Affinage

USF2

Upstream stimulatory factor 2 · UniProt Q15853

Length
346 aa
Mass
37.0 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USF2 is a bHLH-leucine zipper transcription factor that binds E-box and CLEAR motifs as a homodimer or USF1/USF2 heterodimer to activate or repress a broad spectrum of target genes governing metabolism, immunity, fibrosis, autophagy, and tumor suppression. USF2 contains two nuclear localization signals (the basic region and the USF-specific region) and two transactivation domains whose activity depends on alternative splicing and promoter context; it cooperates with coactivators such as p300 and HIF2α, and is inhibited by corepressors including HDAC1, HINT1, and ID1 (PMID:8657110, PMID:10434034, PMID:23991099, PMID:39333072). Under nutrient-rich conditions, USF2 recruits HDAC1 to CLEAR motifs to repress lysosomal and autophagy genes by reducing H3K27 acetylation, and competes with TFEB upon starvation in a manner regulated by GSK3β-mediated phosphorylation of S155, while CDK5 phosphorylation of S155 and S222 independently stabilizes USF2 protein to control cell growth (PMID:39333072, PMID:31013770). USF2 functions as a tumor suppressor in prostate and liver cancers—USF2-null mice develop prostate hyperplasia, and ectopic USF2 suppresses tumorigenicity in prostate cancer xenografts—while also activating proinflammatory cytokine programs in pathogenic Th17 cells and driving fibrotic gene expression (PAI-1, THBS1) through TGF-β signaling (PMID:16186802, PMID:33203678, PMID:34756923).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 High

    Mapping USF2's functional architecture resolved how a bHLH-zip protein achieves nuclear entry and context-dependent transactivation, identifying dual NLS elements and two activation domains modulated by alternative splicing.

    Evidence Deletion mutagenesis fused to GAL4/USF2 DNA-binding domains, immunofluorescence of transfected cells, reporter assays with multiple promoter constructs

    PMID:8657110

    Open questions at the time
    • Crystal structure of USF2 activation domains not determined
    • Mechanism by which exon 4 splicing alters exon 5 domain conformation unknown
  2. 1997 Medium

    Discovery of USF2/c-Maf heterodimerization via the bHLH domain established that USF2 can sequester non-canonical partners to repress their DNA binding, expanding its regulatory repertoire beyond E-box-dependent mechanisms.

    Evidence Yeast two-hybrid, in vitro binding with deletion/mutation mutants, DNA binding assays

    PMID:9070273

    Open questions at the time
    • No in vivo confirmation of USF2–c-Maf interaction
    • Physiological target genes of this heterodimer not identified
  3. 1997 High

    Single-cell antibody microinjection demonstrated that USF2 is required for glucose-stimulated L-PK promoter activity in pancreatic β-cells, providing the first evidence that USF2 mediates metabolic gene regulation in a stimulus-dependent manner.

    Evidence Photon-counting imaging of luciferase in living islet β-cells, anti-USF2 antibody microinjection, promoter deletion constructs

    PMID:9252379

    Open questions at the time
    • Later work in INS-1 cells attributed glucose-responsive L-PK expression to ChREBP rather than USF2, indicating cell-type specificity (PMID:12087089)
  4. 1998 Medium

    Demonstration that USF2 undergoes signal-dependent nuclear translocation in mast cells upon IL-3 or IgE stimulation, with NLS-derived peptide blockade impairing cell survival, established USF2 as a signal-regulated transcription factor controlling immune cell viability.

    Evidence Subcellular fractionation, NLS-peptide inhibition of nuclear translocation, cell viability assays in mast cells

    PMID:9743349

    Open questions at the time
    • Upstream kinase/signaling pathway triggering nuclear import not identified
    • Peptide specificity for USF2 versus other NLS-containing proteins not fully addressed
  5. 1999 Medium

    Identification of p300 as a functional coactivator of USF2 at the ATP synthase α-subunit initiator element revealed a coactivator-dependent mechanism for USF2-mediated transcriptional activation, linking USF2 to the HAT-dependent chromatin remodeling machinery.

    Evidence Reporter assays with E1A mutants (p300-binding-deficient), p300 overexpression rescue

    PMID:10434034

    Open questions at the time
    • Direct physical interaction between USF2 and p300 not demonstrated by co-IP
    • Whether p300 recruitment is required at all USF2 target promoters is unknown
  6. 2001 Medium

    Multiple studies established USF2 as a versatile E-box-dependent transcriptional regulator of diverse target genes including APC, FcεRI, and HOXB4, demonstrating that USF1/USF2 homo- and heterodimers can either activate or repress transcription depending on the target promoter.

    Evidence EMSA with supershift, reporter assays with E-box mutations, antisense knockdown of USF2, cotransfection in multiple cell types (HCT-116, mast cells, K562/CD34+ cells)

    PMID:11085749 PMID:11180124 PMID:11241666

    Open questions at the time
    • Determinants of whether USF2 activates or represses at a given E-box not resolved
    • Genome-wide target repertoire not yet known at this stage
  7. 2002 High

    USF2 was shown to repress iNOS transcription by binding a distal E-box in the iNOS promoter, directly demonstrating a gene-repressive function distinct from its activator role, and was confirmed to be dispensable for glucose-responsive L-PK expression in INS-1 cells.

    Evidence Dominant-negative USF2, cis-decoy experiments, site-directed mutagenesis (iNOS); inducible USF expression, nuclear run-on (L-PK)

    PMID:12087089 PMID:12225970

    Open questions at the time
    • Chromatin-level mechanism of USF2-mediated repression at iNOS not elucidated
    • Cell-type determinants of USF2 dispensability at metabolic promoters unclear
  8. 2003 High

    ChIP and dominant-negative experiments revealed USF2 specifically transactivates IGF2R in nontumorigenic mammary cells but not in breast cancer lines, providing the first evidence that loss of USF2 function could contribute to oncogenesis through deregulation of a specific target gene.

    Evidence ChIP, in vitro binding, reporter assays, dominant-negative USF, endogenous mRNA measurement across MCF-10A and cancer cell lines

    PMID:12857727

    Open questions at the time
    • Mechanism of USF2 inactivation in cancer cells not determined
    • Whether IGF2R loss is the primary mediator of the tumorigenic phenotype was not tested
  9. 2005 Medium

    Functional evidence from multiple systems established USF2 as a regulator of LysRS/Ap4A signaling in mast cells and a suppressor of c-Myc-driven transformation, with transcriptionally active USF2 required to inhibit anchorage-independent growth and in vivo tumorigenesis.

    Evidence Soft agar and nude mouse xenograft with active/inactive USF2 mutants; co-IP of LysRS–USF2 complex, Ap4A functional assays in mast cells

    PMID:15541720 PMID:16199869

    Open questions at the time
    • Whether USF2 tumor suppression is c-Myc-specific or general not resolved
    • HINT1 regulation of USF2 in vivo not validated
  10. 2006 High

    In vivo knockout and xenograft studies definitively established USF2 as a prostate tumor suppressor: USF2 overexpression suppressed PC-3 tumorigenicity by 80–90%, while USF2-null mice developed marked prostate hyperplasia.

    Evidence USF2 KO mice with prostate phenotyping, ectopic expression in PC-3 cells, soft agar/invasion/xenograft assays, IHC of human prostate cancer

    PMID:16186802

    Open questions at the time
    • USF2 target genes mediating prostate tumor suppression not identified
    • Whether USF2 loss is sufficient for frank malignancy versus hyperplasia not resolved
  11. 2008 High

    Genome-wide ChIP-chip in liver cells revealed that USF1/USF2 predominantly bind near transcription start sites, co-occupy bidirectional promoters, and positively correlate with gene expression, establishing USF2 as a widespread promoter-proximal activator with a preference for metabolic and nuclear-mitochondrial genes.

    Evidence ChIP-chip at 35 bp resolution in HepG2 cells, correlation with expression data, co-occupancy analysis with GABPA/NRF-2

    PMID:18230803

    Open questions at the time
    • ChIP-chip performed in a single cell type (HepG2); tissue-specific binding not addressed
    • Causal role of USF binding at individual loci not established
  12. 2009 Medium

    Identification of HINT1 as a USF2-interacting repressor that inhibits cyclin D1 and TGFβ2 expression, and of Fra-1 as a cooperative partner at the HO-1 promoter, revealed that USF2 output depends on its protein interaction network at individual target genes.

    Evidence Co-IP of HINT1–USF2, reporter and endogenous gene assays; USF2–Fra-1 interaction studies with E-box/AP-1 double mutagenesis

    PMID:18331200 PMID:19089909

    Open questions at the time
    • Structural basis of HINT1–USF2 interaction not determined
    • Genome-wide extent of USF2–Fra-1 co-regulation unknown
  13. 2013 High

    Discovery that HIF2α physically interacts with USF2 through its N-TAD domain, and that USF2 is specifically required for RNA Pol II recruitment to HIF2 (but not HIF1) target genes, resolved how hypoxia signaling achieves HIF paralog specificity at select promoters.

    Evidence Co-IP with domain deletion mutants, ChIP for USF2 and Pol II at HIF2 vs HIF1 targets, siRNA knockdown, reporter assays

    PMID:23991099

    Open questions at the time
    • Whether USF2 DNA-binding activity is required for HIF2 cooperation or just protein scaffolding is unclear
    • Genome-wide scope of USF2-dependent HIF2 targets not mapped
  14. 2018 High

    ChIP-seq co-binding analysis in hematopoietic progenitors showed USF2 and PLAG1 co-regulate MSI2 transcription and that their combined activity expands CD34+ cells, positioning USF2 as a regulator of stem cell self-renewal.

    Evidence ChIP-seq, shRNA knockdown, reporter assays, overexpression in cord blood CD34+ cells with expansion assay

    PMID:29641991

    Open questions at the time
    • Broader in vivo hematopoietic phenotype of USF2 loss in this context not characterized
    • Whether USF2–PLAG1 cooperation extends beyond the MSI2 locus unknown
  15. 2019 High

    Identification of CDK5 as a kinase that phosphorylates USF2 at S155 and S222 to stabilize the protein established a post-translational regulatory mechanism controlling USF2 abundance and its effects on cell growth and migration.

    Evidence In vitro kinase assays, phospho-dead mutagenesis (S155A, S222A), protein stability and functional cell assays

    PMID:31013770

    Open questions at the time
    • In vivo confirmation of CDK5-dependent USF2 phosphorylation not provided
    • Downstream targets specifically affected by phosphorylation-stabilized USF2 not identified
  16. 2020 Medium

    shRNA knockdown in primary human Th17 cells identified USF2 as an upstream regulator of the pathogenic Th17 cytokine program (IL-17A, IFN-γ, IL-22, GM-CSF, T-bet), extending USF2's functional scope to adaptive immunity.

    Evidence shRNA knockdown in isolated human Th17 cells, gene expression and gene set enrichment analysis

    PMID:33203678

    Open questions at the time
    • Direct promoter binding of USF2 at Th17 cytokine loci not demonstrated by ChIP
    • In vivo Th17 phenotype of USF2 deficiency not tested
  17. 2021 Medium

    USF2 was shown to transcriptionally activate pro-fibrotic (THBS1) and pro-metastatic (S100A8) target genes through direct promoter binding, linking USF2 to TGF-β-driven pathology in acute kidney injury and colorectal cancer EMT.

    Evidence ChIP/reporter assays for USF2→THBS1 and USF2→S100A8, shRNA knockdown, in vivo AKI and metastasis models

    PMID:33389821 PMID:34756923

    Open questions at the time
    • Whether USF2 is a general mediator of TGF-β transcriptional output or acts at selected targets not resolved
    • Relative contribution of USF2 versus other E-box factors at these loci not quantified
  18. 2024 High

    A comprehensive mechanistic study resolved how USF2 represses lysosomal/autophagy genes under nutrient-rich conditions: USF2 recruits HDAC1 to CLEAR motifs, reduces H3K27 acetylation, and competes with TFEB; GSK3β phosphorylation of S155 governs USF2 DNA-binding activity and this repression, establishing USF2 as a nutrient-sensing transcriptional switch at CLEAR elements.

    Evidence ChIP, chromatin accessibility, histone acetylation profiling, co-IP with HDAC1, USF2–TFEB competition assays, GSK3β kinase assay with S155 mutagenesis, USF2 KO cells and mice

    PMID:39333072

    Open questions at the time
    • Whether mTORC1 or other nutrient sensors act upstream of GSK3β→USF2 not fully delineated
    • Relative importance of CDK5 vs GSK3β phosphorylation at S155 in different cellular contexts not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) how USF2 switches between activator and repressor modes at different E-box-containing promoters, (2) the full phosphorylation-dependent interactome that dictates cofactor choice, and (3) whether USF2 tumor suppressor function in prostate and liver operates through CLEAR-motif lysosomal gene repression, TXNRD1 repression, or additional pathways.
  • Structural basis of activator/repressor switch undetermined
  • No integrative model unifying CDK5 and GSK3β phosphorylation with cofactor selection
  • Causal target genes for prostate tumor suppression remain unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 16 GO:0003677 DNA binding 15 GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-74160 Gene expression (Transcription) 11 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 3 R-HSA-4839726 Chromatin organization 1
Partners
FOSL1HDAC1HIF2AHINT1ID1MAFPLAG1USF1
Complex memberships
USF1/USF2 heterodimer

Evidence

Reading pass · 36 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 highly conserved USF-specific region (USR), both of which are required for nuclear localization. Two transcriptional activation domains were identified: the USR (context-dependent, requires the adenovirus major late minimal promoter or an initiator element) and the exon 5-encoded region (active in multiple contexts). Activity of the exon 5 domain varies with conformation induced by alternatively spliced exon 4. Indirect immunofluorescence of transiently transfected cells, cotransfection assays with deletion mutants fused to DNA-binding domains of USF2 or GAL4, reporter assays with multiple promoter constructs Molecular and cellular biology High 8657110
1997 USF2 (via its bHLH domain) forms heterodimers with the bZip transcription factor c-Maf through the USF2 basic region and HLH motif; the leucine zipper is required for USF2 homodimerization but not for c-Maf heterodimerization. USF2 binding to c-Maf markedly reduces c-Maf DNA-binding activity, suggesting a mechanism of transcriptional repression. Yeast two-hybrid, in vitro binding with USF2 deletion/mutation mutants, DNA binding assays Biochemical and biophysical research communications Medium 9070273
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 this effect depended on the intact upstream L4 box (two E-boxes) in the L-PK promoter. Photon-counting digital imaging of luciferase in single living cells, microinjection of antibodies, promoter deletion constructs The Journal of biological chemistry High 9252379
1998 USF2 undergoes nuclear translocation in mast cells upon activation by IL-3 or IgE-antigen stimulation. Prevention of this translocation using a peptide derived from the USF-specific NLS region significantly inhibited IL-3-mediated mast cell survival, directly linking USF2 nuclear translocation to cell viability. Subcellular fractionation/localization, peptide inhibition of nuclear translocation, cell viability assays Journal of immunology Medium 9743349
1999 The coactivator p300 interacts functionally with USF2 to potentiate USF2-dependent transcriptional activation of the F1F0 ATP synthase alpha-subunit (ATPA) initiator element. Wild-type adenovirus E1A (but not p300-binding-deficient E1A mutants) inhibited this activation; overexpression of p300 reversed the E1A inhibitory effect. Transfection/reporter assays, E1A mutant expression, p300 overexpression rescue experiments Biochimica et biophysica acta Medium 10434034
2000 USF1, USF2, and alpha-Pal/NRF-1 are the major transcription factors binding the FMR1 promoter in brain and testis extracts. Methylation abolishes alpha-Pal/NRF-1 binding and affects USF1/USF2 binding to a lesser degree, suggesting methylation inhibits FMR1 transcription partly by blocking these factor binding events. EMSA with brain and testis extracts, methylation-dependent binding assays, transcriptional activity assays in neuronally derived cells with mutation analysis The Journal of biological chemistry High 11058604
2001 USF1 and USF2 bind to E-box motifs (especially E-box B) in the APC tumor suppressor gene promoter and are required for its basal transcriptional activity; mutation of E-box B abolished basal promoter activity in HCT-116 cells. EMSA, transient transfection with E-box deletion/mutation constructs, cotransfection with USF expression vectors Journal of cellular biochemistry Medium 11241666
2001 A USF1/USF2 heterodimer activates human FcεRI alpha chain gene expression by binding to 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, antisense overexpression, promoter-reporter assays European journal of immunology Medium 11180124
2001 USF1 and USF2 bind the E-box in the proximal promoter of the HOXB4 gene and activate its transcription in hematopoietic stem cells (K562 and CD34+ cells) via activation of the MAPK pathway; this was shown by yeast one-hybrid screening, EMSA, and cotransfection assays. Yeast one-hybrid screen, EMSA, cotransfection with MAPK pathway analysis, reporter assays in K562 and CD34+ cells The Journal of experimental medicine Medium 11085749
2002 ChREBP, not USF2, mediates glucose-stimulated endogenous L-PK expression in INS-1 insulin-secreting cells. Inducible overexpression of USF-1 and USF-2 did not alter basal or glucose-responsive L-PK mRNA, and dominant-negative USF (which abolished USF binding to the L-PK promoter) also had no effect on L-PK expression in INS-1 cells. Tet-on inducible expression of USF1, USF2, and dominant-negative mutants; Northern blot; EMSA; nuclear run-on experiments; Western blot of nuclear fractions The Journal of biological chemistry High 12087089
2002 USF-1 and USF-2 bind an E-box at -893/-888 in the iNOS promoter in vivo and act as transcriptional repressors of IL-1β-induced iNOS expression in murine mesangial cells. Mutation of the E-box augmented iNOS response, and cotransfection of dominant-negative USF-2 or cis-element decoys enhanced IL-1β stimulation. Site-directed mutagenesis of iNOS promoter, EMSA with supershift, cotransfection with USF expression vectors and dominant-negative mutants, cis-decoy experiments American journal of physiology. Cell physiology High 12225970
2003 USF2, but not USF1, specifically transactivates the IGF2R promoter in nontumorigenic mammary epithelial cells (MCF-10A); USF1 and USF2 both bind IGF2R E-boxes in vitro and in chromatin, but a USF-specific dominant-negative mutant markedly decreased IGF2R mRNA. IGF2R promoter activity was USF-independent in breast cancer cell lines, suggesting loss of USF function contributes to IGF2R downregulation in cancer. In vitro DNA binding, chromatin immunoprecipitation (ChIP), transactivation assays with overexpressed USF2 vs USF1, dominant-negative USF expression, endogenous mRNA measurement The Journal of biological chemistry High 12857727
2004 USF1 and USF2 constitutively bind the class B E-box in the proximal promoter of the human HO-1 gene in vivo, are required for high-level HO-1 expression, and enhance HO-1 transcription in response to heme and cadmium in human renal proximal tubular epithelial cells. A single guanine contact point in the E-box is essential for USF binding. DMS in vivo footprinting, ChIP, EMSA, overexpression of USF1/USF2, dominant-negative USF expression, reporter assays The Biochemical journal High 15242350
2004 A novel USF2 isoform (USF2c), generated by alternative splicing using a cryptic acceptor site within exon 6 (missing exons 4, 5, and part of exon 6), encodes a ~29 kDa protein that binds as a homodimer to the cathepsin B promoter E-box and acts as a transcriptional repressor of cathepsin B expression. RT-PCR cloning, in vitro transcription/translation, EMSA, cotransfection reporter assays Gene Medium 15276216
2005 USF1 and USF2 bind to a repressor E-box site at -114 to -119 of the human MCT1 promoter and act as repressors of MCT1 transcription in Caco-2 colonic cells, as shown by EMSA, site-directed mutagenesis, and cotransfection of USF expression vectors decreasing endogenous MCT1 expression. EMSA, site-directed mutagenesis, cotransfection with USF expression vectors, endogenous MCT1 mRNA measurement American journal of physiology. Gastrointestinal and liver physiology Medium 15691871
2005 Transcriptionally active USF2 suppresses the tumorigenicity and anchorage-independent growth of c-Myc-transformed fibroblasts; this required transcriptionally active (not inactive) USF2, and cotransfection assays indicated active USF2 inhibited cellular transformation by preventing c-Myc-mediated transcriptional repression. Stable cell line generation, soft agar colony assay, nude mice xenograft, cotransfection with USF and Myc dominant-negative mutants Experimental cell research Medium 15541720
2005 USF2 (LysRS partner) is regulated by Ap4A in mast cells: LysRS associates with USF2 and negatively regulates its activity; Ap4A produced by LysRS acts as a positive regulator of USF2 transcriptional activity, analogous to the mechanism described for MITF. The Hint protein negatively regulates USF2 in this pathway. Co-immunoprecipitation (Co-IP), functional transcriptional assays in mast cells, biochemical assays of Ap4A synthesis Molecular and cellular biology Medium 16199869
2006 USF2 functions as a tumor suppressor in prostate carcinogenesis: ectopic USF2 expression in androgen-independent PC-3 cells inhibited anchorage-independent growth (90-98%), invasion (80%), and in vivo tumorigenicity (80-90%) in nude mice. USF2-null mice exhibited marked prostate hyperplasia, confirming an in vivo role in normal prostate growth and differentiation. Western blot of cancer cell lines, ectopic overexpression, soft agar assay, Matrigel invasion assay, nude mouse xenograft, USF2 knockout mice generation and phenotyping, IHC of human prostate cancer tissues Oncogene High 16186802
2008 Whole-genome ChIP-chip analysis revealed that USF1 and USF2 bind predominantly near transcription start sites of protein-coding genes in a liver cell line, their binding positively correlates with gene expression levels, and they frequently occupy bidirectional promoters. USF1 and USF2 co-occupy promoters of nuclear-mitochondrial genes and lipid/cholesterol metabolism genes, often in collaboration with GABPA/NRF-2. ChIP-chip (genome-wide, 35 bp resolution) in HepG2 liver cell line, correlation with expression data Genome research High 18230803
2008 USF-2 interacts with Fra-1 (an AP-1 factor) via protein-protein interaction, and this USF-2/Fra-1 cooperation regulates HO-1 promoter activity in opposing ways in primary versus tumor cells. Mutation of either the E-box or AP-1 site in the HO-1 promoter only partially affected USF-dependent regulation; double mutation abolished it. USF-2 lacking its USF-specific region (USR) or exon 4-encoded transactivation domain lost regulatory capacity. Protein-protein interaction studies, promoter mutagenesis (E-box and AP-1 site), USF-2 domain deletion analysis, reporter assays in primary hepatocytes vs tumor cell lines Antioxidants & redox signaling Medium 18331200
2009 HINT1 co-immunoprecipitates with USF2 in HepG2 hepatoma cells and inhibits USF2 transcriptional activity, as well as inhibiting endogenous cyclin D1 and TGFβ2 expression controlled by USF2. Co-immunoprecipitation, reporter assays for USF2 transcriptional activity, endogenous gene expression analysis after HINT1 overexpression International journal of cancer Medium 19089909
2009 The rs1867277 A allele in the FOXE1 5' UTR specifically recruits the USF1/USF2 transcription factor complex (but not the G allele), as demonstrated by DNA-binding assays, and this allele-specific recruitment leads to differential transcriptional regulation of FOXE1. DNA-binding assays (EMSA with USF1/USF2 antibodies), transfection/reporter assays with allele-specific constructs PLoS genetics Medium 19730683
2011 In TGF-β signaling, USF2 operates in a SMAD/p53/USF2→PAI-1 transcriptional axis: SMAD2/3, pp60c-src, EGFR, and p53 activation are each required for TGF-β1-induced PAI-1 expression in the context of renal fibrosis and ureteral obstruction. Pathway inhibitor studies, reporter assays, in vivo UUO mouse model with pathway component activation measured Cell and tissue research Medium 21638209
2011 ID1 inhibits USF2 transcriptional activity in mesangial cells, thereby blocking TGF-β-induced apoptosis. TGF-β upregulates USF2, which increases BAX expression and apoptosis; BMPs induce ID1 which counteracts USF2 activity to exert an anti-apoptotic effect. Expression manipulation of ID1 and USF2, apoptosis assays, BAX expression measurement, reporter assays in human mesangial cells American journal of physiology. Renal physiology Medium 21921026
2013 HIF2α physically interacts with USF2 in a manner dependent on HIF2α's N-TAD domain, and this interaction is required for selective activation of HIF2 target genes. USF2 exhibits specific binding to the promoters of HIF2 (but not HIF1) target genes even when overexpressed, and RNA Pol II association with HIF2 target genes is USF2-dependent. siRNA knockdown, inhibitor studies, reporter assays, chromatin immunoprecipitation (ChIP), co-immunoprecipitation with domain deletion mutants, RNA Pol II ChIP PloS one High 23991099
2018 USF2 binds to E-box motifs in the Smurf1 and Smurf2 promoters (in vitro and in vivo by ChIP) and inhibits their transcriptional activity, resulting in decreased Smurf mRNA and enhanced TGF-β pathway activity in breast cancer cells. Luciferase reporter assays with Smurf promoters, ChIP, overexpression of USF2, endogenous mRNA measurement Cellular signalling Medium 30244169
2018 USF2 and PLAG1 co-regulate MSI2 (Musashi-2) transcription in human hematopoietic stem and progenitor cells; both factors bind the MSI2 promoter (confirmed by ChIP-seq), are required for efficient transactivation of endogenous MSI2, and their coincident overexpression expands CD34+ cells in vitro. Luciferase reporter assays, ChIP-seq (global co-binding analysis), shRNA knockdown of USF2 and PLAG1, overexpression in cord blood cells with CD34+ expansion assay Stem cell reports High 29641991
2019 CDK5 phosphorylates USF2 at two serine residues, S155 and S222; phosphorylation at these sites stabilizes the USF2 protein and regulates cellular growth and migration in cancer cells. In vitro kinase assays, site-directed mutagenesis (S155A and S222A), protein stability assays, functional cell growth and migration assays Cancers High 31013770
2019 USF2 directly binds the ATF4 transcriptional initiation region and regulates its transcriptional activity in periodontal ligament cells; USF2 overexpression promotes osteogenic differentiation (osteoblast-specific gene expression and mineralization), and this effect is reversed by simultaneous ATF4 silencing. Luciferase reporter assays, overexpression and silencing systems, Alizarin red staining, qRT-PCR, ELISA, microarray Journal of periodontal research Medium 31448831
2020 USF2 directly regulates proinflammatory cytokine production (IL-17A, IFN-γ, IL-22, GM-CSF) and T-bet expression in pathogenic Th17 cells; shRNA targeting USF2 in these cells reduced expression of these cytokines, identifying USF2 as an upstream regulator of the Th17 pathogenic transcriptional program. shRNA knockdown of USF2 in isolated 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 by binding to its promoter, promoting oxidative stress and activating the TGF-β/Smad3/NLRP3/Caspase-1 pathway to stimulate pyroptosis in sepsis-induced acute kidney injury. USF2 knockdown reduced THBS1, inhibited this pathway, and ameliorated kidney injury. ChIP/reporter assays for USF2→THBS1 transcriptional activation, USF2 knockdown (shRNA/siRNA), in vivo mouse AKI model, pyroptosis assays (Caspase-1, GSDMD-N, LDH), pathway protein measurements Pharmacological research Medium 34756923
2021 TGF-β upregulates USF2, which transcriptionally activates S100A8 by directly binding its promoter (confirmed by luciferase reporter and ChIP assays), thereby promoting EMT and metastasis in colorectal cancer cells. Extracellular S100A8 conversely suppresses the USF2/S100A8 axis. Luciferase reporter assays, ChIP, Western blot, migration/invasion assays, mouse metastasis models, siRNA knockdown Cancer communications Medium 33389821
2022 USF2 transcriptionally represses TXNRD1 by directly binding to two E-box sites in the TXNRD1 promoter in hepatocellular carcinoma cells, functioning as a tumor suppressor through downstream repression of TXNRD1-Akt/mTOR signaling. ChIP, reporter assays, USF2 overexpression/knockdown, TXNRD1 functional assays, in vitro and in vivo experiments Cell death & disease Medium 36319631
2023 USF2 transcriptionally activates YTHDF1 (an m6A reader) by binding to its promoter; YTHDF1 then suppresses autophagy by increasing m6A-mediated stability of Cdc25A (an autophagy inhibitor), thereby exacerbating ischemia-reperfusion injury in neurons. Usf2 interference improved autophagy and reduced neuronal apoptosis in vitro and in vivo. Promoter binding assays, lentiviral shRNA knockdown, MCAO in vivo model, m6A stability assays, autophagy and apoptosis readouts Molecular neurobiology Medium 37914905
2023 USF2 negatively regulates STX6 transcription in hepatocellular carcinoma; under USF2 control, STX6 promotes autophagosome-lysosome fusion and accelerates LC3B degradation, promoting HCC progression. Reporter assays, USF2 and STX6 overexpression/knockdown, autophagy flux assays, in vitro and in vivo HCC functional experiments International journal of biological sciences Medium 37564208
2024 USF2 acts as a transcriptional repressor of lysosomal and autophagy genes under nutrient-rich conditions by binding CLEAR motifs together with HDAC1, reducing histone H3K27 acetylation and chromatin accessibility. Under starvation, USF2 competes with TFEB for CLEAR motif binding in a phosphorylation-dependent manner; GSK3β-mediated phosphorylation of USF2 S155 governs its DNA-binding activity and lysosomal gene repression. ChIP, chromatin accessibility assays, histone acetylation profiling, reporter assays, co-IP with HDAC1, USF2-TFEB competition assays, GSK3β kinase assays with S155 mutagenesis, USF2 knockout cells/mice 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 180 19074828
2018 The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Veterinary microbiology 162 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
1997 Fip-vvo, a new fungal immunomodulatory protein isolated from Volvariella volvacea. The Biochemical journal 118 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 USF2 knockdown downregulates THBS1 to inhibit the TGF-β signaling pathway and reduce pyroptosis in sepsis-induced acute kidney injury. Pharmacological research 116 34756923
2002 ChREBP rather than USF2 regulates glucose stimulation of endogenous L-pyruvate kinase expression in insulin-secreting cells. The Journal of biological chemistry 90 12087089
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
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 88 9242675
2021 S100A8 promotes epithelial-mesenchymal transition and metastasis under TGF-β/USF2 axis in colorectal cancer. Cancer communications (London, England) 87 33389821
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 60 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 41 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
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
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 36 26996414
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
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
2006 Tumor-suppression function of transcription factor USF2 in prostate carcinogenesis. Oncogene 32 16186802
2010 Cytokines expression induced by Ganoderma sinensis fungal immunomodulatory proteins (FIP-gsi) in mouse spleen cells. Applied biochemistry and biotechnology 31 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
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
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 Role of USF1 and USF2 as potential repressor proteins for human intestinal monocarboxylate transporter 1 promoter. American journal of physiology. Gastrointestinal and liver physiology 27 15691871
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
2022 USF2-mediated upregulation of TXNRD1 contributes to hepatocellular carcinoma progression by activating Akt/mTOR signaling. Cell death & disease 25 36319631
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
2008 Expression and purification of a recombinant Fip-fve protein from Flammulina velutipes in baculovirus-infected insect cells. Journal of applied microbiology 21 18266705
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
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 20 35173971
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
2008 B-cell activation in cats with feline infectious peritonitis (FIP) by FIP-virus-induced B-cell differentiation/survival factors. Archives of virology 20 19043660
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
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
2005 Roles for USF-2 in lung cancer proliferation and bronchial carcinogenesis. The Journal of pathology 19 15856526
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
2018 Characterization of peritoneal cells from cats with experimentally-induced feline infectious peritonitis (FIP) using RNA-seq. Veterinary research 18 30086792
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
2022 hsa-miR-875-5p inhibits tumorigenesis and suppresses TGF-β signalling by targeting USF2 in gastric cancer. Journal of translational medicine 17 35255935
2021 Protective mechanism of apigenin in diabetic nephropathy is related to its regulation of miR-423-5P-USF2 axis. American journal of translational research 17 34017372
2019 Cyclin-Dependent Kinase 5 (CDK5)-Mediated Phosphorylation of Upstream Stimulatory Factor 2 (USF2) Contributes to Carcinogenesis. Cancers 17 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 17 31198490
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
2002 USF-1 and USF-2 trans-repress IL-1beta-induced iNOS transcription in mesangial cells. American journal of physiology. Cell physiology 17 12225970
2001 Automated data processing on beamline FIP (BM30A) at ESRF. Acta crystallographica. Section D, Biological crystallography 17 11679765
2024 USF2 and TFEB compete in regulating lysosomal and autophagy genes. Nature communications 16 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 16 37564208
2018 Implementation of Fragment Ion Protection (FIP) during Ultraviolet Photodissociation (UVPD) Mass Spectrometry. Analytical chemistry 16 29927232
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
2006 Absence of surface expression of feline infectious peritonitis virus (FIPV) antigens on infected cells isolated from cats with FIP. Veterinary microbiology 16 17188823
2017 Characterization of a new fungal immunomodulatory protein, FIP-dsq2 from Dichomitus squalens. Journal of biotechnology 15 28202377
2014 Alleviation of respiratory syncytial virus replication and inflammation by fungal immunomodulatory protein FIP-fve from Flammulina velutipes. Antiviral research 15 25131377
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
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
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
2018 The Zinc-Finger Thylakoid-Membrane Protein FIP Is Involved With Abiotic Stress Response in Arabidopsis thaliana. Frontiers in plant science 13 29720990
2017 FIP-sch2, a new fungal immunomodulatory protein from Stachybotrys chlorohalonata, suppresses proliferation and migration in lung cancer cells. Applied microbiology and biotechnology 13 28078399
2011 ID1 inhibits USF2 and blocks TGF-β-induced apoptosis in mesangial cells. American journal of physiology. Renal physiology 13 21921026
1996 Complete sequencing of the murine USF gene and comparison of its genomic organization to that of mFIP/USF2. Genomics 13 8938446
2023 Usf2 Deficiency Promotes Autophagy to Alleviate Cerebral Ischemia-Reperfusion Injury Through Suppressing YTHDF1-m6A-Mediated Cdc25A Translation. Molecular neurobiology 12 37914905
2020 FCoV Viral Sequences of Systemically Infected Healthy Cats Lack Gene Mutations Previously Linked to the Development of FIP. Pathogens (Basel, Switzerland) 12 32722056