Affinage

HSF2

Heat shock factor protein 2 · UniProt Q03933

Length
536 aa
Mass
60.3 kDa
Annotated
2026-06-10
55 papers in source corpus 33 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSF2 is a stress-responsive and developmentally regulated transcription factor that binds heat shock elements (HSEs) as trimers and stimulates transcription from heat shock promoters (PMID:1871106, PMID:7935474). It binds inverted nGAAn pentameric repeats with lower cooperativity than its paralog HSF1, a difference traced to HSF1-specific sequences in/around the DNA-binding domain (PMID:7935474), and crystal structures of the HSF2 DBD–DNA complex show a C-terminal helix that wraps the coiled-coil around DNA and exposes paralog-specific surfaces for differential modification and cofactor binding (PMID:26727490). A central feature of HSF2 biology is its physical and functional partnership with HSF1: the two interact through their coiled-coil domains (PMID:26727490), form heterotrimeric complexes that bind composite HSEs (e.g. the clusterin CLE) and co-occupy promoters (PMID:16336210, PMID:17213196), and share extensive chromatin occupancy to co-regulate Hsp and non-canonical target genes in stress and cancer (PMID:35294249). HSF2 acts in gene bookmarking, binding HSE-containing promoters (Hsp90, Hsp27, c-Fos, hsp70) during mitosis, and its level must decline in mitosis to permit HSF1/RNA Pol II access to condensed chromatin for stress-inducible transcription (PMID:17915561, PMID:25202032). HSF2 is a short-lived protein whose abundance and activity are set by proteostasis and post-translational modification: proteasome inhibition activates it (PMID:9710593), CBP/EP300-mediated acetylation stabilizes it while HDAC1-driven deacetylation promotes its poly-ubiquitination and degradation (PMID:36385105, PMID:40318841), and SUMOylation at K82 (controlled by MEL18 blockade of UBC9) modulates its target output (PMID:18211895, PMID:29180262, PMID:29270451). Developmentally, HSF2 is essential for spermatogenesis and brain development: knockout mice show meiotic and synaptonemal defects and brain abnormalities (PMID:12032072, PMID:12748967), it occupies and regulates Y-chromosome MSYq multicopy genes required for proper sperm chromatin (PMID:18682557), and a dominant-negative R502H mutation links HSF2 loss-of-function to idiopathic azoospermia (PMID:23064888). In cancer it functions as a stage-specific switch, with TGF-β-driven downregulation enabling EMT and invasion while sustained expression favors proliferation (PMID:40901953), and it maintains genome stability through an HSF2–HSP110 axis that supports RNA Pol II processivity and CTD serine-7 phosphorylation, with HSF2 loss accelerating irradiation-induced lymphoma (PMID:41995727).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1991 High

    Establishing that a distinct human gene encodes an HSE-binding transcriptional activator defined HSF2 as a heat-shock transcription factor separate from HSF1.

    Evidence cDNA cloning with in vitro DNA-binding and reporter assays

    PMID:1871106

    Open questions at the time
    • Did not establish physiological conditions of activation
    • No distinction of HSF2-specific versus HSF1-shared targets
  2. 1994 High

    Defining HSF2 trimerization and its lower DNA-binding cooperativity relative to HSF1 explained how the two paralogs differ biochemically despite recognizing the same HSE.

    Evidence SELEX, HSE mutagenesis, and chimeric HSF1/HSF2 gel-shift analysis; trimer detection and genomic footprinting in EC cells

    PMID:7935474 PMID:8035809

    Open questions at the time
    • Trimerization and nuclear localization insufficient for in vivo binding in unstressed cells — the gating signal was unidentified
    • Did not define endogenous activating stimulus
  3. 1998 High

    Identifying proteasome dysfunction as an HSF2 activating signal showed that HSF2 activity is gated by protein stability rather than only by trimerization.

    Evidence Proteasome inhibitors and ts85 (E1 mutant) cells with DNA-binding and immunoblot readouts

    PMID:9710593

    Open questions at the time
    • Ubiquitin ligase and degron not defined
    • Link between stabilization and target gene choice unclear
  4. 2000 Medium

    Mapping HSF2 binding to the PR65/A scaffold of PP2A, competing with the catalytic subunit, suggested HSF2 could influence phosphatase assembly.

    Evidence Co-IP and pulldown with PR65 point mutants (K416)

    PMID:10872807

    Open questions at the time
    • Functional consequence for PP2A activity or HSF2 signaling not established
    • Single lab, no in vivo validation
  5. 2003 High

    Knockout mice assigned HSF2 essential developmental roles, showing it is required for brain development and meiotic progression in gametogenesis.

    Evidence Targeted gene disruption with histology and immunohistochemistry (replicated by a second group)

    PMID:12032072 PMID:12748967

    Open questions at the time
    • Direct transcriptional targets driving the phenotypes not defined in this study
    • Mechanism of synaptonemal complex defect unresolved
  6. 2003 Medium

    Demonstrating HSF2–HSF1 interaction and shared localization to nuclear stress granules established physical cross-talk between the paralogs during stress.

    Evidence Co-IP, immunofluorescence, deletion mutants, live-cell imaging

    PMID:12865437

    Open questions at the time
    • Functional output of stress-granule localization not defined
    • Stoichiometry of the HSF1-HSF2 complex unknown at this stage
  7. 2004 High

    Double-knockout epistasis showed HSF1 and HSF2 act additively/synergistically in spermatogenesis, demonstrating overlapping transcriptional programs in germ cells.

    Evidence hsf1/hsf2 double-KO mouse genetics, histology, RT-PCR

    PMID:14994269

    Open questions at the time
    • Did not resolve which targets are co-regulated versus paralog-specific
    • Molecular basis of pachytene arrest unclear
  8. 2006 High

    Showing HSF1-HSF2 heterocomplexes bind the clusterin CLE provided direct evidence for heterotrimeric co-occupancy activating a non-Hsp target.

    Evidence Gel shift/supershift, ChIP, co-IP, gel filtration, promoter mutation

    PMID:16336210

    Open questions at the time
    • Heterotrimer subunit ratio inferred from apparent mass, not directly counted
    • Generality across promoters not tested
  9. 2007 High

    Establishing reciprocal dependency — HSF1 required for maximal HSF2 promoter occupancy — refined how the paralogs jointly control Hsp70 induction.

    Evidence ChIP, RT-PCR, HSF2 knockdown/overexpression

    PMID:17213196

    Open questions at the time
    • Whether HSF2 acts as activator or modulator context-dependent
    • No structural basis at this stage
  10. 2007 Medium

    Demonstrating constitutive mitotic HSF2 occupancy of Hsp90, Hsp27 and c-Fos promoters defined HSF2 as a gene-bookmarking factor required for their expression.

    Evidence ChIP plus RNAi with protein-level readout

    PMID:17915561

    Open questions at the time
    • Mechanism allowing binding to condensed chromatin not defined
    • Single lab
  11. 2008 Medium

    Identifying MEL-18/UBC9 control of HSF2 SUMOylation and PRC1 interaction during mitosis linked HSF2 modification state to cell-cycle phase and cytokinesis.

    Evidence Co-IP, RNAi, overexpression, sumoylation assays, ChIP, co-localization

    PMID:18211895 PMID:18570919

    Open questions at the time
    • Functional impact of mitotic SUMOylation on transcription not fully resolved
    • PRC1-HSF2 link to cytokinesis defect correlative
  12. 2008 High

    ChIP-chip in testis assigned HSF2 direct regulation of Y-chromosome MSYq multicopy genes required for correct sperm chromatin packaging.

    Evidence ChIP-chip, Hsf2 KO mouse, RT-PCR, immunofluorescence, TUNEL; staged ChIP of bookmarking in spermatozoa

    PMID:18434628 PMID:18682557

    Open questions at the time
    • Downstream chromatin protein regulation mechanism partial
    • Contribution to post-fertilization genome activation inferred
  13. 2011 Medium

    Showing HSF2 and HSF4 competitively co-repress HIF-1α extended HSF2's repertoire to transcriptional repression with another paralog partner.

    Evidence EST screen, ChIP, reporter assay, siRNA, overexpression

    PMID:21258402

    Open questions at the time
    • Physiological context of HSF2-HSF4 balance untested in vivo
    • Single lab
  14. 2012 Medium

    A dominant-negative R502H mutation abolishing HSF2 transcriptional function linked HSF2 loss-of-function to idiopathic azoospermia in humans.

    Evidence Patient cohort sequencing and functional transcriptional assay of mutant

    PMID:23064888

    Open questions at the time
    • Causality in patients correlative beyond functional assay
    • Penetrance and modifier effects unknown
  15. 2014 High

    Demonstrating that mitotic decline of HSF2 is required to permit HSF1/Pol II chromatin access reframed HSF2 as a restrictor of stress-inducible transcription during mitosis.

    Evidence HSF2 KO/knockdown cells, immunofluorescence, ChIP, flow cytometry, RT-PCR

    PMID:25202032

    Open questions at the time
    • Mechanism timing HSF2 decline not fully defined
    • Relationship to bookmarking role nuanced
  16. 2015 Medium

    Identifying an HSE in the HSF2 promoter that mediates negative autoregulation showed HSF2 tunes its own abundance.

    Evidence Luciferase reporter, ChIP, RT-PCR after HSF2 transfection

    PMID:26260034

    Open questions at the time
    • Physiological conditions where autoregulation dominates unclear
    • Single lab
  17. 2016 High

    Crystal structures of the HSF2 DBD–DNA complex revealed how a C-terminal helix directs coiled-coil wrapping and exposes paralog-specific surfaces, and confirmed direct HSF1-HSF2 coiled-coil interaction.

    Evidence X-ray crystallography and Co-IP of coiled-coil interaction

    PMID:26727490

    Open questions at the time
    • Full-length heterotrimer structure not solved
    • Direct mapping of exposed surfaces to specific modifications not shown
  18. 2017 Medium

    Linking ROS/ERK1/2-driven HSF2 nuclear translocation and deSUMOylation to AT1R/IGF-IIR induction, and miR-18/p53 control of HSF2 levels, placed HSF2 in cardiac stress and hypertrophy signaling.

    Evidence Immunofluorescence, DNA-binding, siRNA/overexpression, SUMOylation site mutagenesis (K82), and in vivo cardiac models

    PMID:28295305 PMID:28796250 PMID:29180262 PMID:29270451

    Open questions at the time
    • Direct versus indirect transcriptional contributions partly inferred
    • Single-lab cardiac models
  19. 2019 Medium

    Showing HSF2-EHMT2 silencing of FBP1 to drive aerobic glycolysis implicated HSF2 in metabolic reprogramming supporting HCC proliferation.

    Evidence Co-IP, siRNA, ChIP, proliferation and glycolysis assays

    PMID:31497345

    Open questions at the time
    • Direct HSF2 binding to FBP1 locus versus EHMT2 recruitment not fully separated
    • Single lab
  20. 2020 Medium

    Identifying HSF1-driven de novo HSF2 transcription during proteasome inhibition explained how HSF2 is induced and contributes to cancer cell migration under proteotoxic stress.

    Evidence ChIP, EMSA, reporter assay, RT-PCR, immunofluorescence, migration assay

    PMID:32607595

    Open questions at the time
    • Migration mechanism downstream of HSF2 not detailed
    • Single lab
  21. 2021 Medium

    Demonstrating HSF2 binds ATP-bound HSP90 like HSF1 placed HSF2 within chaperone-mediated regulation of the heat shock response.

    Evidence Co-IP with HSP90 mutants in HSF1/HSF2 KO cells

    PMID:34331200

    Open questions at the time
    • Functional consequence of HSP90-HSF2 binding for HSF2 activity unclear
    • Stress response shown HSF1-dependent, HSF2 role secondary
  22. 2022 High

    Acetylation/deacetylation control and shared genome-wide co-occupancy with HSF1 established a stability-and-chromatin axis for HSF2 in neurodevelopment and cancer.

    Evidence Co-IP and acetylation assays with patient-derived organoids (CBP/EP300); ChIP-seq, Co-IP and xenografts (HSF1-HSF2 co-regulation)

    PMID:35294249 PMID:36385105

    Open questions at the time
    • Distinguishing HSF2-unique from HSF1-driven occupancy incomplete
    • CBP/EP300-HSF2-N-cadherin cascade mechanism partial
  23. 2025 High

    HDAC1-driven destabilization and TGF-β-mediated downregulation defined HSF2 as a tightly degradation-controlled, stage-specific switch between proliferation and invasion.

    Evidence Unbiased Co-IP screen, catalytic mutant and ubiquitination assays, tissue IHC (HDAC1); cell and zebrafish xenograft models with ectopic expression (TGF-β/EMT)

    PMID:40318841 PMID:40901953

    Open questions at the time
    • E3 ligase mediating HDAC1-coupled ubiquitination not identified
    • TGF-β regulation of HSF2 transcription versus stability not fully separated
  24. 2026 High

    Defining an HSF2-HSP110 axis supporting RNA Pol II processivity and CTD Ser7 phosphorylation established HSF2 as a guardian of genome stability whose loss promotes tumorigenesis.

    Evidence HSF2/HSP110 KO cells, irradiation assays, Pol II ChIP, CTD phosphorylation Westerns, splicing analysis, in vivo lymphoma model

    PMID:41995727

    Open questions at the time
    • Direct molecular step from HSF2 to CTD Ser7 kinase activity not defined
    • Whether transcription-factor versus chaperone-cofactor role dominates unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HSF2's paralog-specific transcriptional outputs, modification states, and partner choices are coordinated to switch between Hsp regulation, developmental programs, metabolic reprogramming and genome maintenance remains unresolved.
  • No unified model linking HSF2 PTM state to target gene selection
  • The E3 ligase(s) and full degron controlling HSF2 turnover are unidentified
  • Direct versus chaperone-cofactor contributions to Pol II regulation not separated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 5 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
CREBBPEP300HDAC1HSF1HSF4HSP110HSP90UBC9
Complex memberships
HSF1-HSF2 heterotrimer

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 HSF2 encodes a protein that binds heat shock elements (HSEs) with specificity identical to HeLa HSF and stimulates transcription from a heat shock promoter, establishing it as a distinct human heat shock transcription factor paralog separate from HSF1. cDNA cloning, in vitro DNA-binding assay, transcriptional reporter assay, antibody cross-reactivity Proceedings of the National Academy of Sciences of the United States of America High 1871106
1994 HSF2 forms trimers and binds HSEs composed of alternating inverted pentameric nGAAn repeats, but exhibits less cooperative DNA binding than HSF1; sequences within or adjacent to the HSF1 DNA-binding domain (not shared by HSF2) confer the higher cooperativity to HSF1, as demonstrated by chimeric HSF1/HSF2 proteins. In vitro DNA-binding selection (SELEX), mutagenesis of HSEs, chimeric protein analysis, gel-shift assays Molecular and cellular biology High 7935474
1994 HSF2 is present as a trimer in mouse embryonal carcinoma (EC) cells and exhibits constitutive HSE-binding activity, but trimerization and nuclear localization of HSF2 are not sufficient for in vivo binding to the hsp70 HSE in unstressed EC cells, and HSF2 does not stimulate hsp70 or hsp86 transcription under these conditions. Gel-shift assay, transcription run-on assay, genomic footprinting, immunoblotting Molecular and cellular biology High 8035809
1998 HSF2 activation is triggered by inhibition of the ubiquitin-proteasome pathway; HSF2 is a labile protein whose activation requires both continued protein synthesis and reduced proteasomal degradation, establishing proteasome dysfunction as a stress signal for HSF2. Proteasome inhibitor treatment (hemin, MG132, lactacystin), ts85 cell line (E1 ubiquitin-activating enzyme mutant), DNA-binding assays, immunoblotting Molecular and cellular biology High 9710593
2000 HSF2 physically interacts with the PR65/A scaffolding subunit of PP2A and competes with the PP2A catalytic subunit for binding; this competition maps to lysine 416 within the intra-repeat loop of HEAT repeat 11 of PR65, shared by both HSF2 and the catalytic subunit binding interface. Co-immunoprecipitation, pulldown with point mutants of PR65 Biochemical and biophysical research communications Medium 10872807
2003 HSF2-null mice exhibit brain abnormalities (enlarged lateral and third ventricles, reduced hippocampus and striatum), meiotic defects in spermatogenesis (apoptosis of spermatocytes, synaptonemal complex structural defects), and female subfertility, demonstrating essential roles in brain development and gametogenesis. Targeted gene disruption (knockout mouse), histology, immunohistochemistry The EMBO journal High 12032072 12748967
2003 HSF2 physically interacts with HSF1 and localizes to nuclear stress granules upon heat shock; deletion mutant analysis shows HSF2 influences HSF1 localization to stress granules; stress granule dynamics coincide with nucleolar Hsp70 accumulation. Co-immunoprecipitation, immunofluorescence, deletion mutant analysis, live-cell imaging Journal of cell science Medium 12865437
2004 Genetic disruption of both hsf1 and hsf2 causes male sterility with more severe spermatogenesis defects than either single knockout alone, including failure of germ cells to progress past pachytene and loss of transcription of spermatogenesis-specific genes, demonstrating additive/synergistic transcriptional roles in spermatogenesis. Double-knockout mouse genetics, histology, RT-PCR Genesis High 14994269
2006 Upon proteasome inhibition, HSF1 and HSF2 form heterocomplexes that bind to the clusterin heat shock element (CLE) and activate clusterin transcription; gel-filtration indicates these heterocomplexes have the same apparent mass as HSF1 homotrimers, suggesting HSF1-HSF2 heterotrimer formation. Gel mobility-shift assay, supershift assay, chromatin immunoprecipitation (ChIP), co-immunoprecipitation, gel-filtration analysis, promoter deletion/mutation studies The Biochemical journal High 16336210
2007 HSF2 participates in heat-shock-inducible hsp70 promoter occupancy and modulates HSF1-mediated Hsp gene expression; intact HSF1 is required for maximal HSF2 promoter occupancy, indicating HSF1 influences HSF2 DNA-binding activity at the hsp70 promoter. Chromatin immunoprecipitation (ChIP), real-time RT-PCR, HSF2 knockdown/overexpression The Journal of biological chemistry High 17213196
2007 HSF2 binds constitutively to HSE elements in the Hsp90, Hsp27, and c-Fos promoters during mitosis (gene bookmarking); RNAi-mediated reduction of HSF2 leads to decreased protein levels of Hsp90, Hsp27, and c-Fos, establishing HSF2 as required for their expression. Chromatin immunoprecipitation, RNA interference (RNAi), immunoblotting Cell stress & chaperones Medium 17915561
2008 HSF2 interacts with the polycomb protein MEL-18 and the SUMO E2 enzyme UBC9; MEL-18 binding to HSF2 inhibits HSF2 sumoylation by blocking UBC9 activity; this interaction decreases during mitosis, explaining the observed increase in HSF2 sumoylation during mitosis. Co-immunoprecipitation, RNA interference, overexpression, sumoylation assay The Journal of biological chemistry Medium 18211895
2008 HSF2 occupies Y chromosome MSYq gene promoters in mouse testis in vivo; HSF2 disruption causes reduced expression of MSYq-resident multicopy genes, sperm head abnormalities, altered chromatin packing proteins, and increased sperm DNA fragmentation, defining HSF2 as a regulator of Y-chromosome gene transcription required for correct chromatin organization in sperm. ChIP-chip (promoter microarray), Hsf2 knockout mouse, RT-PCR, immunofluorescence, TUNEL assay Proceedings of the National Academy of Sciences of the United States of America High 18682557
2008 HSF1 and HSF2 are both bound to the Hspa1b (hsp70.1) promoter in epididymal spermatozoa (gene bookmarking), with HSF2 binding increasing from early to late spermatids, suggesting a mechanism for rapid transcription-competence during zygotic genome activation after fertilization. Chromatin immunoprecipitation (ChIP), Western blot, immunofluorescence Biology of reproduction Medium 18434628
2008 HSF2 directly interacts with PRC1 (Protein Regulating Cytokinesis 1) specifically during mitosis; PRC1 co-localizes with HSF2 during mitosis and is associated with the hsp70i promoter during this phase, suggesting HSF2-PRC1 interaction provides a mechanistic basis for the cytokinesis defects observed in HSF2-null cells. Co-immunoprecipitation, co-localization by immunofluorescence, chromatin immunoprecipitation Experimental cell research Medium 18570919
2011 HSF2 and HSF4 both bind to discontinuous HSE sequences in the HIF-1α promoter and cooperate to maintain HIF-1α transcription in a repressed state; downregulation of either HSF activates HIF-1α transcription, and overexpression of either displaces the other from the promoter, showing a competitive balance is required. Genome-wide EST screen, ChIP, promoter reporter assay, siRNA knockdown, overexpression Oncogene Medium 21258402
2012 A heterozygous missense mutation R502H in human HSF2 causes complete loss of HSF2 transcriptional function and suppresses wild-type HSF2 function through a dominant-negative mechanism, establishing a link between HSF2 loss-of-function and idiopathic azoospermia. Sequencing of patient cohort, functional transcriptional assay of mutant vs. wild-type HSF2 Human genetics Medium 23064888
2014 HSF2 expression declines during mitosis, and this decline allows HSF1 and RNA polymerase II to access condensed chromatin for stress-inducible Hsp expression; HSF2-deficient cells show reduced mitotic errors and improved survival upon acute stress, demonstrating that HSF2 normally restricts stress-inducible transcription during mitosis. HSF2 knockout/knockdown cells, immunofluorescence, ChIP, flow cytometry (mitotic errors, apoptosis), RT-PCR The Journal of cell biology High 25202032
2015 HSF2 negatively autoregulates its own transcription by binding to an HSE in its own promoter (~1.5 kb downstream of TSS), forming a negative autoregulatory loop. Luciferase reporter assay, ChIP, RT-PCR after HSF2 transfection International journal of molecular medicine Medium 26260034
2016 Crystal structures of the human HSF2 DNA-binding domain (DBD) bound to DNA reveal a C-terminal helix that directs wrapping of the coiled-coil domain around DNA, exposing paralog-specific DBD surface sequences for differential post-translational modifications and cofactor interactions; a direct interaction between HSF1 and HSF2 through their coiled-coil domains was also demonstrated. X-ray crystallography, co-immunoprecipitation of HSF1-HSF2 coiled-coil interaction Nature structural & molecular biology High 26727490
2017 DOX-induced mitochondrial ROS activate ERK1/2, which promotes HSF2 nuclear translocation and deSUMOylation, leading to HSF2 binding to the AT1R promoter and upregulating AT1R expression, contributing to cardiomyocyte apoptosis and cardiotoxicity. Immunofluorescence (nuclear translocation), DNA-binding assay, siRNA knockdown, overexpression, in vitro and in vivo cardiomyocyte models Journal of cellular physiology Medium 28295305
2017 MEL18 inhibits SUMO-1-mediated SUMOylation of HSF2 (specifically at lysine 82) by interacting with UBC9 and blocking its activity; loss of HSF2 SUMOylation activates IGF-IIR transcription and induces cardiac hypertrophy; angiotensin II receptor blockade restores HSF2 SUMOylation. Co-immunoprecipitation, SUMOylation assay, site-directed mutagenesis (K82), Western blot, in vivo spontaneously hypertensive rat model International journal of cardiology Medium 29180262 29270451
2017 p53 activation by angiotensin II represses miR-18, which de-represses HSF2 expression; elevated HSF2 then activates IGF-IIR transcription, inducing cardiomyocyte hypertrophy; cardiac-specific miR-18 overexpression protects against hypertension-induced heart failure. miRNA target site validation (3'-UTR luciferase), adenovirus-AAV gene transfer, in vitro NRVM model, in vivo transgenic overexpression Cell death & disease Medium 28796250
2019 HSF2 interacts with EHMT2 (G9a histone methyltransferase) to epigenetically silence FBP1 via histone methylation, thereby promoting aerobic glycolysis (Warburg effect) and HCC cell proliferation. Co-immunoprecipitation, siRNA knockdown, ChIP, proliferation and glycolysis assays American journal of cancer research Medium 31497345
2020 HSF1 directly binds an HSE located 1,397 bp upstream of the HSF2 transcription start site in the HSF2 promoter and drives de novo HSF2 mRNA transcription during proteasome inhibition (bortezomib treatment); bortezomib-induced HSF2 localizes in the nucleus, interacts with HSF1, and participates in cancer cell migration. Chromatin immunoprecipitation, EMSA, promoter-reporter assay, RT-PCR, immunofluorescence, migration assay Cellular and molecular life sciences Medium 32607595
2021 Endogenous HSF2 co-precipitates with ATP-bound (closed-form) HSP90, mirroring HSF1's known interaction with HSP90; treatment with gambogic acid or gambogenic acid disrupts both HSP90-HSF1 and HSP90-HSF2 interactions and induces a thiol-dependent heat shock response that is HSF1-dependent. Co-immunoprecipitation with HSP90 mutants, HSF1/HSF2 knockout cells, immunoblotting Cell stress & chaperones Medium 34331200
2022 CBP/EP300 acetyltransferases directly interact with HSF2 and acetylate it, leading to HSF2 protein stabilization; loss of CBP/EP300 function (as in Rubinstein-Taybi syndrome) reduces HSF2 levels and disrupts a CBP/EP300-HSF2-N-cadherin cascade required for neuroepithelial integrity in cerebral organoids. Co-immunoprecipitation, acetylation assay, patient-derived iPSC organoids, 2D/3D cellular models, Western blot Nature communications High 36385105
2022 HSF2 physically and functionally interacts with HSF1 across diverse cancer types; HSF1 and HSF2 share notably similar chromatin occupancy and co-regulate a common set of target genes (including HSPs and non-canonical cancer-supporting genes); loss of HSF2 impairs response to nutrient stress and reduces tumor progression in xenografts. Co-immunoprecipitation, ChIP-seq, xenograft tumor models, CRISPR/siRNA loss-of-function Science advances High 35294249
2025 HDAC1 interacts with HSF2 and destabilizes the HSF2 protein through its catalytic deacetylase activity, driving HSF2 poly-ubiquitination and proteasomal degradation under both normal and stress conditions; HDAC1 and HSF2 co-localize in developing mouse cortex and human cerebral organoids. Unbiased co-immunoprecipitation screen, catalytic mutant analysis, ubiquitination assay, proteasome inhibitor rescue, immunohistochemistry in mouse cortex and human organoids Cell stress & chaperones High 40318841
2025 TGF-β signaling downregulates HSF2 expression to enable acquisition of an invasive phenotype in breast cancer; ectopic HSF2 expression inhibits TGF-β-mediated EMT gene expression and invasive properties; temporal HSF2 downregulation is required for EMT activation, while sustained HSF2 promotes proliferation over invasion. Cell-based models, in vivo zebrafish xenografts, ectopic expression, human patient tissue analysis (IHC), RT-PCR Science advances Medium 40901953
2026 HSF2 forms a genotoxic stress-responsive axis with its client chaperone HSP110; HSF2 loss increases DNA damage and IR sensitivity by impairing RNA Pol II processivity and CTD phosphorylation at serine 7, leading to transcriptional dysregulation, replication conflicts, altered pre-mRNA splicing, and reduced DNA repair gene expression; in vivo, HSF2 loss accelerates IR-induced T cell lymphoma. HSF2/HSP110 knockout cells, irradiation assays, RNA Pol II ChIP, CTD phosphorylation assays (Western blot), pre-mRNA splicing analysis, in vivo mouse lymphoma model The Journal of cell biology High 41995727

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 Isolation of a cDNA for HSF2: evidence for two heat shock factor genes in humans. Proceedings of the National Academy of Sciences of the United States of America 290 1871106
2007 Heat shock factor 2 (HSF2) contributes to inducible expression of hsp genes through interplay with HSF1. The Journal of biological chemistry 175 17213196
1998 Heat shock response and protein degradation: regulation of HSF2 by the ubiquitin-proteasome pathway. Molecular and cellular biology 174 9710593
2002 Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice. The EMBO journal 148 12032072
2003 Targeted disruption of the heat shock transcription factor (hsf)-2 gene results in increased embryonic lethality, neuronal defects, and reduced spermatogenesis. Genesis (New York, N.Y. : 2000) 120 12748967
1994 Selection of new HSF1 and HSF2 DNA-binding sites reveals difference in trimer cooperativity. Molecular and cellular biology 120 7935474
2006 Up-regulation of the clusterin gene after proteotoxic stress: implication of HSF1-HSF2 heterocomplexes. The Biochemical journal 104 16336210
2004 Essential requirement for both hsf1 and hsf2 transcriptional activity in spermatogenesis and male fertility. Genesis (New York, N.Y. : 2000) 95 14994269
2003 Formation of nuclear stress granules involves HSF2 and coincides with the nucleolar localization of Hsp70. Journal of cell science 92 12865437
2016 Structures of HSF2 reveal mechanisms for differential regulation of human heat-shock factors. Nature structural & molecular biology 70 26727490
1994 Characterization of constitutive HSF2 DNA-binding activity in mouse embryonal carcinoma cells. Molecular and cellular biology 67 8035809
2008 Promoter ChIP-chip analysis in mouse testis reveals Y chromosome occupancy by HSF2. Proceedings of the National Academy of Sciences of the United States of America 62 18682557
2007 HSF2 binds to the Hsp90, Hsp27, and c-Fos promoters constitutively and modulates their expression. Cell stress & chaperones 51 17915561
2012 A dominant-negative mutation of HSF2 associated with idiopathic azoospermia. Human genetics 50 23064888
2017 Mitochondrial ROS-induced ERK1/2 activation and HSF2-mediated AT1 R upregulation are required for doxorubicin-induced cardiotoxicity. Journal of cellular physiology 46 28295305
2011 Regulation of transcription of hypoxia-inducible factor-1α (HIF-1α) by heat shock factors HSF2 and HSF4. Oncogene 45 21258402
2014 Expression of HSF2 decreases in mitosis to enable stress-inducible transcription and cell survival. The Journal of cell biology 37 25202032
2017 p53-mediated miR-18 repression activates HSF2 for IGF-IIR-dependent myocyte hypertrophy in hypertension-induced heart failure. Cell death & disease 36 28796250
1999 Cellular localization of the heat shock transcription factors HSF1 and HSF2 in the rat brain during postnatal development and following hyperthermia. Brain research 36 10064819
2022 HSF2 cooperates with HSF1 to drive a transcriptional program critical for the malignant state. Science advances 31 35294249
2019 HSF2 regulates aerobic glycolysis by suppression of FBP1 in hepatocellular carcinoma. American journal of cancer research 26 31497345
2017 miR-202 Promotes Cell Apoptosis in Esophageal Squamous Cell Carcinoma by Targeting HSF2. Oncology research 24 28277193
2017 Inhibition of HSF2 SUMOylation via MEL18 upregulates IGF-IIR and leads to hypertension-induced cardiac hypertrophy. International journal of cardiology 24 29180262
1999 Transcriptional activation of mouse cytosolic chaperonin CCT subunit genes by heat shock factors HSF1 and HSF2. FEBS letters 24 10561509
2020 The proteostasis guardian HSF1 directs the transcription of its paralog and interactor HSF2 during proteasome dysfunction. Cellular and molecular life sciences : CMLS 22 32607595
2008 MEL-18 interacts with HSF2 and the SUMO E2 UBC9 to inhibit HSF2 sumoylation. The Journal of biological chemistry 20 18211895
2010 Analysis of the Wnt/B-catenin/TCF4 pathway using SAGE, genome-wide microarray and promoter analysis: Identification of BRI3 and HSF2 as novel targets. Cellular signalling 19 20538055
2022 CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder. Nature communications 17 36385105
2021 Gambogic acid and gambogenic acid induce a thiol-dependent heat shock response and disrupt the interaction between HSP90 and HSF1 or HSF2. Cell stress & chaperones 17 34331200
2008 Interaction of HSF1 and HSF2 with the Hspa1b promoter in mouse epididymal spermatozoa. Biology of reproduction 17 18434628
2022 HSF2BP protects against acute liver injury by regulating HSF2/HSP70/MAPK signaling in mice. Cell death & disease 15 36167792
2008 Neurospora crassa heat shock factor 1 Is an essential gene; a second heat shock factor-like gene, hsf2, is required for asexual spore formation. Eukaryotic cell 15 18586951
2011 Expression of Hsf1, Hsf2, and Phlda1 in cells undergoing cryptorchid-induced apoptosis in rat testes. Molecular reproduction and development 14 21480429
2019 Basal and dynamics mRNA expression of muscular HSP108, HSP90, HSF-1 and HSF-2 in thermally manipulated broilers during embryogenesis. BMC veterinary research 13 30849975
2000 Molecular basis of competition between HSF2 and catalytic subunit for binding to the PR65/A subunit of PP2A. Biochemical and biophysical research communications 13 10872807
2021 Aqueous extract of Solanum nigrum attenuates Angiotensin-II induced cardiac hypertrophy and improves cardiac function by repressing protein kinase C-ζ to restore HSF2 deSUMOlyation and Mel-18-IGF-IIR signaling suppression. Journal of ethnopharmacology 12 34634367
2006 Cloning of zebrafish (Danio rerio) heat shock factor 2 (HSF2) and similar patterns of HSF2 and HSF1 mRNA expression in brain tissues. Biochimie 12 16938384
2024 Comprehensive analysis of human tissues reveals unique expression and localization patterns of HSF1 and HSF2. Cell stress & chaperones 11 38458311
2012 Heat shock factor 4a (HSF4a) represses HSF2 expression and HSF2-mediated transcriptional activity. Journal of cellular physiology 10 21792930
2003 Cloning and characterization of the rat Hsf2 promoter: a critical role of proximal E-box element and USF protein in Hsf2 regulation in different compartments of the brain. Biochimica et biophysica acta 10 12527426
1999 Genomic structure and chromosomal localization of the mouse Hsf2 gene and promoter sequences. Gene 10 10333528
2008 PRC1 associates with the hsp70i promoter and interacts with HSF2 during mitosis. Experimental cell research 9 18570919
2020 DUOX2 participates in skin aging induced by UVB in HSF2 cells by activating NF-κB signaling. Experimental and therapeutic medicine 7 33456524
2017 Data supporting the angiotensin II activates MEL18 to deSUMOylate HSF2 for hypertension-related heart failure. Data in brief 7 29270451
2025 HSF2 drives breast cancer progression by acting as a stage-specific switch between proliferation and invasion. Science advances 5 40901953
2022 Heat shock transcription factor HSF2 modulates the autophagy response through the BTG2-SOD2 axis. Biochemical and biophysical research communications 5 35182974
2024 The Expression and Epigenetic Characteristics of the HSF2 Gene in Cattle-Yak and the Correlation with Its Male Sterility. Animals : an open access journal from MDPI 4 38791628
2023 Overexpression of HSF2 binding protein suppresses endoplasmic reticulum stress via regulating subcellular localization of CDC73 in hepatocytes. Cell & bioscience 4 36964632
2024 Hsf1 and Hsf2 in normal, healthy human tissues: Immunohistochemistry provokes new questions. Cell stress & chaperones 3 38641046
2023 Genome-wide association study reveals HSF2, GJA1 and TRIM36 as susceptibility genes for preeclampsia: a community-based population study in Tianjin, China. Hypertension in pregnancy 3 37735976
2015 HSF2 autoregulates its own transcription. International journal of molecular medicine 3 26260034
2025 HDAC1 is involved in the destabilization of the HSF2 protein under nonstress and stress conditions. Cell stress & chaperones 2 40318841
2021 Male infertility is not liked with HSF1, HSF2 and UBE2I gene polymorphisms among Indian subjects. Bioinformation 1 35540693
2026 Retraction: miR-202 Promotes Cell Apoptosis in Esophageal Squamous Cell Carcinoma by Targeting HSF2. Oncology research 0 41613802
2026 HSF2-HSP110 axis supports genome stability via RNA polymerase II transcription and DNA repair. The Journal of cell biology 0 41995727

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