Affinage

HSF1

Heat shock factor protein 1 · UniProt Q00613

Length
529 aa
Mass
57.3 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSF1 is the master transcriptional regulator of the proteotoxic stress response, integrating signals from chaperone availability, kinase cascades, and protein homeostasis to control expression of heat shock proteins, metabolic enzymes, and diverse stress-adaptive genes. In unstressed cells, Hsp70/Hsc70 directly binds HSF1's transactivation domain via its substrate-binding domain, maintaining HSF1 in an inactive monomeric state; upon heat shock or proteotoxic stress, newly synthesized misfolded proteins titrate Hsp70 away, releasing HSF1 to trimerize—a step requiring AKT1-mediated phosphorylation at T142—translocate to the nucleus, and form liquid-liquid phase-separated condensates at target gene loci that concentrate transcription machinery (PMID:31552827, PMID:35256776, PMID:35080342). Attenuation proceeds through Hsc70/DnaJB1-driven entropic unzipping of the HSF1 leucine-zipper trimer from DNA, while HSP70 disperses nuclear condensates to prevent gel-like transitions that impair transcription (PMID:32490574, PMID:32015439). HSF1 activity and stability are further tuned by multi-site phosphorylation (MEK, PLK1, PIM2, AMPKα), ubiquitin-mediated degradation (NEDD4, FBXW7), SIRT1-dependent deacetylation of K80, and CHIP-mediated trimerization, and HSF1 is co-opted in cancer through RAS/MAPK, PI3K/AKT/mTOR, and HER2 signaling to sustain pro-tumorigenic transcriptional programs (PMID:25679764, PMID:31409638, PMID:26503960, PMID:14532117, PMID:24384723).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1991 High

    The identity of the human heat shock transcription factor was unknown; cloning HSF1 revealed a leucine-zipper-containing protein whose intrinsic DNA-binding activity is constitutively repressed in human cells, establishing that HSF1 regulation is post-translational.

    Evidence cDNA cloning, recombinant protein expression in E. coli, DNA-binding assay

    PMID:1871105

    Open questions at the time
    • Mechanism of intracellular repression unidentified
    • No stress-dependent activation pathway yet mapped
  2. 1994 High

    How HSF1 distinguished its target sites from those of HSF2 was unclear; SELEX and chimera experiments showed HSF1 binds extended HSE sequences with higher cooperativity than HSF2 through a transferable domain adjacent to the DNA-binding domain.

    Evidence In vitro selection (SELEX), EMSA, chimeric protein analysis

    PMID:7935474

    Open questions at the time
    • Structural basis of cooperative binding unresolved
    • In vivo target discrimination not tested
  3. 1998 High

    The mechanism keeping HSF1 transcriptionally silent despite DNA binding was unknown; Hsp70 and co-chaperone Hdj1 were shown to directly bind the HSF1 transactivation domain and repress transcription without affecting DNA binding, establishing chaperone-mediated autoregulation as the core attenuation mechanism.

    Evidence Co-immunoprecipitation, GAL4 fusion reporter assay, EMSA

    PMID:9499401

    Open questions at the time
    • Whether Hsp70 also controls HSF1 trimerization or only transactivation was unclear
    • In vivo reconstitution lacking
  4. 2003 High

    Whether co-chaperones could positively regulate HSF1 was untested; CHIP was shown to induce HSF1 trimerization and transcriptional activation, and CHIP-knockout mice exhibited temperature sensitivity and stress-induced apoptosis, identifying CHIP as a positive regulator.

    Evidence CHIP knockout mouse, trimerization assay, transcriptional reporter

    PMID:14532117

    Open questions at the time
    • CHIP-HSF1 interaction domain not yet mapped
    • Relationship between CHIP E3 ligase activity and HSF1 trimerization not separated
  5. 2006 Medium

    Whether HSF1 targets extended beyond classical chaperones was uncertain; discovery that HSF1 directly transactivates the proapoptotic gene Tdag51, whose product is then buffered by HSPs, revealed that HSF1 controls a pro-death/pro-survival gene balance under stress.

    Evidence ChIP, direct HSP-Tdag51 binding assay, Tdag51-null mouse

    PMID:17024176

    Open questions at the time
    • Full scope of non-chaperone HSF1 target genes unknown at this point
    • Generalizability beyond heat stress unclear
  6. 2011 Medium

    HSF1's role in DNA damage responses was unexplored; loss-of-function experiments showed HSF1 is required for radiation-induced G2 arrest and 53BP1 recruitment to damage sites, extending HSF1 function beyond proteostasis to genome integrity.

    Evidence HSF1-deficient cells, flow cytometry, γ-H2AX/53BP1 immunofluorescence

    PMID:21557666

    Open questions at the time
    • Whether this requires HSF1 transcriptional activity or a direct scaffolding role was unresolved
    • Mechanism of 53BP1 recruitment failure not defined
  7. 2013 High

    Whether translational flux controlled HSF1 was unclear; blocking translation in cancer cells inactivated HSF1, linking the supply of newly synthesized (potentially misfolded) proteins to HSF1 activation and establishing a rationale for translation inhibitors as HSF1-targeting anticancer agents.

    Evidence Chemical-genetic analysis with translation inhibitors, HSF1 reporter assays, metabolic profiling

    PMID:23869022

    Open questions at the time
    • Whether misfolded nascent chains were the direct signal or an indirect effect was unresolved
  8. 2014 Medium

    Upstream kinase pathways converging on HSF1 in cancer were being mapped; HER2 was shown to constitutively activate HSF1 via the PI3K-AKT-mTOR axis with S326 phosphorylation as the key mark, and AMPKα was identified as an inhibitory kinase phosphorylating S303.

    Evidence Kinase inhibitors, siRNA, phospho-S326 immunoblot, in vivo breast cancer model (HER2); Co-IP, kinase assay, S303 mutagenesis (AMPKα)

    PMID:24384723 PMID:24412756

    Open questions at the time
    • How S326 and S303 phosphorylation integrate with trimerization was unclear
    • AMPKα-HSF1 axis independently replicated only in limited contexts
  9. 2015 High

    Multiple layers of HSF1 protein turnover were defined: MEK was identified as a direct HSF1 kinase guarding proteome stability; NEDD4 was shown to ubiquitinate HSF1 for proteasomal degradation regulated by SIRT1 deacetylation of K80; and PP2A/B55 was found to dephosphorylate and activate HSF1 through IER5.

    Evidence In vitro kinase assays (MEK), mass spectrometry, ubiquitination/degradation assays (NEDD4/SIRT1/K80), Co-IP and reporter (PP2A/B55/IER5)

    PMID:25679764 PMID:25816751 PMID:26503960

    Open questions at the time
    • Relative contributions of NEDD4 vs. FBXW7 to HSF1 turnover in different tissues not delineated
    • IER5-PP2A-HSF1 axis awaits independent replication
  10. 2017 Medium

    HSF1's transcriptional repertoire expanded dramatically: it was shown to directly regulate NAMPT (NAD+ salvage), CALM1 (CaM-Akt signaling in hepatic glucose metabolism), HMGB1 (inflammation), and ATG4B (autophagy), and to scaffold a PARP13-PARP1-HDAC1 complex for DNA repair.

    Evidence ChIP at multiple promoters, KO mice/hepatocytes, metabolic profiling, Co-IP for PARP13 complex, reporter assays

    PMID:28183717 PMID:28246289 PMID:28889000 PMID:29158484 PMID:31825792

    Open questions at the time
    • Many non-chaperone targets identified in single labs; genome-wide target validation incomplete
    • PARP13-HSF1 interaction mechanism not structurally resolved
  11. 2019 High

    Key regulatory inputs were refined: PIM2 phosphorylates HSF1-T120 to block FBXW7-mediated degradation; PDK3 binds HSF1 and shields it from GSK3β-directed FBXW7 ubiquitination; Hsp70's two independent binding sites on HSF1 were mapped; and the chaperone-titration model was reconstituted in vitro with purified yeast proteins.

    Evidence In vitro kinase assays, ubiquitination assays, mutagenesis (T120, Hsp70 binding sites), in vitro reconstitution with purified proteins

    PMID:31239354 PMID:31244938 PMID:31409638 PMID:31552827

    Open questions at the time
    • Whether dual Hsp70-binding site regulation applies identically in mammalian cells not confirmed
    • PDK3-HSF1 positive feedback loop known from single lab
  12. 2020 High

    The molecular mechanism of HSF1 attenuation was solved: Hsc70/DnaJB1 disassemble DNA-bound HSF1 trimers by entropic unzipping of the leucine zipper; concurrently, prolonged stress was shown to convert fluid HSF1 nuclear condensates into gel-like states that impair transcription.

    Evidence In vitro reconstitution with purified proteins (entropic pulling), live-cell FRAP and biophysical characterization (condensate maturation)

    PMID:32015439 PMID:32490574

    Open questions at the time
    • Whether entropic pulling applies to all HSF1 target loci in vivo untested
    • Molecular determinants of liquid-to-gel transition not fully defined
  13. 2022 High

    HSF1 activation was integrated across multiple scales: AKT1 was mapped as the kinase phosphorylating T142 (trimerization), S230, S326, T527 (transactivation/cofactor recruitment); PLK1 phosphorylation of S419 recruits TRRAP-TIP60 to establish active chromatin via H2B-K120 monoubiquitination; HSF1 phase-separated condensates were shown to concentrate transcription machinery at target loci with HSP70 dispersing them; and HSF1-HSF2 heterotypic interactions were found to co-regulate cancer-relevant genes.

    Evidence In vitro kinase/MS, mutagenesis, ChIP-seq, super-resolution imaging, phase separation reconstitution, Co-IP (HSF2), xenograft models

    PMID:35080342 PMID:35256776 PMID:35294249 PMID:35906200

    Open questions at the time
    • Structural basis of HSF1 condensate formation unresolved
    • How HSF1-HSF2 stoichiometry is regulated remains unclear
    • T527 phosphorylation site not yet independently validated
  14. 2022 Medium

    Non-nuclear functions of HSF1 emerged: mitochondrial HSF1 accumulation in Huntington's disease models activates Drp1-S616 phosphorylation for mitochondrial fission and suppresses SSBP1 oligomerization causing mtDNA deletion; separately, circadian disruption was shown to enhance HSF1 nuclear accumulation promoting KRAS-driven lung tumorigenesis.

    Evidence Subcellular fractionation, mitochondria-targeted constructs, iPSC organoids, peptide inhibitor (DH1); nuclear fractionation, chronic jetlag mouse model

    PMID:35670111 PMID:36170373

    Open questions at the time
    • Whether mitochondrial HSF1 localization is physiological or pathological artifact needs clarification
    • Circadian-HSF1 coupling mechanism not molecularly defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of HSF1 phase separation and liquid-to-gel transition; the full chromatin-level mechanism integrating multi-site phosphorylation with condensate dynamics; how HSF1 balances cytoprotective versus pro-tumorigenic transcriptional programs in vivo; and whether mitochondrial HSF1 functions represent a physiologically relevant non-transcriptional role.
  • No high-resolution structure of full-length HSF1 trimer on DNA
  • Genome-wide mapping of phosphorylation-dependent condensate targets incomplete
  • In vivo reconstitution of chaperone titration model in mammalian system lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-8953897 Cellular responses to stimuli 6 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-392499 Metabolism of proteins 3 R-HSA-73894 DNA Repair 2 R-HSA-9612973 Autophagy 1
Partners
AKT1DNAJB1HSF2HSPA1AHSPA8NEDD4SIRT1STUB1
Complex memberships
HSF1 homotrimerHSF1-HSF2 complexHSF1-PARP13-PARP1-HDAC1 complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 Human HSF1 was molecularly cloned and shown to encode a protein with four conserved leucine zipper motifs. HSF1 produced in E. coli in the absence of heat shock is active as a DNA-binding transcription factor, indicating that its intrinsic activity is under negative control in human cells. cDNA cloning, recombinant protein expression in E. coli, DNA-binding assay Proceedings of the National Academy of Sciences of the United States of America High 1871105
1998 Hsp70 and the co-chaperone Hdj1 directly interact with the transactivation domain of HSF1 and repress HSF1 transcriptional activity without affecting its DNA binding or inducible phosphorylation, identifying chaperone-mediated repression of the transactivation domain as the primary autoregulatory mechanism during attenuation of the heat shock response. Co-immunoprecipitation, GAL4 fusion overexpression assay, transactivation reporter assay, gel-shift (EMSA) Genes & development High 9499401
1994 mHSF1 binds extended heat shock element (HSE) sequences with higher cooperativity than mHSF2; the cooperative DNA-binding domain of mHSF1 maps to sequences within or adjacent to its DNA-binding domain and is transferable to mHSF2 in chimeric proteins. Single base substitutions in the HSE can alter affinity for a specific HSF. In vitro selection (SELEX), EMSA, mutagenesis of HSE, chimeric protein analysis Molecular and cellular biology High 7935474
2003 The co-chaperone/ubiquitin ligase CHIP induces trimerization and transcriptional activation of HSF1, and CHIP-deficient mice are temperature-sensitive and undergo apoptosis in multiple organs after stress, establishing CHIP as a positive regulator of the HSF1 stress response. CHIP knockout mouse phenotype, cell-based trimerization assay, transcriptional reporter assay The EMBO journal High 14532117
2015 HSF1 is a direct substrate of MEK; MEK phosphorylates and activates HSF1 to guard proteome stability, and MEK inhibition inactivates HSF1 causing protein destabilization, aggregation, and amyloidogenesis that is particularly toxic to tumor cells. In vitro kinase assay (MEK→HSF1), mass spectrometry, cell-based aggregation/amyloid assay, in vivo tumor model Cell High 25679764
2015 NEDD4 ubiquitin E3 ligase mediates HSF1 degradation through the ubiquitin-proteasome system in the context of α-synuclein aggregation, and the acetylation status of Lys80 in the HSF1 DNA-binding domain modulates both HSF1 transcriptional activity and protein stability. SIRT1-mediated deacetylation attenuates NEDD4-dependent HSF1 degradation. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K80), proteasome inhibitor treatment, neuroblastoma cell and mouse model Human molecular genetics High 26503960
2019 Hsp70 binds HSF1 via its canonical substrate-binding domain, inhibiting HSF1 DNA-binding activity. During heat shock, cytoplasmic misfolded proteins derived from ongoing translation titrate Hsp70 away from HSF1, releasing HSF1 to activate the heat shock response. This chaperone-titration mechanism is reconstituted in vitro with purified budding yeast proteins. In vitro reconstitution with purified proteins, EMSA, translation inhibition genetics, yeast cell biology eLife High 31552827
2020 Hsc70 and DnaJB1 dissociate trimeric HSF1 from DNA in vitro by successive cycles of entropic pulling that unzip the triple leucine-zipper, monomerizing HSF1 trimers. Hsc70 first binds a high-affinity site in the HSF1 transactivation domain to attenuate transcription, then at higher concentrations removes HSF1 from DNA to restore resting state. In vitro reconstitution with purified proteins, EMSA, biochemical dissociation assay, binding affinity measurements The EMBO journal High 32490574
2022 HSF1 forms liquid-liquid phase-separated condensates at heat-shock-protein gene loci during heat shock, enriching transcription apparatus through co-phase separation to promote target gene transcription. Phosphorylation within the regulatory domain fine-tunes phase-separation capability. HSP70 disperses HSF1 condensates to attenuate transcription and prevents gel-like phase transition under extended stress. Super-resolution imaging, in vitro reconstitution of phase separation, high-throughput sequencing (ChIP/RNA-seq), phosphorylation site mutagenesis, FRAP Nature cell biology High 35256776
2020 During prolonged heat stress, HSF1 nuclear condensates (foci) transition from small fluid liquid condensates to enlarged gel-like arrangements with immobilized HSF1; this transition reduces chaperone gene induction and correlates with increased apoptosis, revealing that foci dissolution promotes HSF1 transcriptional activity and cell survival. Live-cell microscopy, FRAP, single-cell analysis, multiplexed tissue imaging, biophysical characterization of condensate state Nature cell biology High 32015439
2013 Blocking protein translation in cancer cells inactivates HSF1 transcriptional activity, linking translational flux to HSF1 regulation. Translation initiation inhibitors (rocaglates) deprived cancer cells of chaperone and energy support, selectively impairing proliferation. Chemical-genetic analysis, translation inhibition, HSF1 reporter assays, metabolic profiling Science (New York, N.Y.) High 23869022
2019 AKT activates HSF1 via phosphorylation at Ser230, enabling HSF1 to physically neutralize soluble amyloid oligomers (AOs) directly, and shields HSP60 from AO assault, averting mitochondrial proteome collapse and apoptosis. In vitro kinase assay, phospho-site mutagenesis, direct binding assay between HSF1 and amyloid oligomers, cell viability and apoptosis assays Science advances High 33177089
2022 AKT1 phosphorylates HSF1 at T142, S230, S326, and T527 (the latter being newly identified). Phosphorylation at T142 is necessary for HSF1 trimerization; S230, S326, and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. AKT2 and other kinases (mTOR, p38, MEK1, DYRK2) phosphorylate S326 but are less potent activators than AKT1. In vitro kinase assay, mass spectrometry, site-directed mutagenesis, co-immunoprecipitation of TFIIB and CDK9, reporter assay The FEBS journal High 35080342
2017 HSF1 recruits PARP1 through the scaffold protein PARP13; activated PARP1 dissociates from the HSF1-PARP13 complex upon DNA damage and redistributes to DNA lesions. HDAC1 maintains PARP1 in the ternary complex by deacetylating and inactivating it. Disruption of this complex impairs PARP1 redistribution, reducing DNA repair and gene expression. Co-immunoprecipitation, chromatin immunoprecipitation, reconstitution assay, HDAC inhibition, knockdown/KO cell lines Nature communications High 29158484
2022 HSF1 recruits the TRRAP-TIP60 acetyltransferase complex to the HSP72 promoter in a manner dependent on phosphorylation of HSF1-S419 (mediated by PLK1). TIP60-mediated acetylation then recruits TRIM33, which cooperates with TRIM24 for mono-ubiquitination of histone H2B at K120, stabilizing the HSF1-transcription complex and establishing active chromatin. Co-immunoprecipitation, ChIP-seq, phospho-site mutagenesis, kinase inhibition (PLK1), histone modification analysis Nature communications High 35906200
2015 IER5 interacts with protein phosphatase 2A (PP2A) and its B55 regulatory subunits; IER5/B55 expression leads to HSF1 dephosphorylation and activation of HSF1 target genes. B55 subunits directly bind HSF1, identifying IER5 as a positive feedback regulator that activates HSF1 via PP2A/B55-mediated dephosphorylation. Co-immunoprecipitation, gene reporter assay, dephosphorylation assay FEBS letters Medium 25816751
2014 AMPKα phosphorylates HSF1 at Ser303, leading to transcriptional suppression of HSP70 and HSP27. PP2A B56δ dephosphorylates AMPKα at Thr172, relieving this suppression; PP2A B56δ physically interacts with AMPKα, establishing a PP2A-AMPKα-HSF1 signaling axis. Co-immunoprecipitation, kinase assay, phospho-site mutagenesis, siRNA knockdown, reporter assay Cellular signalling Medium 24412756
2019 PIM2 kinase phosphorylates HSF1 at Thr120, disrupting HSF1 binding to the E3 ubiquitin ligase FBXW7 and thereby preventing FBXW7-mediated polyubiquitination and proteasomal degradation of HSF1. This stabilization promotes PD-L1 expression and breast cancer tumorigenesis. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (T120), ubiquitination assay Cancer research High 31409638
2017 SIRT1-mediated deacetylation of HSF1 enhances its binding to HSP gene promoters and increases HSP70 and HSP40 expression to alleviate hepatic ER stress. Inhibition or knockout of SIRT1 diminishes exenatide-induced HSF1 deacetylation and HSP expression, establishing the SIRT1/HSF1/HSP pathway. ChIP assay, SIRT1 KO mouse model, lentiviral shRNA knockdown, Western blot Hepatology (Baltimore, Md.) Medium 28439947
2022 HSF1 accumulates in the mitochondria in Huntington's disease models and activates dynamin-related protein 1 (Drp1) phosphorylation at S616 to promote mitochondrial fission; mitochondria-targeted HSF1 also suppresses SSBP1 oligomer formation, causing mitochondrial DNA deletion. A peptide inhibitor (DH1) blocking HSF1 mitochondrial localization abolishes these effects. Subcellular fractionation, mitochondria-targeting HSF1 construct overexpression, Drp1 phosphorylation assay, mouse model, human iPSC organoids, peptide inhibitor EMBO molecular medicine Medium 35670111
2019 Hsp70 interacts with HSF1 via two independent sites in the N-terminal and C-terminal transcriptional activation domains (CE2 site and a newly identified N-terminal site) through its substrate-binding domain. Disrupting either site dysregulates HSF1 transcriptional activity, and dual disruption has synergistic effects on both gene expression and cellular fitness. Co-immunoprecipitation, binding domain mutagenesis, transcriptional assay (yeast Saccharomyces cerevisiae) The Journal of biological chemistry High 31239354
2020 ABL2 tyrosine kinase directly interacts with HSF1 protein through its SH3 domain at a non-canonical proline-independent SH3 interaction motif, regulating HSF1 protein expression. Pharmacologic (allosteric, not ATP-competitive) inhibition of ABL2 disrupts this interaction and impairs HSF1 expression and HSF1-E2F transcriptional targets in brain-metastatic lung cancer cells. Co-immunoprecipitation, domain mapping (SH3), allosteric vs. ATP-competitive inhibitor comparison, shRNA knockdown, cell viability assay Proceedings of the National Academy of Sciences of the United States of America Medium 33318173
2022 HSF2 physically and functionally interacts with HSF1 across diverse cancer types; HSF1 and HSF2 have similar chromatin occupancy and regulate a common set of cancer-relevant genes. Loss of either factor dysregulates nutrient stress responses and reduces tumor progression in xenografts. Co-immunoprecipitation, ChIP-seq, xenograft tumor model, genetic KD Science advances Medium 35294249
2011 Loss of HSF1 prevents radiation-induced G2 arrest and reduces double-strand break repair; 53BP1 fails to accumulate at DNA damage sites in HSF1-deficient cells, revealing that HSF1 is required for DNA damage checkpoint activation and repair via the 53BP1 mediator pathway. HSF1 loss-of-function cell lines, flow cytometry (G2 arrest), gamma-H2AX foci, 53BP1 immunofluorescence Radiation research Medium 21557666
2014 HSF1 protects neurons through a trimerization-independent and HSP-independent mechanism that requires cooperation with SIRT1 and classical HDACs, but not CaMK, PKA, CK2, or Raf-MEK-ERK and PI3K-Akt pathways. HSF1 trimerization-defective mutants, HSP70 knockdown, HSP90 blockade, HDAC inhibition, epistasis in neuronal cultures The Journal of neuroscience Medium 24478344
2006 CHIP directly interacts with HSF1 via its tetratricopeptide repeat (TPR) domain to mediate HSF1 stability and nuclear translocation, suppressing IGF-IIR expression under physiological conditions. Doxorubicin attenuates the CHIP-HSF1 interaction, leading to proteasomal HSF1 degradation and IGF-IIR-dependent cardiomyocyte apoptosis. Co-immunoprecipitation, domain mapping (TPR domain), proteasome inhibitor assay, HSF1 overexpression/knockdown, cardiomyocyte apoptosis assay Cell death & disease Medium 27809308
2021 HSF1 activation requires concurrent protein synthesis; misfolded proteins derived from ongoing translation—not pre-existing proteins—are the primary signal activating HSF1. Disrupting assembly or subcellular localization of newly synthesized proteins is sufficient to activate HSF1 in budding yeast. Systematic translation inhibition genetics, orthogonal stress induction, quantitative transcriptomics Molecular biology of the cell Medium 34191586
2017 HSF1 directly binds the ATG4B gene promoter (site -1429 to -1417), transcriptionally upregulating ATG4B, which enhances protective autophagy in hepatocellular carcinoma cells treated with epirubicin. Luciferase reporter assay, chromatin immunoprecipitation (ChIP), ATG4B knockdown, autophagy flux assay Cancer letters Medium 28889000
2015 Hsf4b interacts with HSF1 via N-terminal hydrophobic regions, impairs HSF1's intramolecular interaction between N- and C-terminal hydrophobic regions (which normally maintains HSF1 as inactive monomer), and causes cytosolic retention and proteasomal/lysosomal degradation of HSF1, thereby inhibiting HSP70 expression. Co-immunoprecipitation, domain mapping, proteasome/lysosome inhibitor assay, ChIP assay Biochimica et biophysica acta Medium 25601714
2019 PDK3 localizes to the nucleus, binds HSF1, and disrupts HSF1 phosphorylation by GSK3β, preventing FBXW7-catalyzed polyubiquitination and proteasomal degradation of HSF1. HSF1 transcriptionally activates PDK3, forming a positive feedback loop that promotes glycolysis in chemoresistant cancer cells. Immunoprecipitation, subcellular fractionation, kinase inhibition (GSK3β), ubiquitination assay, ChIP Theranostics Medium 31244938
2017 HSF1 directly binds the HMGB1 promoter and negatively regulates HMGB1 transcription, as demonstrated by ChIP assay and luciferase reporter assay. HSF1 knockdown enhances TLR4/MyD88/NF-κB-mediated airway inflammation through increased HMGB1 expression. ChIP assay, luciferase reporter assay, siRNA knockdown, OVA asthma mouse model Life sciences Medium 31825792
2022 HSF1 directly binds Bdnf gene promoters I and IV in mouse hippocampus in vivo following kainic acid or footshock stress, co-occupying these promoters with phospho-CREB. HSF1 overexpression increases BDNF mRNA and protein via promoter activation, linking HSF1 to neuronal plasticity and neuroprotection through direct BDNF transcriptional control. ChIP-qPCR in vivo, immunohistochemistry, luciferase reporter assay, viral HSF1 overexpression in primary neurons Journal of neurochemistry Medium 36227087
2021 WT p53 represses HSF1 activity by activating CDKN1A/p21, causing cell cycle inhibition and suppression of E2F target MLK3; MLK3 links cell cycle progression to MAPK-HSF1 activation. Loss of WT p53 (LOH) eliminates this repressive axis, unleashing HSF1 tumor-promoting functions. Genetic epistasis in colorectal tumor organoids, p53 LOH analysis, MLK3 knockdown, MAPK pathway analysis Nature communications Medium 34188043
2017 In the absence of HSF1, NAD+ and ATP are not efficiently maintained in hepatic cells due to transcriptional repression of nicotinamide phosphoribosyltransferase (NAMPT) in the NAD+ salvage pathway. The resulting NAD+ deficiency reduces NAD+-dependent deacetylase (SIRT) activity, increases protein acetylation, and impairs mitochondrial integrity. HSF1 KO in hepatocytes, metabolic profiling (NAD+/ATP), ChIP (NAMPT promoter), SIRT activity assay The Journal of cell biology Medium 28183717
2017 HSF1 upregulates HSF1 expression and activates CALM1 transcription to increase calmodulin (CaM) protein levels in hepatocytes, which then activates Akt independently of Ca2+ and insulin, repressing gluconeogenic gene expression. This FAM3C-HSF1-CaM-Akt axis controls hepatic glucose metabolism. Luciferase reporter assay (CALM1 promoter), Akt phosphorylation assay, siRNA knockdown, KO mouse model Diabetes Medium 28246289
2014 HER2/ErbB2 overexpression constitutively activates HSF1 through the PI3K-AKT-mTOR axis, as shown by pharmacological (Lapatinib, CP724.714) and siRNA-mediated HER2 inhibition reducing phospho-Ser326 HSF1 levels. Inactivated HSF1 reduces HSP90 chaperone activity, destabilizing HSP90 clients including MIF, AKT, and mutant p53. Kinase inhibitors, siRNA knockdown, phospho-HSF1 (S326) immunoblot, in vivo ErbB2-driven breast cancer mouse model Cell death & disease Medium 24384723
2017 HSF1 transcriptionally activates the PFKFB3 gene (a key glycolysis enzyme) in endometriosis cells, promoting glycolysis. ChIP or reporter assays confirm HSF1 binding to the PFKFB3 promoter. Gene expression analysis, glucose/lactate measurement, HSF1 inhibitor (KRIBB11), in vivo mouse endometriosis model Reproductive biology and endocrinology Low 34107992
2006 A proapoptotic HSF1 target gene, Tdag51, is directly transactivated by HSF1 during heat stress. HSPs bind directly to the N-terminal pleckstrin-homology-like (PHL) domain of Tdag51, suppressing its C-terminal pro-death activity. Cell fate under proteotoxic stress is determined by the balance between Hsp and Tdag51 levels. Chromatin immunoprecipitation (ChIP), direct binding assay (Hsps to Tdag51 PHL domain), Tdag51-null mouse The EMBO journal Medium 17024176
2022 Circadian disruption (chronic jetlag) disrupts the highly rhythmic nuclear trafficking of HSF1 in mouse lung, resulting in enhanced accumulation of HSF1 in the nucleus and increased expression of HSF1 target genes, promoting KRAS-driven lung tumorigenesis. Nuclear fractionation, ChIP/target gene expression, genetic and pharmacological HSF1 inhibition, mouse lung cancer model Science advances Medium 36170373

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annual review of biochemistry 591 21417720
1998 Molecular chaperones as HSF1-specific transcriptional repressors. Genes & development 483 9499401
1991 Molecular cloning and expression of a human heat shock factor, HSF1. Proceedings of the National Academy of Sciences of the United States of America 414 1871105
2003 CHIP activates HSF1 and confers protection against apoptosis and cellular stress. The EMBO journal 273 14532117
2014 HSF1 at a glance. Journal of cell science 240 24421309
2013 Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science (New York, N.Y.) 230 23869022
2017 Rethinking HSF1 in Stress, Development, and Organismal Health. Trends in cell biology 204 28890254
2009 Inhibiting the transcription factor HSF1 as an anticancer strategy. Expert opinion on therapeutic targets 191 19335068
2019 Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts. Nature communications 139 30631061
2015 MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1. Cell 136 25679764
2022 Reversible phase separation of HSF1 is required for an acute transcriptional response during heat shock. Nature cell biology 128 35256776
1994 Selection of new HSF1 and HSF2 DNA-binding sites reveals difference in trimer cooperativity. Molecular and cellular biology 120 7935474
2014 HSF1 deficiency and impaired HSP90-dependent protein folding are hallmarks of aneuploid human cells. The EMBO journal 98 25205676
2019 Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1. eLife 97 31552827
2020 HSF1 phase transition mediates stress adaptation and cell fate decisions. Nature cell biology 92 32015439
2019 HSF1 as a Cancer Biomarker and Therapeutic Target. Current cancer drug targets 92 30338738
2006 A novel HSF1-mediated death pathway that is suppressed by heat shock proteins. The EMBO journal 84 17024176
2020 Feedback regulation of heat shock factor 1 (Hsf1) activity by Hsp70-mediated trimer unzipping and dissociation from DNA. The EMBO journal 80 32490574
2014 HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer. Cell death & disease 79 24384723
2016 Hsf1 and Hsp90 orchestrate temperature-dependent global transcriptional remodelling and chromatin architecture in Candida albicans. Nature communications 77 27226156
2015 NEDD4-mediated HSF1 degradation underlies α-synucleinopathy. Human molecular genetics 76 26503960
2022 Heat Shock Proteins and HSF1 in Cancer. Frontiers in oncology 75 35311075
2019 Phosphorylation of HSF1 by PIM2 Induces PD-L1 Expression and Promotes Tumor Growth in Breast Cancer. Cancer research 75 31409638
2020 Regulation of Hsf1 and the Heat Shock Response. Advances in experimental medicine and biology 73 32297210
2017 Loss of AMPK activation promotes the invasion and metastasis of pancreatic cancer through an HSF1-dependent pathway. Molecular oncology 71 28783244
2017 SIRT1/HSF1/HSP pathway is essential for exenatide-alleviated, lipid-induced hepatic endoplasmic reticulum stress. Hepatology (Baltimore, Md.) 67 28439947
2016 Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic-Induced Apoptosis. Molecular cancer therapeutics 67 27777286
2006 HSF1 and constitutively active HSF1 improve vascular endothelial function (heat shock proteins improve vascular endothelial function). Atherosclerosis 65 16678833
2016 HSF1 stress response pathway regulates autophagy receptor SQSTM1/p62-associated proteostasis. Autophagy 62 27846364
2017 The HSF1-PARP13-PARP1 complex facilitates DNA repair and promotes mammary tumorigenesis. Nature communications 61 29158484
2014 Moderate alcohol induces stress proteins HSF1 and hsp70 and inhibits proinflammatory cytokines resulting in endotoxin tolerance. Journal of immunology (Baltimore, Md. : 1950) 61 25024384
2015 Multifaceted roles of HSF1 in cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 59 26108999
2018 Genetic and epigenetic determinants establish a continuum of Hsf1 occupancy and activity across the yeast genome. Molecular biology of the cell 57 30332327
2022 Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease. EMBO molecular medicine 56 35670111
2020 HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity. Cells 56 32331382
2012 Transcriptional regulation of small HSP-HSF1 and beyond. The international journal of biochemistry & cell biology 55 22750029
2019 Regulation of the Hsf1-dependent transcriptome via conserved bipartite contacts with Hsp70 promotes survival in yeast. The Journal of biological chemistry 54 31239354
2014 HSF1 protects neurons through a novel trimerization- and HSP-independent mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 54 24478344
2019 HMGB1 was negatively regulated by HSF1 and mediated the TLR4/MyD88/NF-κB signal pathway in asthma. Life sciences 53 31825792
2020 Emerging roles of HSF1 in cancer: Cellular and molecular episodes. Biochimica et biophysica acta. Reviews on cancer 52 32653364
2017 Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation. PLoS genetics 49 28678786
2022 Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer. Science advances 46 36170373
2019 Metabolic enzyme PDK3 forms a positive feedback loop with transcription factor HSF1 to drive chemoresistance. Theranostics 46 31244938
2018 HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target. Clinical cancer research : an official journal of the American Association for Cancer Research 44 29391353
2016 Doxorubicin attenuates CHIP-guarded HSF1 nuclear translocation and protein stability to trigger IGF-IIR-dependent cardiomyocyte death. Cell death & disease 44 27809308
2017 The transcriptional regulator of the chaperone response HSF1 controls hepatic bioenergetics and protein homeostasis. The Journal of cell biology 43 28183717
2018 Phenethyl Isothiocyanate, a Dual Activator of Transcription Factors NRF2 and HSF1. Molecular nutrition & food research 41 29710398
2014 Pleiotropic role of HSF1 in neoplastic transformation. Current cancer drug targets 40 24467529
1991 GST pi gene is frequently coamplified with INT2 and HSTF1 proto-oncogenes in human breast cancers. Oncogene 40 1826346
2020 The Maize Hairy Sheath Frayed1 (Hsf1) Mutation Alters Leaf Patterning through Increased Cytokinin Signaling. The Plant cell 38 32205456
2017 HSF1 upregulates ATG4B expression and enhances epirubicin-induced protective autophagy in hepatocellular carcinoma cells. Cancer letters 38 28889000
2019 Neuroprotective Effects of HSF1 in Retinal Ischemia-Reperfusion Injury. Investigative ophthalmology & visual science 37 30884523
2017 Cadmium-Mediated Activation of the HSP90/HSF1 Pathway Regulated by Reactive Persulfides/Polysulfides. Toxicological sciences : an official journal of the Society of Toxicology 37 28115653
2017 Combined inhibition of AKT and HSF1 suppresses breast cancer stem cells and tumor growth. Oncotarget 37 29088759
2022 HIF1, HSF1, and NRF2: Oxidant-Responsive Trio Raising Cellular Defenses and Engaging Immune System. Chemical research in toxicology 36 35948068
2021 Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML. Leukemia 36 34127794
2020 The Multifaceted Role of HSF1 in Tumorigenesis. Advances in experimental medicine and biology 36 32297212
2019 HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia. International journal of cancer 36 31044428
2017 Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice. Diabetes 36 28246289
2021 Multifaceted roles of HSF1 in cell death: A state-of-the-art review. Biochimica et biophysica acta. Reviews on cancer 33 34273469
2022 AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation. The FEBS journal 32 35080342
2017 Transcription factors NRF2 and HSF1 have opposing functions in autophagy. Scientific reports 31 28887499
2015 HSF1 transcriptional activity is modulated by IER5 and PP2A/B55. FEBS letters 31 25816751
2009 Protective role of HSF1 and HSP70 against gastrointestinal diseases. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 31 20021227
2014 PP2A-AMPKα-HSF1 axis regulates the metal-inducible expression of HSPs and ROS clearance. Cellular signalling 30 24412756
2022 HSF2 cooperates with HSF1 to drive a transcriptional program critical for the malignant state. Science advances 29 35294249
2021 Hsf1 activation by proteotoxic stress requires concurrent protein synthesis. Molecular biology of the cell 28 34191586
2011 Loss of HSF1 results in defective radiation-induced G(2) arrest and DNA repair. Radiation research 28 21557666
2021 HSF1 promotes endometriosis development and glycolysis by up-regulating PFKFB3 expression. Reproductive biology and endocrinology : RB&E 26 34107992
2020 HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection. Science advances 26 33177089
2020 The ABL2 kinase regulates an HSF1-dependent transcriptional program required for lung adenocarcinoma brain metastasis. Proceedings of the National Academy of Sciences of the United States of America 26 33318173
2019 Heat shock factor 1 (HSF1)-targeted anticancer therapeutics: overview of current preclinical progress. Expert opinion on therapeutic targets 26 30931649
2019 17β-Estradiol Activates HSF1 via MAPK Signaling in ERα-Positive Breast Cancer Cells. Cancers 25 31614463
2017 HSF1 acetylation decreases its transcriptional activity and enhances glucolipotoxicity-induced apoptosis in rat and human beta cells. Diabetologia 24 28547133
2012 Longevity pathways: HSF1 and FoxO pathways, a new therapeutic target to prevent age-related diseases. Current aging science 24 21834787
2023 The Emerging Role of Heat Shock Factor 1 (HSF1) and Heat Shock Proteins (HSPs) in Ferroptosis. Pathophysiology : the official journal of the International Society for Pathophysiology 23 36976734
2021 Insulin/IGF-1 signaling and heat stress differentially regulate HSF1 activities in germline development. Cell reports 23 34469721
2002 Redox signaling of cardiac HSF1 DNA binding. American journal of physiology. Cell physiology 23 12107049
2022 HSF1 phosphorylation establishes an active chromatin state via the TRRAP-TIP60 complex and promotes tumorigenesis. Nature communications 22 35906200
2021 Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity. Nature communications 22 34188043
2022 A novel HSF1 activator ameliorates non-alcoholic steatohepatitis by stimulating mitochondrial adaptive oxidation. British journal of pharmacology 21 34783017
2021 The EGFR-HSF1 axis accelerates the tumorigenesis of pancreatic cancer. Journal of experimental & clinical cancer research : CR 21 33422093
2019 HSF1 Regulates Mevalonate and Cholesterol Biosynthesis Pathways. Cancers 21 31540279
2018 Regulation of HSF1 protein stabilization: An updated review. European journal of pharmacology 21 29341886
2016 Upregulation of HSF1 in estrogen receptor positive breast cancer. Oncotarget 21 27713164
2013 HSF1-mediated regulation of tumor cell apoptosis: a novel target for cancer therapeutics. Future oncology (London, England) 21 24106905
2015 Hsf4 counteracts Hsf1 transcription activities and increases lens epithelial cell survival in vitro. Biochimica et biophysica acta 19 25601714
2008 HSP70 and constitutively active HSF1 mediate protection against CDCrel-1-mediated toxicity. Molecular therapy : the journal of the American Society of Gene Therapy 18 18398426
2023 HSF1, Aging, and Neurodegeneration. Advances in experimental medicine and biology 17 35995906
2022 Heat shock factor HSF1 regulates BDNF gene promoters upon acute stress in the hippocampus, together with pCREB. Journal of neurochemistry 16 36227087
2021 Inhibition of HSF1 and SAFB Granule Formation Enhances Apoptosis Induced by Heat Stress. International journal of molecular sciences 16 34067147
2019 Association of HSF1 Genetic Variation with Heat Tolerance in Chinese Cattle. Animals : an open access journal from MDPI 16 31775331
2023 HSF1 inhibits microglia activation to attenuate neuroinflammation via regulating miR-214-3p and NFATc2 in Parkinson's disease. Folia neuropathologica 15 37114961
2022 HSF1-Activated Non-Coding Stress Response: Satellite lncRNAs and Beyond, an Emerging Story with a Complex Scenario. Genes 15 35456403
2017 Overexpressed HSF1 cancer signature genes cluster in human chromosome 8q. Human genomics 15 29268782
2016 2'-Hydroxycinnamaldehyde induces apoptosis through HSF1-mediated BAG3 expression. International journal of oncology 15 27922674
2022 Anticancer Effects of Cinnamaldehyde Through Inhibition of ErbB2/HSF1/LDHA Pathway in 5637 Cell Line of Bladder Cancer. Anti-cancer agents in medicinal chemistry 14 34315398
2020 Reflections and Outlook on Targeting HSP90, HSP70 and HSF1 in Cancer: A Personal Perspective. Advances in experimental medicine and biology 14 32297218
2014 Identification of Hsf1 as a novel androgen receptor-regulated gene in mouse Sertoli cells. Molecular reproduction and development 14 24599545
2011 Expression of Hsf1, Hsf2, and Phlda1 in cells undergoing cryptorchid-induced apoptosis in rat testes. Molecular reproduction and development 14 21480429