Affinage

USF2

Upstream stimulatory factor 2 · UniProt Q15853

Length
346 aa
Mass
37.0 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USF2 is a basic-helix-loop-helix leucine-zipper transcription factor that binds E-box (CANNTG) and CLEAR motifs in target promoters to either activate or repress transcription in a context- and partner-dependent manner (PMID:12857727, PMID:15242350, PMID:39333072). Its activity is governed by two transactivation domains (the USF-specific region/USR and an exon 5-encoded region) and two nuclear localization signals residing in the basic region and the USR (PMID:8657110), and nuclear translocation is inducibly triggered in mast cells by IL-3 or IgE-antigen activation signals to support cell survival (PMID:9743349). Transcriptional output is set by recruited cofactors and binding partners: USF2 engages the coactivator p300 to drive activation (PMID:10434034), partners with HDAC1 at CLEAR motifs to repress lysosomal/autophagy genes and lower H3K27 acetylation under nutrient-rich conditions, then is overridden under starvation when GSK3β phosphorylates Ser155 to reduce DNA binding and de-repress these genes in competition with TFEB (PMID:39333072), and physically associates with HIF2α to confer HIF2-specific (versus HIF1) target-gene activation and Pol II recruitment under hypoxia (PMID:23991099). USF2 is itself stabilized by CDK5 phosphorylation at Ser155/Ser222 (PMID:31013770) and is negatively regulated by HINT1 binding (PMID:19089909) and modulated by a LysRS/Ap4A axis (PMID:16199869). Functionally, USF2 behaves as a tumor suppressor: it restrains c-Myc-dependent and prostate carcinogenesis, with USF2-null mice developing prostate hyperplasia (PMID:15541720, PMID:16186802), and it represses oncogenic targets such as TXNRD1 in hepatocellular carcinoma (PMID:36319631). It directly governs an extensive target repertoire including IGF2R, HO-1, Smurf1/2, THBS1, S100A8, TREM1, and HOXB4, linking it to autophagy/lysosomal homeostasis, TGF-β signaling, inflammation, and hematopoietic self-renewal (PMID:12857727, PMID:15242350, PMID:30244169, PMID:34756923, PMID:33389821, PMID:35100093, PMID:11085749). USF2 also acts as an upstream regulator of proinflammatory cytokine production in pathogenic Th17 cells (PMID:33203678).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1996 High

    Establishing the domain architecture answered how USF2 partitions its activation and nuclear-targeting functions, defining the USR and exon 5 region as transactivation domains and identifying two distinct NLSs.

    Evidence Immunofluorescence and GAL4/USF2 fusion reporter assays with deletion mutants in transfected cells

    PMID:8657110

    Open questions at the time
    • Did not address endogenous target genes
    • Context-restricted USR activation mechanism not fully resolved
  2. 1997 Medium

    Early studies tested whether USF2 mediates glucose-responsive metabolic gene transcription and whether it heterodimerizes beyond its own family, implicating it in L-PK activation and in inhibiting c-Maf DNA binding.

    Evidence Antibody microinjection with L4-box mutant reporters in living beta-cells; yeast two-hybrid and gel-shift with c-Maf

    PMID:9070273 PMID:9252379

    Open questions at the time
    • L-PK role later contradicted in INS-1 cells
    • c-Maf interaction shown only in vitro/yeast
  3. 1998 Medium

    Linking nuclear translocation to a cellular outcome showed that USF2 nuclear entry, driven through its USR-derived NLS, is required for IL-3-mediated mast cell survival.

    Evidence Subcellular fractionation and NLS-peptide inhibition with cell viability readout in mast cells

    PMID:9743349

    Open questions at the time
    • Downstream survival genes not identified
    • Single lab/system
  4. 1999 Medium

    Identifying p300 as the coactivator answered how USF2 transactivates through initiator elements, defining a coactivator-dependent activation mechanism.

    Evidence Cotransfection reporter assays with E1A mutants and p300 rescue on the ATPA promoter

    PMID:10434034

    Open questions at the time
    • Direct USF2-p300 binding not mapped
    • Promoter-specific generalization untested
  5. 2000 Medium

    Genome-promoter binding surveys established USF1/USF2 as direct regulators across diverse promoters (FMR1, APC, FcεRI, HOXB4) and showed methylation can block their binding.

    Evidence EMSA with tissue extracts, methylation interference, yeast one-hybrid, and reporter assays across multiple promoters

    PMID:11058604 PMID:11085749 PMID:11180124 PMID:11241666

    Open questions at the time
    • USF1 vs USF2 specificity not resolved at most promoters
    • Largely correlative for endogenous regulation
  6. 2002 High

    A rigorous inducible system overturned the earlier L-PK model, showing ChREBP rather than USF mediates glucose-responsive L-PK expression and clarifying the limits of USF2's metabolic role.

    Evidence Tet-on overexpression/dominant-negative, Northern blot, EMSA, nuclear run-on in INS-1 cells

    PMID:12087089

    Open questions at the time
    • Does not exclude USF2 metabolic roles in other tissues
    • Mechanism of dispensability at the bound promoter unexplained
  7. 2003 High

    Comparing USF1 and USF2 at IGF2R revealed paralog-specific activation, showing USF2 (not USF1) transactivates despite both occupying the promoter, and that this is lost in breast cancer cells.

    Evidence EMSA, ChIP, overexpression/dominant-negative, and Northern blot in mammary epithelial vs cancer lines

    PMID:12857727

    Open questions at the time
    • Molecular basis of USF2-specific activation unresolved
    • Cause of USF-independence in cancer cells unknown
  8. 2004 High

    Studies of HO-1 and a repressive splice isoform established that USF2 output is bidirectional and isoform-dependent, with USF2c acting as a homodimeric repressor.

    Evidence ChIP, in vivo footprinting, EMSA on HO-1; RT-PCR cloning, in vitro translation, and reporter assays for USF2c

    PMID:15242350 PMID:15276216

    Open questions at the time
    • Switch between activation and repression not mechanistically defined
    • USF2c tissue distribution and physiological role limited
  9. 2005 Medium

    Regulatory inputs and additional repressive targets were defined: a LysRS/Hint/Ap4A axis tunes USF2 activity, USF2 represses MCT1, and active USF2 suppresses c-Myc-driven transformation.

    Evidence Co-IP of LysRS with USF2 plus Ap4A functional assays; MCT1 EMSA/reporter; soft agar and nude mouse assays for c-Myc transformation

    PMID:15541720 PMID:15691871 PMID:16199869

    Open questions at the time
    • LysRS/Ap4A mechanism inferred by analogy to MITF
    • Anti-transformation mechanism only partially mapped
  10. 2006 High

    Genetic and xenograft evidence established USF2 as a bona fide tumor suppressor in prostate, with knockout mice developing prostate hyperplasia.

    Evidence Soft agar, invasion, xenograft assays in PC-3, USF2-knockout mouse, and human tissue IHC

    PMID:16186802

    Open questions at the time
    • Tumor-suppressive target genes in prostate not fully defined
    • Mechanism of hyperplasia in knockout unresolved
  11. 2008 Medium

    The cell-type-dependent reversal of HO-1 regulation was explained by USF2's partnership with the AP-1 factor Fra-1 and its requirement for both E-box and AP-1 sites plus the USR/exon 4 domains.

    Evidence Promoter mutagenesis, Co-IP with Fra-1, and domain-deletion analysis in hepatocytes vs tumor lines

    PMID:18331200

    Open questions at the time
    • Determinants selecting activation vs repression per cell type unresolved
    • Single lab
  12. 2008 Medium

    Genome-wide mapping placed USF1/USF2 binding predominantly at active transcription start sites and bidirectional promoters, framing them as broad promoter-proximal regulators.

    Evidence ChIP-chip at 35-bp resolution in HepG2 correlated with expression data

    PMID:18230803

    Open questions at the time
    • No functional follow-up for individual USF2 targets
    • Single cell line
  13. 2009 Medium

    Negative regulation by HINT1 and allele-specific recruitment at FOXE1 refined understanding of USF2 control and its role in disease-associated variants.

    Evidence Co-IP and reporter assays for HINT1; EMSA supershift and allele-specific reporter at FOXE1 rs1867277

    PMID:19089909 PMID:19730683

    Open questions at the time
    • HINT1 inhibition mechanism not structurally defined
    • FOXE1 regulation shown largely in vitro
  14. 2013 High

    Identifying the HIF2α interaction answered how HIF2 versus HIF1 target-gene specificity is achieved, showing USF2 is required for HIF2 target activation and Pol II recruitment under hypoxia.

    Evidence siRNA, ChIP, reporter assays, and Co-IP with HIF2α domain-mapping mutants

    PMID:23991099

    Open questions at the time
    • Structural basis of HIF2α-USF2 contact not resolved
    • In vivo relevance across tissues untested
  15. 2018 Medium

    USF2 was linked to TGF-β signaling and hematopoietic self-renewal by repressing Smurf1/2 and co-activating MSI2 with PLAG1.

    Evidence ChIP/ChIP-seq, reporter assays, and overexpression with CD34+ expansion phenotype

    PMID:29641991 PMID:30244169

    Open questions at the time
    • Direct vs indirect contribution to TGF-β output not fully separated
    • Single lab per study
  16. 2019 Medium

    Post-translational and target-level mechanisms advanced: CDK5 phosphorylation at S155/S222 stabilizes USF2, and USF2 directly regulates ATF4 to drive osteogenic differentiation.

    Evidence In vitro kinase assay with S155/S222 mutagenesis; reporter assays and ATF4 silencing rescue in periodontal ligament cells

    PMID:31013770 PMID:31448831

    Open questions at the time
    • How S155/S222 phosphorylation stabilizes the protein unresolved
    • Single-lab phenotypes
  17. 2020 Medium

    USF2 was established as an upstream regulator of pathogenic Th17 cytokine programs, extending its role to inflammation.

    Evidence shRNA knockdown in primary human CCR6+ Th17 cells with cytokine readouts and GSEA

    PMID:33203678

    Open questions at the time
    • Direct USF2 target promoters in Th17 cells not mapped
    • Mechanism upstream of cytokine genes inferred
  18. 2021 Medium

    Disease-context studies defined USF2-driven transcriptional axes (THBS1, S100A8) that promote pyroptosis/AKI and colorectal EMT/metastasis via TGF-β signaling.

    Evidence ChIP/reporter for direct binding plus in vitro and in vivo functional models

    PMID:33389821 PMID:34756923

    Open questions at the time
    • Context that switches USF2 between tumor-suppressive and pro-metastatic roles unresolved
    • Single lab per target
  19. 2022 Medium

    USF2's tumor-suppressive output was further mechanized through direct repression of TXNRD1 (gating Akt/mTOR via PTEN) and activation of TREM1 in inflammation.

    Evidence ChIP and reporter assays for direct promoter binding with knockdown/overexpression and pathway readouts

    PMID:35100093 PMID:36319631

    Open questions at the time
    • Determinants of repressor vs activator role at different promoters unresolved
    • Single lab per study
  20. 2023 Medium

    USF2 was tied to autophagy regulation through transcriptional control of YTHDF1 and STX6, linking it to neuronal I/R injury and HCC autophagic flux.

    Evidence Reporter assays and genetic rescue in neurons/HCC models with autophagy readouts

    PMID:37564208 PMID:37914905

    Open questions at the time
    • STX6 transcriptional link supported by limited direct evidence (Low confidence)
    • Direct vs indirect autophagy control not fully separated
  21. 2024 High

    A unifying mechanism for autophagy/lysosomal control was established: USF2 represses CLEAR-motif genes with HDAC1 under nutrient-rich conditions, and GSK3β phosphorylation at S155 de-represses them under starvation in competition with TFEB.

    Evidence ChIP for USF2/HDAC1 co-occupancy, H3K27ac and ATAC-seq, competitive TFEB binding, GSK3β phosphorylation, S155 mutagenesis, and disease-model validation

    PMID:39333072

    Open questions at the time
    • How S155 phosphorylation by GSK3β versus CDK5 produces opposite functional outcomes unresolved
    • Generality of TFEB competition across cell types untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • What molecular features dictate USF2's switch between activator and repressor (cofactor identity, partner, post-translational state) across cell types remains the central unresolved question.
  • No structural model of context-dependent cofactor selection
  • Conflicting S155 phosphorylation outcomes (CDK5 stabilizing vs GSK3β inhibiting) not reconciled
  • USF1 vs USF2 paralog division of labor incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-9612973 Autophagy 3 R-HSA-4839726 Chromatin organization 1
Partners
C-MAFFOSL1HDAC1HIF2AHINT1KARS1P300USF1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 USF2 contains two distinct nuclear localization signals: the basic region and the conserved USF-specific region (USR). Two transcriptional activation domains were identified: the USR and an exon 5-encoded region. The USR activates transcription only in its natural context upstream of the USF2 basic region and only with reporter constructs containing the adenovirus major late minimal promoter (not E1b minimal promoter), unless an initiator element is inserted downstream of the TATA box. The exon 4-encoded region modulates the potency of the exon 5 activation domain. Indirect immunofluorescence with transiently transfected cells; cotransfection assays with deletion mutants fused to USF2 or GAL4 DNA-binding domains; reporter gene assays Molecular and cellular biology High 8657110
1997 USF2 activity is required for glucose-stimulated L-pyruvate kinase (L-PK) promoter activity in single living islet beta-cells. Microinjection of anti-USF2 antibodies inhibited L-PK promoter activity by 71–87% at high glucose, and the effect was dependent on an intact L4 box (E-box elements at −165 and −154 bp). Photon-counting digital imaging of firefly luciferase in single living cells; microinjection of USF2-specific antibodies; reporter constructs with mutated L4 box The Journal of biological chemistry Medium 9252379
1997 USF2 (FIP) interacts with the bZip transcription factor c-Maf via its bHLH domain. USF2 mutants lacking the leucine zipper formed heterodimers with c-Maf but did not homodimerize; deletion of the basic region or mutation of helices abolished c-Maf binding without affecting homodimerization. In the presence of USF2, the DNA binding activity of c-Maf was markedly reduced, suggesting a tetrameric USF2–c-Maf complex that inhibits c-Maf DNA binding. Yeast two-hybrid; in vitro binding with USF2 deletion/point mutants; gel-shift DNA binding assays Biochemical and biophysical research communications Medium 9070273
1998 USF2 undergoes nuclear translocation in mast cells upon activation by IL-3 or IgE–antigen crosslinking. Prevention of USF2 nuclear translocation using a peptide derived from the USF-specific NLS region significantly inhibited IL-3-mediated mast cell survival, linking USF2 nuclear entry to cell viability. Subcellular fractionation; peptide inhibition of nuclear translocation; cell viability assay Journal of immunology Medium 9743349
1999 USF2-dependent transcriptional activation of the F1F0 ATP synthase alpha-subunit (ATPA) initiator element is mediated by the coactivator p300. Wild-type adenovirus E1A (which binds p300) inhibited USF2-dependent ATPA transactivation, whereas E1A mutants lacking p300-binding sites did not; overexpression of p300 reversed E1A inhibition. Cotransfection reporter assays; E1A mutant analysis; p300 overexpression rescue experiments Biochimica et biophysica acta Medium 10434034
2000 USF1 and USF2 are the major transcription factors binding the FMR1 promoter in brain and testis extracts. Methylation of the FMR1 promoter reduces USF1/USF2 binding (to a lesser degree than its abolition of alpha-Pal/NRF-1 binding), suggesting methylation inhibits FMR1 transcription partly by blocking USF factor binding. Electrophoretic mobility shift assay (EMSA) with brain/testis nuclear extracts; identification of conserved binding sites; methylation interference assays The Journal of biological chemistry Medium 11058604
2001 USF1 and USF2 bind to E-box elements in the APC tumor suppressor gene promoter (preferentially the E-box B site) and activate APC transcription. Mutation of E-box B completely abolished basal APC promoter activity; ectopic USF1/USF2 expression activated the APC promoter in HCT-116 cells. Transient transfection reporter assays; E-box site-directed mutagenesis; cotransfection with USF1/USF2 expression vectors Journal of cellular biochemistry Medium 11241666
2001 USF1/USF2 heterodimer activates the human FcεRI alpha chain gene by binding a CAGCTG E-box element in the first intron. Overexpression of USF2 antisense repressed the FcεRI alpha chain promoter and decreased alpha chain mRNA in mast cell lines. EMSA with antibodies and in vitro translation products; USF2 antisense overexpression; promoter-reporter assays European journal of immunology Medium 11180124
2001 USF-2 and USF-1 co-activate the HOXB4 promoter through an E-box (HXRE-2) in hematopoietic stem cells and K562 cells via the MAP kinase pathway, promoting stem cell self-renewal. MITF bound the same E-box but did not activate the HOXB4 promoter. USF-2 was identified by yeast one-hybrid screening of bone marrow and K562 libraries. Yeast one-hybrid assay; EMSA with K562 nuclear extracts; cotransfection in K562 and CD34+ cells; MAP kinase pathway inhibitor experiments The Journal of experimental medicine Medium 11085749
2002 ChREBP, not USF2, mediates glucose-stimulated L-PK expression in INS-1 insulin-secreting cells. Overexpression or dominant-negative suppression of USF1/USF2 (using tet-on inducible system) had no effect on basal or glucose-responsive endogenous L-PK mRNA, despite dramatically altering USF binding to the L-PK promoter (shown by EMSA). Tet-on inducible overexpression; dominant-negative USF mutants; quantitative Northern blot; EMSA; nuclear run-on assay; ChREBP overexpression The Journal of biological chemistry High 12087089
2002 USF-1 and USF-2 bind the E-box at −893/−888 of the murine iNOS promoter in vivo and act as transcriptional repressors of basal and IL-1β-induced iNOS expression in mesangial cells. Mutation of the E-box augmented iNOS response; cotransfection of dominant-negative USF-2 lacking the DNA-binding domain also augmented IL-1β stimulation. Site-directed mutagenesis of E-box; cotransfection reporter assays; EMSA with USF supershift antibodies; dominant-negative cotransfection American journal of physiology. Cell physiology Medium 12225970
2003 USF2 (but not USF1) is a specific transcriptional activator of the IGF2R (IGF2 receptor) gene in non-tumorigenic mammary epithelial cells (MCF-10A). Both USF1 and USF2 bound IGF2R E-box elements in vitro and were present at the IGF2R promoter chromatin in vivo, but only overexpressed USF2 transactivated the IGF2R promoter. A USF dominant-negative mutant decreased IGF2R mRNA. In breast cancer cell lines (MCF-7, MDA-MB-231), IGF2R promoter activity was USF-independent. In vitro DNA binding (EMSA); ChIP; overexpression and dominant-negative transfection; Northern blot The Journal of biological chemistry High 12857727
2004 USF1 and USF2 constitutively bind the class B E-box in the proximal human HO-1 promoter in vivo. Overexpression of USF1 or USF2 enhanced basal HO-1 expression; dominant-negative USF reduced HO-1 expression. A specific guanine contact point is essential for USF binding. USF proteins mediate HO-1 induction by haem and cadmium in human renal proximal tubular epithelial cells. ChIP; EMSA; dimethylsulphate in vivo footprinting; USF overexpression and dominant-negative transfection; E-box mutagenesis The Biochemical journal High 15242350
2004 A novel USF2 isoform (USF2c), generated by alternative splicing that removes exons 4, 5, and part of exon 6, binds as a homodimer to the E-box of the cathepsin B promoter and acts as a transcriptional repressor of cathepsin B expression. USF2c (~29 kDa) is expressed in prostate and glioblastoma cancer cell lines. RT-PCR cloning; in vitro transcription/translation; EMSA; cotransfection reporter assays Gene Medium 15276216
2005 Lysyl tRNA synthetase (LysRS) associates with USF2 in mast cells. Hint negatively regulates USF2, and Ap4A (synthesized by LysRS) acts as a positive regulator of USF2 activity by a mechanism similar to that described for MITF regulation by LysRS. Co-immunoprecipitation of LysRS with USF2; functional assays measuring USF2 transcriptional activity in the presence of Hint and Ap4A Molecular and cellular biology Medium 16199869
2005 USF1 and USF2 act as repressors of the human MCT1 (monocarboxylate transporter 1) promoter via binding to the site at −114/−119. Site-directed mutagenesis and cotransfection with USF1/USF2 expression vectors confirmed the repressor role; endogenous MCT1 expression was decreased in USF2-overexpressing Caco-2 cells. EMSA; site-directed mutagenesis; cotransfection reporter assays; endogenous mRNA measurement American journal of physiology. Gastrointestinal and liver physiology Medium 15691871
2005 Active USF2 overexpression inhibits c-Myc-dependent cellular transformation: in c-Myc-transformed (but not E1A-transformed) rat embryo fibroblasts, transcriptionally active USF2 reduced anchorage-independent growth, decreased tumor formation in nude mice by >30-fold, and cotransfection assays indicated USF2 acts by preventing transcriptional repression by c-Myc. Stable clone generation; soft agar colony assay; nude mouse xenograft; cotransfection with dominant-negative Myc/USF mutants Experimental cell research Medium 15541720
2006 USF2 functions as a tumor suppressor in prostate carcinogenesis. Ectopic USF2 expression in PC-3 cells inhibited anchorage-independent growth (90–98%), invasion (80%), and in vivo tumorigenicity (80–90% in nude mice). USF2-null mice developed marked prostate hyperplasia, confirming an in vivo role in normal prostate growth/differentiation. Western blot; soft agar assay; Matrigel invasion assay; nude mouse xenograft; USF2-knockout mouse generation; IHC of human prostate cancer tissues Oncogene High 16186802
2008 USF2 opposes HO-1 regulation in a cell-type-dependent manner: USF-2 inhibits HO-1 expression in primary hepatocytes but induces it in tumor cell lines. This differential regulation requires both an E-box and an AP-1 site in the HO-1 promoter and involves USF-2 interaction with Fra-1 (an AP-1 factor). The USF-specific region (USR) and exon 4 transactivation domain of USF-2 are required for the differential activity. Reporter assays with E-box and AP-1 site mutations; protein–protein interaction studies (co-immunoprecipitation of USF with Fra-1); USF-2 domain deletion mutants Antioxidants & redox signaling Medium 18331200
2008 USF1 and USF2 binding profiles across the entire human genome in a liver cell line (ChIP-chip) show that they bind predominantly near transcription start sites of protein-coding genes, that their binding positively correlates with gene expression, that they frequently co-occupy bidirectional promoters, and that USF1 preferentially binds and potentially regulates nuclear mitochondrial genes and lipid/cholesterol metabolism genes in collaboration with GABPA/NRF-2. Genome-wide ChIP-chip at 35-bp resolution in liver cell line (HepG2); correlation with gene expression data Genome research Medium 18230803
2009 DNA-binding assays (EMSA) showed that the A allele of rs1867277 in the FOXE1 5' UTR specifically recruits the USF1/USF2 transcription factor complex; transfection studies confirmed allele-dependent transcriptional regulation of FOXE1, indicating USF1/USF2 binding to this sequence drives FOXE1 expression. EMSA; supershift with USF1/USF2 antibodies; transfection reporter assays PLoS genetics Medium 19730683
2009 HINT1 co-immunoprecipitates with USF2 in HepG2 cell extracts and overexpression of HINT1 inhibits USF2 transcriptional activity, reducing expression of USF2-regulated genes including cyclin D1 and TGFβ2 in hepatoma cells. Co-immunoprecipitation; reporter assays; Western blot of downstream targets International journal of cancer Medium 19089909
2013 USF2 is specifically required for activation of HIF2 target genes under hypoxia. HIF2α physically interacts with USF2 in a manner dependent on the HIF2α N-TAD (and involving both N- and C-TADs). USF2 exhibits specific binding to the promoters of HIF2 (not HIF1) target genes. Addition of functional USF2 binding sites to a HIF1 target gene promoter increases its response to HIF2+USF2 activation. RNA Pol II association with HIF2 target genes is USF2-dependent. siRNA knockdown; reporter gene assays; ChIP; co-immunoprecipitation (HIF2α–USF2 interaction) with domain-mapping mutants PloS one High 23991099
2018 USF2 inhibits transcription of Smurf1 and Smurf2 (negative regulators of TGF-β signaling) by binding their E-box-containing promoters both in vitro and in vivo, thereby enhancing TGF-β pathway activity. Luciferase reporter assay; ChIP; overexpression of USF2; mRNA quantification Cellular signalling Medium 30244169
2018 USF2 and PLAG1 co-regulate MSI2 expression in hematopoietic stem and progenitor cells: both factors bind the MSI2 promoter (confirmed by ChIP-seq), their coincident overexpression in cord blood CD34+ cells enhances MSI2 transcription and expands CD34+ cells similarly to direct MSI2 overexpression. Luciferase reporter assay; ChIP-seq; lentiviral overexpression in cord blood CD34+ cells; CD34+ cell expansion assay Stem cell reports Medium 29641991
2019 CDK5 phosphorylates USF2 at serine 155 and serine 222, stabilizing the USF2 protein and regulating cellular growth and migration. In vitro kinase assay; site-directed mutagenesis of S155 and S222; Western blot; cell growth and migration assays Cancers Medium 31013770
2019 USF2 binds the transcriptional initiation region of ATF4 and regulates ATF4 transcription; overexpression of USF2 promotes osteogenic differentiation of periodontal ligament cells (PDLCs), and simultaneous USF2 overexpression with ATF4 silencing reverses this osteogenic effect. Luciferase reporter assay; USF2 and ATF4 overexpression/silencing; qRT-PCR; Alizarin red staining Journal of periodontal research Medium 31448831
2020 USF2 acts as an upstream transcriptional regulator of proinflammatory cytokines (IL-17A, IFN-γ, IL-22, GM-CSF) and T-bet in pathogenic Th17 cells; shRNA targeting USF2 reduced expression of these cytokines in CCR6+ T cells from rheumatoid arthritis patients. shRNA knockdown of USF2 in primary human Th17 cells; gene expression analysis; gene set enrichment analysis identifying USF2 as upstream regulator Proceedings of the National Academy of Sciences of the United States of America Medium 33203678
2021 USF2 transcriptionally activates THBS1, promoting oxidative stress and activating TGF-β/Smad3/NLRP3/Caspase-1 signaling to stimulate pyroptosis in sepsis-induced acute kidney injury. USF2 knockdown downregulates THBS1, inhibits TGF-β/Smad3 pathway activation, and reduces pyroptosis. USF2 knockdown (siRNA); ChIP/luciferase reporter for USF2–THBS1 promoter interaction; mouse AKI model; measurement of NLRP3/Caspase-1/GSDMD-N/IL-1β/IL-18; LDH assay Pharmacological research Medium 34756923
2021 USF2 transcriptionally regulates S100A8 expression by directly binding to the S100A8 promoter; TGF-β enhances the USF2/S100A8 signaling axis in colorectal cancer cells, promoting EMT and metastasis. Luciferase reporter and ChIP assays confirmed direct USF2 binding to the S100A8 promoter. Luciferase reporter assay; ChIP; USF2/S100A8 overexpression and knockdown; in vitro migration/invasion assay; in vivo mouse metastasis model Cancer communications Medium 33389821
2022 USF2 directly binds two E-box sites in the TXNRD1 promoter and functions as a transcriptional suppressor of TXNRD1 in hepatocellular carcinoma; USF2 acts as a tumor suppressor through downstream repression of TXNRD1, which otherwise activates Akt/mTOR signaling by attenuating PTEN. ChIP; luciferase reporter assay; USF2 and TXNRD1 knockdown/overexpression; in vitro and in vivo functional assays; Akt/mTOR pathway readouts Cell death & disease Medium 36319631
2022 USF2 transcriptionally activates TREM1 by binding its promoter (confirmed by luciferase reporter and ChIP assays), and USF2 knockdown reduces inflammatory cytokines (IL-6, IL-1β, TNF-α) in LPS-induced endometrial epithelial cells via the TREM1–TLR2/4–NF-κB axis. Luciferase reporter assay; ChIP; Co-IP (TREM1–TLR2/4); siRNA knockdown; ELISA Bioengineered Medium 35100093
2023 USF2 is a transcriptional activator of YTHDF1; USF2 knockdown in ischemia/reperfusion-injured neurons reduces YTHDF1, which otherwise suppresses autophagy via m6A-mediated stabilization of Cdc25A (an autophagy inhibitor), thereby worsening neuronal injury. Usf2 interference improved autophagy and alleviated I/R injury in MCAO mice. Luciferase reporter (USF2 binding to YTHDF1 promoter); lentiviral Usf2 shRNA in HT22 neurons and MCAO mice; YTHDF1 overexpression rescue; m6A/Cdc25A stability assays; autophagy and apoptosis readouts Molecular neurobiology Medium 37914905
2023 USF2 negatively regulates STX6 transcription in hepatocellular carcinoma; STX6 facilitates autophagosome–lysosome fusion and accelerates LC3B degradation by promoting autophagic flux, promoting HCC progression downstream of USF2. Gain- and loss-of-function experiments; mechanistic reporter assays; co-localization of autophagosomes and lysosomes; in vitro and in vivo proliferation/metastasis assays International journal of biological sciences Low 37564208
2024 USF2 represses lysosomal and autophagy genes under nutrient-rich conditions by binding CLEAR motifs together with HDAC1, reducing histone H3K27 acetylation and restricting chromatin accessibility. Under starvation, USF2 competes with TFEB for binding to target gene promoters. GSK3β phosphorylates USF2 at serine 155, reducing its DNA-binding activity and thereby de-repressing lysosomal gene expression. This mechanism was validated as a potential therapeutic target for α1-antitrypsin deficiency. ChIP for USF2 and HDAC1 co-occupancy at CLEAR motifs; histone acetylation (H3K27ac) assays; ATAC-seq (chromatin accessibility); competitive TFEB/USF2 binding assays; GSK3β phosphorylation assay; S155 mutagenesis; starvation-dependent gene regulation assays; disease model validation Nature communications High 39333072

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1984 Replacement of the fip gene of Escherichia coli by an inactive gene cloned on a plasmid. Journal of bacteriology 206 6384177
2000 FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis. Current biology : CB 183 11137014
2008 Down-regulation of hsa-miR-10a in chronic myeloid leukemia CD34+ cells increases USF2-mediated cell growth. Molecular cancer research : MCR 181 19074828
2018 The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Veterinary microbiology 173 29778200
1999 Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis. Proceedings of the National Academy of Sciences of the United States of America 147 9927690
1995 A new fungal immunomodulatory protein, FIP-fve isolated from the edible mushroom, Flammulina velutipes and its complete amino acid sequence. European journal of biochemistry 139 7705335
2009 The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors. PLoS genetics 132 19730683
2011 TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis. Cell and tissue research 131 21638209
2021 USF2 knockdown downregulates THBS1 to inhibit the TGF-β signaling pathway and reduce pyroptosis in sepsis-induced acute kidney injury. Pharmacological research 123 34756923
1997 Fip-vvo, a new fungal immunomodulatory protein isolated from Volvariella volvacea. The Biochemical journal 119 9163352
1996 Functional domains of the transcription factor USF2: atypical nuclear localization signals and context-dependent transcriptional activation domains. Molecular and cellular biology 118 8657110
2021 S100A8 promotes epithelial-mesenchymal transition and metastasis under TGF-β/USF2 axis in colorectal cancer. Cancer communications (London, England) 92 33389821
2002 ChREBP rather than USF2 regulates glucose stimulation of endogenous L-pyruvate kinase expression in insulin-secreting cells. The Journal of biological chemistry 91 12087089
1997 Dimerization of the N-terminal amphipathic alpha-helix domain of the fungal immunomodulatory protein from Ganoderma tsugae (Fip-gts) defined by a yeast two-hybrid system and site-directed mutagenesis. The Journal of biological chemistry 89 9242675
2013 MiRNA-362-3p induces cell cycle arrest through targeting of E2F1, USF2 and PTPN1 and is associated with recurrence of colorectal cancer. International journal of cancer 88 23280316
2008 Whole-genome maps of USF1 and USF2 binding and histone H3 acetylation reveal new aspects of promoter structure and candidate genes for common human disorders. Genome research 86 18230803
2000 Interaction of the transcription factors USF1, USF2, and alpha -Pal/Nrf-1 with the FMR1 promoter. Implications for Fragile X mental retardation syndrome. The Journal of biological chemistry 77 11058604
2002 The novel Rab11-FIP/Rip/RCP family of proteins displays extensive homo- and hetero-interacting abilities. Biochemical and biophysical research communications 71 11944901
2005 Nonconventional involvement of LysRS in the molecular mechanism of USF2 transcriptional activity in FcepsilonRI-activated mast cells. Molecular and cellular biology 62 16199869
1997 Upstream stimulatory factor-2 (USF2) activity is required for glucose stimulation of L-pyruvate kinase promoter activity in single living islet beta-cells. The Journal of biological chemistry 62 9252379
2003 82-FIP, a novel FMRP (fragile X mental retardation protein) interacting protein, shows a cell cycle-dependent intracellular localization. Human molecular genetics 61 12837692
1985 Thioredoxin is the bacterial protein encoded by fip that is required for filamentous bacteriophage f1 assembly. Journal of bacteriology 58 3881414
2001 A comparison of lymphatic tissues from cats with spontaneous feline infectious peritonitis (FIP), cats with FIP virus infection but no FIP, and cats with no infection. Journal of comparative pathology 55 11578135
2005 Natural FCoV infection: cats with FIP exhibit significantly higher viral loads than healthy infected cats. Journal of feline medicine and surgery 52 16213766
2001 Upstream stimulating factor-1 (USF1) and USF2 bind to and activate the promoter of the adenomatous polyposis coli (APC) tumor suppressor gene. Journal of cellular biochemistry 51 11241666
1983 A bacterial gene, fip, required for filamentous bacteriophage fl assembly. Journal of bacteriology 51 6343342
2018 Circulation and genetic diversity of Feline coronavirus type I and II from clinically healthy and FIP-suspected cats in China. Transboundary and emerging diseases 46 30468573
1984 Characterization of the cloned fip gene and its product. Journal of bacteriology 45 6319363
2018 USF2 inhibits the transcriptional activity of Smurf1 and Smurf2 to promote breast cancer tumorigenesis. Cellular signalling 42 30244169
2000 Hematopoietic expression of HOXB4 is regulated in normal and leukemic stem cells through transcriptional activation of the HOXB4 promoter by upstream stimulating factor (USF)-1 and USF-2. The Journal of experimental medicine 39 11085749
2009 HINT1 inhibits beta-catenin/TCF4, USF2 and NFkappaB activity in human hepatoma cells. International journal of cancer 38 19089909
2016 Recombinant FIP-gat, a Fungal Immunomodulatory Protein from Ganoderma atrum, Induces Growth Inhibition and Cell Death in Breast Cancer Cells. Journal of agricultural and food chemistry 37 26996414
2013 STAT3 or USF2 contributes to HIF target gene specificity. PloS one 37 23991099
2013 Interruption of lung cancer cell migration and proliferation by fungal immunomodulatory protein FIP-fve from Flammulina velutipes. Journal of agricultural and food chemistry 37 24274472
2001 Promoter I of the ovine acetyl-CoA carboxylase-alpha gene: an E-box motif at -114 in the proximal promoter binds upstream stimulatory factor (USF)-1 and USF-2 and acts as an insulin-response sequence in differentiating adipocytes. The Biochemical journal 35 11583573
1995 Structure, sequence, and chromosomal location of the gene for USF2 transcription factors in mouse. Genomics 35 7774954
2003 The IGF2 receptor is a USF2-specific target in nontumorigenic mammary epithelial cells but not in breast cancer cells. The Journal of biological chemistry 34 12857727
1996 Structure, sequence, and chromosome 19 localization of human USF2 and its rearrangement in a patient with multicystic renal dysplasia. Genomics 34 8954795
2006 Tumor-suppression function of transcription factor USF2 in prostate carcinogenesis. Oncogene 33 16186802
1998 Antibody and cytokine responses in kittens during the development of feline infectious peritonitis (FIP). Veterinary immunology and immunopathology 33 9839876
1997 Molecular cloning and expression of a fungal immunomodulatory protein, FIP-fve, from Flammulina velutipes. Journal of the Formosan Medical Association = Taiwan yi zhi 33 9262056
2010 Cytokines expression induced by Ganoderma sinensis fungal immunomodulatory proteins (FIP-gsi) in mouse spleen cells. Applied biochemistry and biotechnology 32 20174887
2004 Upstream stimulatory factors, USF1 and USF2, bind to the human haem oxygenase-1 proximal promoter in vivo and regulate its transcription. The Biochemical journal 31 15242350
2006 Functional expression of FIP-gts, a fungal immunomodulatory protein from Ganoderma tsugae in Sf21 insect cells. Bioscience, biotechnology, and biochemistry 30 17090952
2022 USF2-mediated upregulation of TXNRD1 contributes to hepatocellular carcinoma progression by activating Akt/mTOR signaling. Cell death & disease 29 36319631
2020 Aberrant expression of USF2 in refractory rheumatoid arthritis and its regulation of proinflammatory cytokines in Th17 cells. Proceedings of the National Academy of Sciences of the United States of America 29 33203678
2012 Effect of the fungal immunomodulatory protein FIP-fve on airway inflammation and cytokine production in mouse asthma model. Cytokine 29 23107824
2001 Laboratory profiles in cats with different pathological and immunohistochemical findings due to feline infectious peritonitis (FIP). Journal of feline medicine and surgery 29 11876632
2005 Role of USF1 and USF2 as potential repressor proteins for human intestinal monocarboxylate transporter 1 promoter. American journal of physiology. Gastrointestinal and liver physiology 28 15691871
2003 Vaccine efficacy of a cell lysate with recombinant baculovirus-expressed feline infectious peritonitis (FIP) virus nucleocapsid protein against progression of FIP. Veterinary microbiology 28 14637036
2016 Immunomodulatory proteins FIP-gts and chloroquine induce caspase-independent cell death via autophagy for resensitizing cisplatin-resistant urothelial cancer cells. Phytomedicine : international journal of phytotherapy and phytopharmacology 27 27823620
2005 Cellular composition and interferon-gamma expression of the local inflammatory response in feline infectious peritonitis (FIP). Veterinary microbiology 27 16183217
2004 Decreased sialylation of the acute phase protein alpha1-acid glycoprotein in feline infectious peritonitis (FIP). Veterinary immunology and immunopathology 26 15135988
2018 PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells. Stem cell reports 24 29641991
2009 Coadministration of the fungal immunomodulatory protein FIP-Fve and a tumour-associated antigen enhanced antitumour immunity. Immunology 24 19740349
2005 The roles of Sp1, Sp3, USF1/USF2 and NRF-1 in the regulation and three-dimensional structure of the Fragile X mental retardation gene promoter. The Biochemical journal 24 15479157
2014 Mutations in the 3c and 7b genes of feline coronavirus in spontaneously affected FIP cats. Research in veterinary science 23 25128417
1997 USF2/FIP associates with the b-Zip transcription factor, c-Maf, via its bHLH domain and inhibits c-Maf DNA binding activity. Biochemical and biophysical research communications 22 9070273
2022 Outbreak of feline infectious peritonitis (FIP) in shelter-housed cats: molecular analysis of the feline coronavirus S1/S2 cleavage site consistent with a 'circulating virulent-avirulent theory' of FIP pathogenesis. JFMS open reports 21 35173971
2008 Expression and purification of a recombinant Fip-fve protein from Flammulina velutipes in baculovirus-infected insect cells. Journal of applied microbiology 21 18266705
2008 B-cell activation in cats with feline infectious peritonitis (FIP) by FIP-virus-induced B-cell differentiation/survival factors. Archives of virology 21 19043660
2005 Decreased tumorigenicity of c-Myc-transformed fibroblasts expressing active USF2. Experimental cell research 21 15541720
2003 Shifts in circulating lymphocyte subsets in cats with feline infectious peritonitis (FIP): pathogenic role and diagnostic relevance. Veterinary immunology and immunopathology 21 14592727
2013 Functional expression of FIP-fve, a fungal immunomodulatory protein from the edible mushroom Flammulina velutipes in Pichia pastoris GS115. Journal of biotechnology 20 24070903
2009 FIP-fve stimulates interferon-gamma production via modulation of calcium release and PKC-alpha activation. Journal of agricultural and food chemistry 20 19919129
2005 Roles for USF-2 in lung cancer proliferation and bronchial carcinogenesis. The Journal of pathology 20 15856526
1999 Transcriptional activation of the F(1)F(0) ATP synthase alpha-subunit initiator element by USF2 is mediated by p300. Biochimica et biophysica acta 20 10434034
2019 USF2 enhances the osteogenic differentiation of PDLCs by promoting ATF4 transcriptional activities. Journal of periodontal research 19 31448831
2018 Characterization of peritoneal cells from cats with experimentally-induced feline infectious peritonitis (FIP) using RNA-seq. Veterinary research 19 30086792
2014 FIP-gts potentiate autophagic cell death against cisplatin-resistant urothelial cancer cells. Anticancer research 19 24922662
2013 Transcriptional profiling of feline infectious peritonitis virus infection in CRFK cells and in PBMCs from FIP diagnosed cats. Virology journal 19 24209771
2001 A complex composed of USF1 and USF2 activates the human FcepsilonRI alpha chain expression via a CAGCTG element in the first intron. European journal of immunology 19 11180124
1996 [Detection of feline coronavirus using RT-PCR: basis for the study of the pathogenesis of feline infectious peritonitis (FIP)]. Schweizer Archiv fur Tierheilkunde 19 8720731
2024 USF2 and TFEB compete in regulating lysosomal and autophagy genes. Nature communications 18 39333072
2023 Syntaxin-6 promotes the progression of hepatocellular carcinoma and alters its sensitivity to chemotherapies by activating the USF2/LC3B axis. International journal of biological sciences 18 37564208
2021 Protective mechanism of apigenin in diabetic nephropathy is related to its regulation of miR-423-5P-USF2 axis. American journal of translational research 18 34017372
2019 Cyclin-Dependent Kinase 5 (CDK5)-Mediated Phosphorylation of Upstream Stimulatory Factor 2 (USF2) Contributes to Carcinogenesis. Cancers 18 31013770
2019 Protective Function of Novel Fungal Immunomodulatory Proteins Fip-lti1 and Fip-lti2 from Lentinus tigrinus in Concanavalin A-Induced Liver Oxidative Injury. Oxidative medicine and cellular longevity 18 31198490
2002 FIP-2, an IkappaB-kinase-gamma-related protein, is associated with the Golgi apparatus and translocates to the marginal band during chicken erythroblast differentiation. Experimental cell research 18 12169269
2002 USF-1 and USF-2 trans-repress IL-1beta-induced iNOS transcription in mesangial cells. American journal of physiology. Cell physiology 18 12225970
2022 hsa-miR-875-5p inhibits tumorigenesis and suppresses TGF-β signalling by targeting USF2 in gastric cancer. Journal of translational medicine 17 35255935
2018 Implementation of Fragment Ion Protection (FIP) during Ultraviolet Photodissociation (UVPD) Mass Spectrometry. Analytical chemistry 17 29927232
2008 Opposite expression of the antioxidant heme oxygenase-1 in primary cells and tumor cells: regulation by interaction of USF-2 and Fra-1. Antioxidants & redox signaling 17 18331200
2001 Automated data processing on beamline FIP (BM30A) at ESRF. Acta crystallographica. Section D, Biological crystallography 17 11679765
2017 Characterization of a new fungal immunomodulatory protein, FIP-dsq2 from Dichomitus squalens. Journal of biotechnology 16 28202377
2014 Production and functional characterization of a novel fungal immunomodulatory protein FIP-SN15 shuffled from two genes of Ganoderma species. Applied microbiology and biotechnology 16 24682474
2014 Alleviation of respiratory syncytial virus replication and inflammation by fungal immunomodulatory protein FIP-fve from Flammulina velutipes. Antiviral research 16 25131377
2006 Absence of surface expression of feline infectious peritonitis virus (FIPV) antigens on infected cells isolated from cats with FIP. Veterinary microbiology 16 17188823
2011 Characterization of an immunomodulatory Der p 2-FIP-fve fusion protein produced in transformed rice suspension cell culture. Transgenic research 15 21556691
2001 Sites on FIP-3 (NEMO/IKKgamma) essential for its phosphorylation and NF-kappaB modulating activity. Biochemical and biophysical research communications 15 11444880
1998 Nuclear translocation of upstream stimulating factor 2 (USF2) in activated mast cells: a possible role in their survival. Journal of immunology (Baltimore, Md. : 1950) 15 9743349
2023 Usf2 Deficiency Promotes Autophagy to Alleviate Cerebral Ischemia-Reperfusion Injury Through Suppressing YTHDF1-m6A-Mediated Cdc25A Translation. Molecular neurobiology 14 37914905
2022 Upstream stimulatory factor 2 (USF2) induced upregulation of triggering receptor expressed on myeloid cells 1 (TREM1) promotes endometritis by regulating toll-like receptor (TLR) 2/4-nuclear factor-kappaB (NF-κB) signaling pathway. Bioengineered 14 35100093
2017 FIP-sch2, a new fungal immunomodulatory protein from Stachybotrys chlorohalonata, suppresses proliferation and migration in lung cancer cells. Applied microbiology and biotechnology 14 28078399
2004 Isolation of a novel USF2 isoform: repressor of cathepsin B expression. Gene 14 15276216
2023 Knockdown of USF2 inhibits pyroptosis of podocytes and attenuates kidney injury in lupus nephritis. Journal of molecular histology 13 37341818
2011 ID1 inhibits USF2 and blocks TGF-β-induced apoptosis in mesangial cells. American journal of physiology. Renal physiology 13 21921026
2020 FCoV Viral Sequences of Systemically Infected Healthy Cats Lack Gene Mutations Previously Linked to the Development of FIP. Pathogens (Basel, Switzerland) 12 32722056
2019 Identification of a Novel Anti-cancer Protein, FIP-bbo, from Botryobasidium botryosum and Protein Structure Analysis using Molecular Dynamic Simulation. Scientific reports 12 30967569
1996 Complete sequencing of the murine USF gene and comparison of its genomic organization to that of mFIP/USF2. Genomics 12 8938446

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