Hsp25 was found to coimmunoprecipitate with p53 and vice versa. Further studies indicated that the Dox-induced higher levels of Hsp25 transactivated p53 leading to higher levels of the pro-apoptotic protein Bax, but other p53-related proteins remained unaltered. Moreover, HSF-1−/− mice showed significantly reduced Dox-induced heart failure and higher survival rate, and there was no change in Bax upon treating with Dox in HSF-1−/− mice. From these results we propose a novel mechanism for Dox-induced heart failure: increased expression of Hsp25 because of oxidant-induced activation of HSF-1 transactivates p53 to increase Bax levels, which leads to heart failure.

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Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update

Archives of Toxicology ◽

10.1007/s00204-012-0918-z ◽

2012 ◽

Vol 87 (1) ◽

pp. 19-48 ◽

Cited By ~ 155

Author(s):

Daniel R. Ciocca ◽

Andre Patrick Arrigo ◽

Stuart K. Calderwood

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Tumor Development ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Shock Proteins

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Heat-shock cognate 70 is required for the activation of heat-shock factor 1 in mammalian cells

Biochemical Journal ◽

10.1042/bj20050412 ◽

2005 ◽

Vol 392 (1) ◽

pp. 145-152 ◽

Cited By ~ 37

Author(s):

Sang-Gun Ahn ◽

Soo-A Kim ◽

Jung-Hoon Yoon ◽

Panayiotis Vacratsis

Keyword(s):

Heat Shock ◽

Mammalian Cells ◽

Cellular Response ◽

Target Genes ◽

Affinity Purification ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Small Interfering Rnas ◽

Heat Shock Cognate 70

HSF1 (heat-shock factor 1) plays an essential role in mediating the appropriate cellular response to diverse forms of physiological stresses. However, it is not clear how HSF1 is regulated by interacting proteins under normal and stressful conditions. In the present study, Hsc70 (heat-shock cognate 70) was identified as a HSF1-interacting protein using the TAP (tandem affinity purification) system and MS. HSF1 can interact with Hsc70 in vivo and directly in vitro. Interestingly, Hsc70 is required for the regulation of HSF1 during heat stress and subsequent target gene expression in mammalian cells. Moreover, cells transfected with siRNAs (small interfering RNAs) targeted to Hsc70 showed greatly decreased HSF1 activation with expression of HSF1 target genes being dramatically reduced. Finally, loss of Hsc70 expression in cells resulted in an increase in stress-induced apoptosis. These results indicate that Hsc70 is a necessary and critical regulator of HSF1 activities.

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ATF1 Modulates the Heat Shock Response by Regulating the Stress-Inducible Heat Shock Factor 1 Transcription Complex

Molecular and Cellular Biology ◽

10.1128/mcb.00754-14 ◽

2014 ◽

Vol 35 (1) ◽

pp. 11-25 ◽

Cited By ~ 28

Author(s):

Ryosuke Takii ◽

Mitsuaki Fujimoto ◽

Ke Tan ◽

Eiichi Takaki ◽

Naoki Hayashida ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Response ◽

Mammalian Cells ◽

Target Genes ◽

Acute Stress ◽

Heat Shock Factor ◽

Metabolic Adaptation ◽

Heat Shock Factor 1 ◽

Creb Binding Protein ◽

Shock Response

The heat shock response is an evolutionally conserved adaptive response to high temperatures that controls proteostasis capacity and is regulated mainly by an ancient heat shock factor (HSF). However, the regulation of target genes by the stress-inducible HSF1 transcription complex has not yet been examined in detail in mammalian cells. In the present study, we demonstrated that HSF1 interacted with members of the ATF1/CREB family involved in metabolic homeostasis and recruited them on theHSP70promoter in response to heat shock. The HSF1 transcription complex, including the chromatin-remodeling factor BRG1 and lysine acetyltransferases p300 and CREB-binding protein (CBP), was formed in a manner that was dependent on the phosphorylation of ATF1. ATF1-BRG1 promoted the establishment of an active chromatin state andHSP70expression during heat shock, whereas ATF1-p300/CBP accelerated the shutdown of HSF1 DNA-binding activity during recovery from acute stress, possibly through the acetylation of HSF1. Furthermore, ATF1 markedly affected the resistance to heat shock. These results revealed the unanticipated complexity of the primitive heat shock response mechanism, which is connected to metabolic adaptation.

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