Affinage

E2F4

Transcription factor E2F4 · UniProt Q16254

Length
413 aa
Mass
44.0 kDa
Annotated
2026-06-09
100 papers in source corpus 45 papers cited in narrative 43 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

E2F4 is a DP-heterodimerizing transcription factor that serves as the principal effector of pocket-protein-mediated transcriptional repression, silencing cell cycle-dependent genes in quiescent and arrested cells and accounting for the majority of endogenous E2F DNA-binding activity (PMID:7958925, PMID:7958924, PMID:8657117). E2F4 lacks an intrinsic nuclear localization signal and depends on cytoplasmic binding to pocket proteins p130, p107, or pRB (or the NLS-bearing DP3δ isoform) for nuclear entry, where partner choice is cell cycle-dependent: p130 sequesters E2F4 in quiescence and is exchanged for pRB/p107 across the G1/S transition (PMID:8657117, PMID:9144196, PMID:9537223). Nuclear residence is opposed by CRM1-dependent export through two hydrophobic export sequences, and CDK-driven hyperphosphorylation of p130/p107 dissociates the repressor complexes to permit S-phase gene induction (PMID:8710362, PMID:11158323, PMID:12006580). In G0, E2F4/p130 nucleates the DREAM complex (with LIN-9/37/52/54 and RBBP4) that occupies more than 800 promoters, and assembles HDAC1-, mSin3A-, KDM5A-, and SWI/SNF-containing co-repressor modules that deacetylate and compact chromatin at target promoters such as cdc2, PARP1, and ER-alpha (PMID:17531812, PMID:12789259, PMID:22179826, PMID:23093672, PMID:28842672). E2F4/p130 repression is integrated into multiple arrest and stress pathways: it executes p53/p21-dependent gene silencing, maintains genotoxic G2 arrest by repressing mitotic genes, suppresses BRCA1/RAD51 to limit homologous-directed repair, and functions downstream of TGF-β via a preformed cytoplasmic Smad3/E2F4/DP1/p107 complex that represses c-myc (PMID:11032828, PMID:24096481, PMID:17043659, PMID:20133863, PMID:12150994). Genetically, E2F4 is dispensable for cell cycle progression itself but required for pocket-protein-mediated G1 arrest, and in vivo it controls maturation of erythroid, intestinal, airway-ciliated, and neural lineages, partly through cell-cycle-independent functions (PMID:11030352, PMID:10983976, PMID:10983977, PMID:16861343, PMID:17383628, PMID:17537963). In RB-family-null embryonic stem cells E2F4 instead acts as a direct transcriptional activator of cell cycle genes, and post-translational inputs—USP2-mediated deubiquitination/stabilization and p38MAPK phosphorylation at Thr261/263—redirect E2F4 toward activation of autophagy or cell-cycle-reentry programs (PMID:31270324, PMID:35253629, PMID:22586272).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1994 High

    Established E2F4 as a DP-dependent E2F-family transcription factor whose activity is constrained by the pocket protein p107, defining its core biochemical identity.

    Evidence Co-IP, yeast two-hybrid, reporter and focus-formation/transformation assays in rodent cells

    PMID:7958924 PMID:7958925

    Open questions at the time
    • Did not establish the in vivo target gene set
    • NLS deficiency noted but mechanism of nuclear entry unresolved
  2. 1995 High

    Identified p130 as a cell-cycle-stage-specific E2F4 partner and showed p130 represses E2F4 transactivation through a mechanism biochemically distinct from RB, positioning E2F4/p130 at quiescence.

    Evidence Yeast two-hybrid, Co-IP, in vivo footprinting and promoter mutagenesis at the cdc2 promoter

    PMID:7705662 PMID:7892279 PMID:8524257

    Open questions at the time
    • Genome-wide target scope unknown
    • Phosphorylation sites controlling complex assembly not yet defined
  3. 1996 High

    Showed E2F4 switches pocket-protein partners across the cell cycle and that p130 phosphorylation state governs complex assembly and dissociation, explaining temporal control of repression.

    Evidence Cell-cycle fractionation with specific antisera, EMSA, in vitro CDK kinase assays

    PMID:8657117 PMID:8710362

    Open questions at the time
    • Precise p130 phosphosite requirements only later mapped
    • Did not address subcellular trafficking
  4. 1998 High

    Resolved how an NLS-less transcription factor reaches the nucleus, showing E2F4 is imported as a passenger of pocket proteins or the NLS-containing DP3δ isoform, coupling localization to growth arrest.

    Evidence Immunofluorescence, subcellular fractionation, cotransfection and cell-cycle analysis

    PMID:9144196 PMID:9537223

    Open questions at the time
    • Mechanism of nuclear exit not yet defined
    • Endogenous stoichiometry of import partners unclear
  5. 2000 High

    Defined CRM1-dependent nuclear export via hydrophobic export signals as the counterbalance to partner-mediated import, and used genetics to show E2F4/E2F5 are required specifically for pocket-protein-mediated G1 arrest rather than cycling.

    Evidence Leptomycin B, export-signal mutagenesis, CRM1 overexpression, and E2F4/E2F5 double-knockout MEFs challenged with p16INK4a

    PMID:11030352 PMID:11158323

    Open questions at the time
    • Signals that trigger export switching not fully mapped
    • Redundancy with E2F5 obscures E2F4-specific roles
  6. 2000 High

    Connected E2F4/p130 repression to the p53/p21 tumor-suppressor axis and revealed cell-autonomous developmental roles in hematopoietic, erythroid, and gut lineages.

    Evidence EMSA, reporter assays, p21 antisense, and knockout-mouse histopathology

    PMID:10983976 PMID:10983977 PMID:11032828

    Open questions at the time
    • Direct vs indirect developmental targets not separated
    • Tissue-specific cofactors undefined
  7. 2002 High

    Placed E2F4 downstream of TGF-β via a preformed cytoplasmic Smad3/E2F4/DP1/p107 complex repressing c-myc, and established in vivo genetic epistasis showing E2F4 loss suppresses Rb-deficient tumorigenesis by freeing p107/p130 to regulate activator E2Fs.

    Evidence Co-IP, fractionation, ChIP, reporter assays, and Rb+/-;E2f4-/- compound mouse tumor models

    PMID:12006580 PMID:12150994 PMID:12498715

    Open questions at the time
    • Generality of Smad-E2F coupling across TGF-β targets unclear
    • p130 phosphosite hierarchy tested in reporters not endogenous loci
  8. 2003 Medium

    Defined the chromatin-modifying machinery recruited by E2F4 repressor complexes (HDAC1, SUV39H1, DNMT1, p300) at the ER-alpha promoter and identified additional regulatory inputs through CRM1-dependent export hijacked by EBV LMP1.

    Evidence ChIP, Co-IP of multimolecular complexes, and viral oncoprotein/leptomycin B perturbation

    PMID:12789259 PMID:12860972

    Open questions at the time
    • ER-alpha complex composition from a single cell-line study
    • Direct vs cooperative recruitment of each modifier not dissected
  9. 2003 High

    Demonstrated a pocket-protein-independent, cell-cycle-independent role for E2F4 in adipocyte differentiation, separating its differentiation functions from its canonical repressor activity.

    Evidence Compound-knockout MEF differentiation and gene-expression assays

    PMID:12604789

    Open questions at the time
    • Molecular partner mediating the pocket-protein-independent function unidentified
  10. 2006 High

    Showed E2F4/p130 enforces a stable post-genotoxic G2 arrest by repressing mitotic genes and confirmed direct HCF-1 binding as a transcriptional co-activator input, while a knockout study revealed E2F4 directly activates cell cycle genes to drive fetal erythroid proliferation.

    Evidence ChIP, immunofluorescence, siRNA and clonogenic survival; GST pulldown/Co-IP for HCF-1; knockout-mouse microarray and BrdU

    PMID:16633736 PMID:16861343 PMID:17043659

    Open questions at the time
    • How E2F4 toggles between repressor and activator at the same loci unclear
    • HCF-1 study single lab
  11. 2007 High

    Defined the DREAM complex at the molecular and genome-wide level, establishing E2F4/p130 with the MuvB module as the master quiescence repressor of >800 promoters, and extended E2F4 to cell-fate decisions in airway ciliated cells and ventral telencephalon via Shh.

    Evidence Affinity-purification/MS, ChIP-chip, RNAi; Co-IP for LIN-9; knockout-mouse histology and genetic Shh epistasis with agonist rescue

    PMID:17383628 PMID:17531812 PMID:17537963 PMID:17563750

    Open questions at the time
    • Mechanism linking E2F4 to Shh transcription not fully resolved
    • Determinants of MuvB-to-MYB submodule switching incomplete
  12. 2009 High

    Linked E2F4/p130 repression to DNA repair regulation (XPC, NER) controlled by ARF disruption of the E2F4-DP1 interaction, and tied E2F4 nuclear localization in intestine to proliferation and p38 MAPK signaling.

    Evidence Co-IP, ChIP, ARF-knockout cells, NER assay; fractionation, Ki67 co-staining, p38 inhibition

    PMID:15040009 PMID:19562678 PMID:19644500

    Open questions at the time
    • How ARF accesses the E2F4-DP1 interface mechanistically undefined
    • Intestinal p38 study single lab/Medium confidence
  13. 2010 High

    Demonstrated that E2F4/p130 represses homologous-recombination genes (BRCA1, RAD51), making the complex a determinant of PARP-inhibitor cytotoxicity.

    Evidence ChIP, siRNA, HPV E7 disruption of p130, GFP-HDR assay and clonogenic survival

    PMID:20133863

    Open questions at the time
    • Signal coupling PARP inhibition to increased E2F4/p130 occupancy unresolved
  14. 2011 Medium

    Genome-wide mapping placed E2F4 at both promoters and distal enhancers and confirmed it can function as activator or repressor depending on cofactor context.

    Evidence ChIP-seq and overexpression reporter assays

    PMID:21247883

    Open questions at the time
    • Context determinants of activation vs repression not defined
    • Single-lab genome-wide dataset
  15. 2012 High

    Identified KDM5A as a cooperating repressor at E2F4 targets during ES differentiation and showed E2F4/p130-HDAC1 directly represses pro-apoptotic genes in cardiomyocytes, defining tissue-specific cytoprotective repression.

    Evidence ChIP-seq with KDM5A knockout ESCs; ChIP, E2F4-knockout mouse heart, dominant-negative HDAC1/p130 mutants, hypoxia apoptosis

    PMID:22985930 PMID:23093672

    Open questions at the time
    • Whether KDM5A and DREAM act sequentially or cooperatively unresolved
    • Cardiac target-gene generality limited
  16. 2012 High

    Showed p38MAPK phosphorylation of E2F4 at Thr261/263 converts it into a promoter-recruited driver of cell cycle reentry and apoptosis in differentiating neurons, defining a phosphorylation switch in E2F4 function.

    Evidence In vitro kinase assay, phospho-specific antibody, ChIP, phospho-mimetic/dead E2F4 mutants

    PMID:22586272

    Open questions at the time
    • Whether Thr261/263 phosphorylation operates outside neuronal context untested
  17. 2013 High

    Established that p53/p21-dependent gene repression globally requires recruitment of E2F4 repressor complexes via pocket proteins, marking E2F4 occupancy as a signature of p53-repressed targets.

    Evidence ChIP, siRNA of pocket proteins, ChIP-seq integration, reporter assays; plus MEK/ERK+GSK3 control of E2F4 nuclear entry

    PMID:23919615 PMID:24096481

    Open questions at the time
    • How p21-CDK inhibition selects specific E2F4 targets unclear
    • MEK/ERK-GSK3 study single lab/Medium confidence
  18. 2014 Medium

    Extended E2F4/p130 repression to neuroprotection through basal silencing of B-Myb, with stress-induced loss of occupancy driving neuronal death.

    Evidence ChIP, Co-IP, in vitro and in vivo ischemia models with E2F4 gain/loss-of-function

    PMID:24828495

    Open questions at the time
    • Signal triggering complex eviction from B-Myb undefined
    • Single-lab study
  19. 2017 Medium

    Defined an E2F4-RBL2-HDAC1-BRM(SWI/SNF) complex that compacts chromatin to silence PARP1 during differentiation-associated cell cycle exit, detailing the chromatin-remodeling arm of repression.

    Evidence ChIP, Co-IP, HDAC inhibitor, siRNA, chromatin-accessibility analysis

    PMID:28842672

    Open questions at the time
    • Order of HDAC vs SWI/SNF recruitment unresolved
    • Single-lab study
  20. 2018 Medium

    Identified E2F4 as a required co-activator for Multicilin-driven multiciliated-cell differentiation and centriole amplification, reinforcing an activator role in organelle biogenesis.

    Evidence Adenoviral E2F4 and E2F4-VP16 overexpression in primary fibroblasts with centriole quantification

    PMID:30120325

    Open questions at the time
    • Endogenous activator mechanism vs VP16 fusion artifact not separated
    • Single-lab gain-of-function
  21. 2019 High

    Demonstrated in RB-family-null ESCs that E2F4 directly activates cell cycle genes and increases histone acetylation at their promoters, formally establishing an RB-independent activator function.

    Evidence E2F4 knockout in RB triple-mutant ESCs with ChIP for acetylation, RNA-seq, proliferation assays

    PMID:31270324

    Open questions at the time
    • Identity of activating chromatin partners not fully resolved
    • Whether this occurs in RB-proficient cells unknown
  22. 2022 High

    Showed USP2 deubiquitinates and stabilizes E2F4, redirecting it to directly activate autophagy genes (ATG2A, ULK2) for cytoprotective autophagy in gastric cancer, linking E2F4 turnover to an activator output.

    Evidence Co-IP, GST pulldown, CHX chase/ubiquitination, ChIP, gain/loss-of-function, xenograft

    PMID:35253629

    Open questions at the time
    • E3 ligase opposing USP2 on E2F4 unidentified
    • Whether autophagy activation generalizes beyond gastric cancer untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How E2F4 is selectively switched between its dominant repressor mode and context-specific activator mode at individual loci, and which cofactors and post-translational modifications dictate that choice, remains unresolved.
  • No unified model integrating phosphorylation, ubiquitination, and cofactor identity in choosing activation vs repression
  • Activator partners largely uncharacterized relative to the well-defined repressor machinery

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2 R-HSA-73894 DNA Repair 2 R-HSA-9612973 Autophagy 1
Partners
HDAC1LIN9RB1RBL1RBL2SMAD3TFDP1USP2
Complex memberships
DREAM complexE2F4-RBL2-HDAC1-BRM(SWI/SNF) complexSmad3/E2F4/DP1/p107 complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 E2F4 associates with p107 in vivo (co-immunoprecipitation), requires DP-1 for efficient DNA binding and transcriptional activation of E2F site-containing promoters, and lacks nuclear localization signal leading to distinct subcellular distribution compared to E2F-1. Co-immunoprecipitation, transient transfection reporter assays, cell cycle analysis Genes & development High 7958924 7958925
1994 E2F4 forms heterodimers with DP family members, and p107 binding suppresses E2F4 transcriptional activity and its ability to transform immortalized rodent cells. Yeast two-hybrid, Co-IP, focus-formation/transformation assays, reporter gene assays Genes & development High 7958924 7958925
1995 E2F4 interacts with p130 in a yeast two-hybrid system and forms differentially phosphorylated complexes with p130 throughout the cell cycle; E2F4 is present throughout the cell cycle unlike E2F-1/-2/-3. Yeast two-hybrid, Co-immunoprecipitation, Western blot Genes & development High 7705662 7892279
1995 p130 effectively suppresses E2F4-mediated transactivation, and coexpression of E2F4 overcomes p130-mediated G1 arrest more efficiently than RB-induced G1 blockade, revealing biochemically distinct mechanisms for p130 versus RB in cell cycle arrest. Transient transfection, reporter assays, cell cycle analysis Genes & development High 7705662
1995 p130-E2F4 complexes occupy the cdc2 promoter at a non-canonical E2F site located at position -20 in quiescent cells (G0/G1), and release of this complex at S phase entry correlates with cdc2 induction; mutation of the -20 element de-represses cdc2 in quiescent cells. In vivo footprinting, Co-IP, transient transfection with promoter mutants Molecular and cellular biology High 8524257
1996 E2F4 switches pocket protein partners in a cell cycle-dependent manner: it is sequestered by p130 in arrested/quiescent cells but associates with both pRB and p107 as cells pass the G1-to-S transition; E2F4 accounts for the vast majority of endogenous E2F activity. Specific antisera immunoprecipitation, cell cycle fractionation, EMSA Molecular and cellular biology High 8657117
1996 During G1-to-G0 transition, p130 undergoes CDK-independent phosphorylation (form 2) that promotes p130-E2F4 complex formation characteristic of G0; subsequent CDK-mediated hyperphosphorylation (form 3) in mid-G1 dissociates E2F4 from p130. Cell cycle synchronization, Western blot, in vitro kinase assay with cyclin/CDK Oncogene High 8710362
1997 E2F4 subcellular localization is cell cycle-dependent: it is predominantly cytoplasmic when ectopically expressed, but nuclear localization is induced by cotransfection of p107, p130, or DP-2 (but not DP-1); nuclear E2F4 shows markedly enhanced transcriptional activity, and endogenous E2F4 has high nuclear/cytoplasmic ratios in G0/early G1, shifting to more cytoplasmic as cells approach S phase. Immunofluorescence, subcellular fractionation, reporter assays, cell synchronization Proceedings of the National Academy of Sciences of the United States of America High 9144196
1998 E2F4 lacks a nuclear localization signal and requires cytoplasmic binding partners (p107, pRb2/p130, or the NLS-containing DP3δ isoform) to enter the nucleus; nuclear accumulation via p107 or p130 correlates with growth arrest, whereas E2F4/DP3δ-induced cell cycle reactivation is counteracted by p107 or p130 overexpression. Immunoprecipitation, subcellular fractionation, cotransfection, cell cycle analysis Cancer research High 9537223
2000 E2F4 is actively exported from the nucleus in a CRM1-dependent manner via two hydrophobic nuclear export sequences; mutation of both export signals prevents cytoplasmic localization, and CRM1 overexpression can prevent p16INK4a-induced cell cycle arrest (an E2F4-dependent process). Leptomycin B treatment, export sequence mutagenesis, CRM1 overexpression, cell cycle analysis Molecular and cellular biology High 11158323
2000 E2F4 and E2F5 double knockout mouse embryonic fibroblasts fail to arrest in G1 in response to p16INK4a, demonstrating that E2F4 and E2F5 are dispensable for cell cycle progression per se but are necessary for pocket protein-mediated G1 arrest of cycling cells. Double knockout mouse model, MEF isolation, cell cycle analysis, p16INK4a challenge Molecular cell High 11030352
2000 Loss of E2F4 in mice causes a cell-autonomous defect in late-stage erythroid maturation and abnormalities in hematopoietic lineage development, as well as gut epithelial defects, indicating E2F4 controls the maturation of multiple cell lineages. Knockout mouse model, histopathology, bone marrow analysis Molecular cell High 10983976 10983977
2000 p130/E2F4 complex binds and represses the cdc2 promoter via the R box (positions -22 to -2) in response to p53; this repression requires p21/WAF1, which inhibits CDK activity, thereby facilitating p130 dephosphorylation and p130/E2F4 binding. Promoter reporter assays, EMSA, Co-IP, p21 antisense experiments The Journal of biological chemistry High 11032828
2002 A preformed cytoplasmic complex containing Smad3, E2F4/5, DP1, and the corepressor p107 translocates to the nucleus in response to TGF-β, associates with Smad4, and binds a composite Smad-E2F site on the c-myc promoter to repress c-myc transcription. Co-immunoprecipitation, subcellular fractionation, ChIP, reporter assays, dominant-negative experiments Cell High 12150994
2002 E2F4 loss suppresses pituitary and thyroid tumor development in Rb+/- mice and suppresses inappropriate proliferation of pRB-deficient cells; biochemical analysis indicates this occurs because E2F4 loss allows p107 and p130 to regulate the pRB-specific activator E2Fs. Compound knockout mouse model, tumor monitoring, Western blot, cell proliferation assays Cancer cell High 12498715
2002 p130 requires at least nine phosphorylation sites (three Cdk4/6-specific plus six additional serines: S413, S639, S662, S1044, S1080, S1112) for full regulation of E2F4 activity and cell cycle control; p107 regulation of E2F4 requires its three Cdk4/6-specific sites only. Alanine substitution mutagenesis, E2F reporter assays, cell cycle analysis The Journal of biological chemistry High 12006580
2003 pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 multimolecular complexes occupy the ER-alpha promoter in vivo in ER-negative breast cancer cells, mediating transcriptional repression of ER-alpha. ChIP, Co-IP, in vivo promoter occupancy analysis Oncogene Medium 12789259
2003 The p16INK4a-RB pathway is blocked by EBV LMP1 in part through CRM1-dependent nuclear export of E2F4/5, preventing E2F4/5 from mediating p16INK4a-induced cell cycle arrest. Subcellular fractionation, leptomycin B treatment, cell cycle analysis, reporter assays The Journal of cell biology High 12860972
2003 E2F4 loss in mice prevents spontaneous adipocyte differentiation independently of changes in E2F-responsive gene expression or cell cycle regulation, and this anti-adipogenic function of E2F4 operates independently of its interaction with pocket proteins. Compound knockout MEF differentiation assays, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 12604789
2004 Ionizing radiation increases E2F4 protein levels and promotes E2F4 nuclear accumulation and binding to p130 (but not p107) in prostate carcinoma cells via p130 dephosphorylation and dissociation from CDK2; siRNA knockdown of E2F4 prevents E2F4/p130 complex formation and sensitizes cells to radiation-induced apoptosis. Western blot, nuclear fractionation, Co-IP, siRNA knockdown, apoptosis assays Cancer research High 15231644
2006 E2f4 promotes fetal erythroid proliferation by directly activating cell cycle control genes; loss of E2f4 results in impaired cell cycle progression and decreased erythroid proliferation, causing macrocytic anemia. E2f4 knockout mouse model, cDNA microarray, cell cycle analysis, BrdU incorporation Blood High 16861343
2006 Following radiation treatment, E2F4 colocalizes with p130 in the nucleus during G2-phase arrest and represses mitotic genes (Bub3, Pttg1) as identified by ChIP; siRNA knockdown of E2F4 sensitizes cells to radiation-induced DNA damage and cell death. Immunofluorescence, ChIP, siRNA knockdown, microarray, clonogenic survival assay Oncogene High 17043659
2006 Host Cell Factor-1 (HCF-1) directly interacts with E2F4 via multiple determinants: E2F4 targets both the kelch domain (through its HBM tetrapeptide DHXY motif) and the basic domain of HCF-1; HCF-1 co-activates E2F4/DP-1 transcriptional activity. GST pulldown, Co-IP, mutagenesis, transient transfection reporter assays, temperature-sensitive HCF-1 rescue assay Molecular and cellular biochemistry Medium 16633736
2007 The mammalian DREAM complex contains p130 and E2F4 (along with LIN-9, LIN-37, LIN-52, LIN-54, RBBP4) and binds to more than 800 human promoters in G0 to repress cell cycle-dependent genes; in S phase, MuvB proteins dissociate from p130 and form a distinct submodule with MYB. Affinity purification/mass spectrometry, ChIP-chip, RNAi knockdown, genome-wide promoter analysis Molecular cell High 17531812
2007 Mip/LIN-9 forms a repressor complex with E2F4 and p107 or p130 in G0/early G1; phosphorylation of pocket proteins by CDK4 drives dissociation of Mip/LIN-9 from E2F4/p107/p130; expression of p107 blocks B-Myb/Mip/LIN-9-induced activation of the cyclin B promoter. Co-immunoprecipitation, reporter assays, cell cycle synchronization, CDK4 overexpression Oncogene Medium 17563750
2007 E2f4 deficiency in mice leads to complete absence of ciliated cells from the airway epithelium and nasal sinuses, replaced by columnar secretory cells, and reduced Clara cell marker expression, demonstrating a cell-cycle-independent requirement of E2f4 in determining airway epithelial cell fate. E2f4 knockout mouse model, histology, immunohistochemistry, BrdU cell proliferation analysis Developmental biology High 17383628
2007 E2F4 deficiency in mice results in loss of ventral telencephalic structures and impaired neural precursor self-renewal associated with dramatic reduction in Shh expression; genetic interaction between E2F4 and Shh pathways was confirmed by compound heterozygous crosses and Hh agonist rescue. Knockout mouse model, genetic epistasis (compound heterozygous cross), Shh enhancer reporter assay, Hh agonist rescue The Journal of neuroscience High 17537963
2008 TGF-β suppresses survivin expression in prostate epithelial cells via Smad2/3-dependent hypophosphorylation of Rb, which enables Rb/E2F4 repressor complexes to bind CDE/CHR repressor elements in the survivin promoter. Co-IP, ChIP, promoter reporter assays, viral overexpression/silencing of survivin Oncogene Medium 18504435
2009 ARF disrupts the interaction between E2F4 and DP1, reducing occupancy of the E2F4-p130 repressor complex at the XPC promoter, thereby increasing XPC expression and enabling nucleotide excision repair; cells lacking ARF are NER-deficient and ARF expression restores repair. Co-IP, ChIP, genetic ARF knockout cells, NER functional assay EMBO reports High 19644500
2009 E2F4 nuclear localization in intestinal cells is proliferation-dependent; cytoplasmic retention and sequestration by Rb proteins represent critical steps in cell cycle exit; inhibition of p38 MAP kinase induces E2F4 nuclear translocation and transcriptional activity. Subcellular fractionation, immunofluorescence, Ki67 co-staining, p38 inhibitor treatment Journal of cellular physiology Medium 15040009 19562678
2010 PARP inhibition causes increased occupancy of BRCA1 and RAD51 promoters by repressive E2F4/p130 complexes, leading to suppression of HDR; disruption of p130 by HPV E7 expression or siRNA knockdown reverses both the transcriptional repression and the cytotoxicity. ChIP, siRNA knockdown, GFP-based HDR assay, clonogenic survival Proceedings of the National Academy of Sciences of the United States of America High 20133863
2011 E2F4 binding sites are present both near transcription start sites and at distal enhancer-like elements (>20 kb from annotated TSS); overexpression of E2F4 with RB family members and DP-1 reveals that E2F4 can act as both a transcriptional activator and a repressor. ChIP-seq, overexpression studies, functional reporter assays Nucleic acids research Medium 21247883
2011 p27Kip1 directly interacts with p130 and E2F4 through its carboxy-half (demonstrated by affinity chromatography), is recruited to target promoters by p130, and is required for subsequent recruitment of HDAC and mSin3A to repress transcription. Co-IP, affinity chromatography, ChIP, luciferase reporter assays Oncogene Medium 22179826
2012 KDM5A (H3K4 demethylase) co-occupies E2F4 target gene promoters; during ES cell differentiation, KDM5A and E2F4 cooperate to repress cell cycle genes, with p130 (DREAM component) also binding these targets in terminally differentiated cells; KDM5A is recruited independently of E2F4 but cooperates with E2F4 for deepened repression. ChIP-seq, KDM5A knockout ES cells, ChIP, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 23093672
2012 E2F4-p130 repressor complex directly represses transcription of apoptosis-related genes (E2F1, Apaf-1, p73α) in cardiomyocytes through HDAC1 recruitment; loss of E2F4 in vivo leads to enhanced cardiomyocyte apoptosis; HDAC-binding deficient p130 or kinase-dead HDAC1 mutants abolish the anti-apoptotic function. ChIP, E2F4 knockout mouse histology, dominant-negative HDAC1/p130 mutants, hypoxia apoptosis assay Journal of molecular and cellular cardiology High 22985930
2012 p38MAPK phosphorylates E2F4 at Thr261/Thr263 residues in differentiating chick retinal neurons downstream of NGF/p75NTR signaling; phosphorylated E2F4 is recruited to the E2F-responsive cdc2 promoter to trigger cell cycle reentry and apoptosis; constitutively active E2F4-T261E/T263E mimics this, while dominant-negative T261A/T263A blocks NGF-induced reactivation. In vitro kinase assay, phospho-specific antibody, ChIP, constitutively active and dominant-negative E2F4 mutants, cell cycle analysis Molecular and cellular biology High 22586272
2013 p53-mediated repression of target genes (survivin, CDC25C, CDC25B) is mediated through p21-dependent recruitment of E2F4 repressor complexes to promoters; inactivation of RB pocket proteins (not RB alone) prevents E2F4 recruitment and gene repression; E2F4 promoter occupancy globally marks p53-repression targets but not p53-activation targets. ChIP, siRNA knockdown of pocket proteins, ChIP-seq integration, reporter assays Oncogene High 24096481
2013 MEK/ERK activation and GSK3 inhibition are both required for E2F4 phosphorylation, nuclear translocation, and G1/S phase entry in human intestinal epithelial cells; EGF activates ERK but fails to promote E2F4 nuclear translocation unless GSK3 is concomitantly inhibited. MEK inhibitor (U0126), GSK3 inhibitor (SB216763), phosphorylation analysis, immunofluorescence, cell cycle analysis BMC cell biology Medium 23919615
2014 E2F4 plays a protective role in neurons against ischemia/DNA damage by forming repressive complexes at the B-Myb promoter under basal conditions; following stress, E2F4-p130 complexes are lost from B-Myb promoter sites, B-Myb expression increases, and neuronal death ensues. ChIP, Co-IP, in vitro ischemia/hypoxia models, in vivo global ischemia model, E2F4 gain/loss-of-function The Journal of biological chemistry Medium 24828495
2017 E2F4-RBL2(p130)-HDAC1-BRM(SWI/SNF) repressor complex assembles at the PARP1 promoter during differentiation-associated cell cycle exit, deacetylating nucleosomes and compacting chromatin to silence PARP1; HDAC inhibition restores PARP1 expression without disrupting complex-chromatin interaction. ChIP, Co-IP, HDAC inhibitor treatment, siRNA knockdown, chromatin accessibility analysis Scientific reports Medium 28842672
2018 Multicilin transcriptional activity in multiciliated cell (MCC) differentiation requires E2F4 as a co-activator; a fusion of E2F4 with the VP16 activation domain (E2F4VP16) in combination with Multicilin is sufficient to bypass the transcriptional block in primary fibroblasts and drive massive centriole expansion via the deuterosome pathway. Adenoviral overexpression in primary MEFs, centriole expansion quantification, temporal organelle biogenesis analysis Scientific reports Medium 30120325
2019 In mouse embryonic stem cells, E2F4 acts as a transcriptional activator of cell cycle genes independently of the RB family; E2F4 functionally interacts with chromatin regulators associated with gene activation, and loss of E2F4 in RB family-mutant cells decreases histone acetylation at E2F target gene promoters. E2F4 knockout in RB family triple-mutant ESCs, ChIP for histone acetylation, RNA-seq, proliferation assays Nature communications High 31270324
2022 USP2 deubiquitinase stabilizes E2F4 protein through physical interaction and deubiquitination; stabilized E2F4 directly activates transcription of autophagy genes ATG2A and ULK2 to drive cytoprotective autophagy and zinc homeostasis in gastric cancer cells. Co-IP, GST pulldown, CHX chase/ubiquitination assays, ChIP, gain/loss-of-function studies, in vivo xenograft Autophagy High 35253629

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 399 12150994
1994 E2F-4, a new member of the E2F gene family, has oncogenic activity and associates with p107 in vivo. Genes & development 352 7958925
1994 E2F-4, a new member of the E2F transcription factor family, interacts with p107. Genes & development 345 7958924
2007 Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Molecular cell 341 17531812
1995 E2F-4 and E2F-5, two members of the E2F family, are expressed in the early phases of the cell cycle. Proceedings of the National Academy of Sciences of the United States of America 326 7892279
1996 E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry. Molecular and cellular biology 313 8657117
1995 Functional interaction between E2F-4 and p130: evidence for distinct mechanisms underlying growth suppression by different retinoblastoma protein family members. Genes & development 305 7705662
2000 E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Molecular cell 237 11030352
2010 Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proceedings of the National Academy of Sciences of the United States of America 173 20133863
2007 A comprehensive ChIP-chip analysis of E2F1, E2F4, and E2F6 in normal and tumor cells reveals interchangeable roles of E2F family members. Genome research 173 17908821
1997 The subcellular localization of E2F-4 is cell-cycle dependent. Proceedings of the National Academy of Sciences of the United States of America 171 9144196
1995 In vivo structure of the human cdc2 promoter: release of a p130-E2F-4 complex from sequences immediately upstream of the transcription initiation site coincides with induction of cdc2 expression. Molecular and cellular biology 165 8524257
2000 E2F4 is essential for normal erythrocyte maturation and neonatal viability. Molecular cell 155 10983976
2000 Loss of E2F4 activity leads to abnormal development of multiple cellular lineages. Molecular cell 137 10983977
2011 Wide-ranging functions of E2F4 in transcriptional activation and repression revealed by genome-wide analysis. Nucleic acids research 123 21247883
2000 A pure estrogen antagonist inhibits cyclin E-Cdk2 activity in MCF-7 breast cancer cells and induces accumulation of p130-E2F4 complexes characteristic of quiescence. The Journal of biological chemistry 122 10991938
1997 Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors. Cancer research 115 9192806
2003 pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 multimolecular complexes mediate the transcription of estrogen receptor-alpha in breast cancer. Oncogene 113 12789259
2002 E2F4 loss suppresses tumorigenesis in Rb mutant mice. Cancer cell 109 12498715
2019 Long non-coding RNA GAS5 inhibits DDP-resistance and tumor progression of epithelial ovarian cancer via GAS5-E2F4-PARP1-MAPK axis. Journal of experimental & clinical cancer research : CR 106 31391118
2007 Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex. Oncogene 99 17563750
2000 p130/E2F4 binds to and represses the cdc2 promoter in response to p53. The Journal of biological chemistry 93 11032828
2016 Novel functions for the transcription factor E2F4 in development and disease. Cell cycle (Georgetown, Tex.) 92 27753528
2000 Glucocorticoids inhibit developmental stage-specific osteoblast cell cycle. Dissociation of cyclin A-cyclin-dependent kinase 2 from E2F4-p130 complexes. The Journal of biological chemistry 92 10867026
2001 E2F4 is exported from the nucleus in a CRM1-dependent manner. Molecular and cellular biology 89 11158323
1996 G1 cyclin/CDK-independent phosphorylation and accumulation of p130 during the transition from G1 to G0 lead to its association with E2F-4. Oncogene 84 8710362
2003 Epstein-Barr virus LMP1 blocks p16INK4a-RB pathway by promoting nuclear export of E2F4/5. The Journal of cell biology 83 12860972
2000 E2F4 and E2F1 have similar proliferative properties but different apoptotic and oncogenic properties in vivo. Molecular and cellular biology 83 10779331
2017 MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes. Cancer letters 80 28987387
2013 p53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes. Oncogene 80 24096481
2005 Divergent siblings: E2F2 and E2F4 but not E2F1 and E2F3 induce DNA synthesis in cardiomyocytes without activation of apoptosis. Circulation research 73 15718499
2012 Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation. Proceedings of the National Academy of Sciences of the United States of America 71 23093672
2006 E2f4 regulates fetal erythropoiesis through the promotion of cellular proliferation. Blood 71 16861343
2009 E2F4 expression is required for cell cycle progression of normal intestinal crypt cells and colorectal cancer cells. Journal of cellular physiology 67 19562678
2002 Distinct phosphorylation events regulate p130- and p107-mediated repression of E2F-4. The Journal of biological chemistry 67 12006580
2011 p27Kip1 represses transcription by direct interaction with p130/E2F4 at the promoters of target genes. Oncogene 66 22179826
1997 Inhibition of E2F-4/DP-1-stimulated transcription by p202. Oncogene 65 9233764
1996 E2F-1 but not E2F-4 can overcome p16-induced G1 cell-cycle arrest. Current biology : CB 65 8723352
2008 Rb/E2F4 and Smad2/3 link survivin to TGF-beta-induced apoptosis and tumor progression. Oncogene 64 18504435
1998 Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability. Cancer research 61 9485005
1996 Mutations of E2F-4 trinucleotide repeats in colorectal cancer with microsatellite instability. Biochemical and biophysical research communications 61 8878551
2019 E2F4 regulates transcriptional activation in mouse embryonic stem cells independently of the RB family. Nature communications 60 31270324
2007 E2f4 is required for normal development of the airway epithelium. Developmental biology 56 17383628
1999 E2F4 actively promotes the initiation and maintenance of nerve growth factor-induced cell differentiation. Molecular and cellular biology 56 10454552
2022 Therapeutic targeting of the USP2-E2F4 axis inhibits autophagic machinery essential for zinc homeostasis in cancer progression. Autophagy 53 35253629
2006 E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma. Oncogene 50 17043659
2000 Opposite functions for E2F1 and E2F4 in human epidermal keratinocyte differentiation. The Journal of biological chemistry 50 11005809
2007 Cell cycle genes are the evolutionarily conserved targets of the E2F4 transcription factor. PloS one 49 17957245
2016 E2f4 and E2f5 are essential for the development of the male reproductive system. Cell cycle (Georgetown, Tex.) 48 26825228
2006 An antisense transcript induced by Wnt/beta-catenin signaling decreases E2F4. The Journal of biological chemistry 48 17121828
2018 Interplay between NRF1, E2F4 and MYC transcription factors regulating common target genes contributes to cancer development and progression. Cellular oncology (Dordrecht, Netherlands) 43 30047092
2015 Dietary myo-inositol modulates immunity through antioxidant activity and the Nrf2 and E2F4/cyclin signalling factors in the head kidney and spleen following infection of juvenile fish with Aeromonas hydrophila. Fish & shellfish immunology 42 26702562
2003 The role of E2F4 in adipogenesis is independent of its cell cycle regulatory activity. Proceedings of the National Academy of Sciences of the United States of America 42 12604789
1998 Regulation of E2F4 mitogenic activity during terminal differentiation by its heterodimerization partners for nuclear translocation. Cancer research 41 9537223
2022 Unveiling E2F4, TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multi-omics analysis. Protein & cell 38 35023014
2020 Benzo[a]pyrene represses DNA repair through altered E2F1/E2F4 function marking an early event in DNA damage-induced cellular senescence. Nucleic acids research 38 33166399
2018 Multicilin and activated E2f4 induce multiciliated cell differentiation in primary fibroblasts. Scientific reports 38 30120325
1999 Transcriptional repression of the E2F-1 gene by interferon-alpha is mediated through induction of E2F-4/pRB and E2F-4/p130 complexes. Oncogene 38 10208422
2020 LncRNA HAND2-AS1 represses cervical cancer progression by interaction with transcription factor E2F4 at the promoter of C16orf74. Journal of cellular and molecular medicine 36 32314545
2019 Overexpressing p130/E2F4 in mesenchymal stem cells facilitates the repair of injured alveolar epithelial cells in LPS-induced ARDS mice. Stem cell research & therapy 36 30841904
2016 Characterization of the promoter region of the bovine long-chain acyl-CoA synthetase 1 gene: Roles of E2F1, Sp1, KLF15, and E2F4. Scientific reports 36 26782942
2000 Genomic structure and mutation screening of the E2F4 gene in human tumors. International journal of cancer 36 10797289
2020 Long non-coding RNA LINC00337 induces autophagy and chemoresistance to cisplatin in esophageal squamous cell carcinoma cells via upregulation of TPX2 by recruiting E2F4. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 35 32239565
2018 ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research 33 29581135
2008 Transcription factor FBI-1 acts as a dual regulator in adipogenesis by coordinated regulation of cyclin-A and E2F-4. Journal of molecular medicine (Berlin, Germany) 33 18368381
2012 Nerve growth factor-induced cell cycle reentry in newborn neurons is triggered by p38MAPK-dependent E2F4 phosphorylation. Molecular and cellular biology 32 22586272
2010 Curcumin Induces Downregulation of E2F4 Expression and Apoptotic Cell Death in HCT116 Human Colon Cancer Cells; Involvement of Reactive Oxygen Species. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 32 21311680
2001 A novel tetracycline-dependent transactivator with E2F4 transcriptional activation domain. Nucleic acids research 32 11160943
2017 Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes. Scientific reports 31 28842672
2007 E2F4 function in G2: maintaining G2-arrest to prevent mitotic entry with damaged DNA. Cell cycle (Georgetown, Tex.) 31 17507799
2006 Id2 leaves the chromatin of the E2F4-p130-controlled c-myc promoter during hepatocyte priming for liver regeneration. The Biochemical journal 31 16776654
2004 Genotoxic stress induces expression of E2F4, leading to its association with p130 in prostate carcinoma cells. Cancer research 30 15231644
2018 Distinct requirements of E2f4 versus E2f5 activity for multiciliated cell development in the zebrafish embryo. Developmental biology 29 30218642
2004 The nucleocytoplasmic shuttling of E2F4 is involved in the regulation of human intestinal epithelial cell proliferation and differentiation. Journal of cellular physiology 29 15040009
2021 E2F4 Promotes the Proliferation of Hepatocellular Carcinoma Cells through Upregulation of CDCA3. Journal of Cancer 28 34335934
2009 ARF stimulates XPC to trigger nucleotide excision repair by regulating the repressor complex of E2F4. EMBO reports 28 19644500
2009 E2F4 is required for cardiomyocyte proliferation. Cardiovascular research 28 19955219
2006 Host cell factor-1 and E2F4 interact via multiple determinants in each protein. Molecular and cellular biochemistry 28 16633736
2004 E2F4 deficiency promotes drug-induced apoptosis. Cancer biology & therapy 28 15611646
2017 Dietary myo-inositol deficiency decreased the growth performances and impaired intestinal physical barrier function partly relating to nrf2, jnk, e2f4 and mlck signaling in young grass carp (Ctenopharyngodon idella). Fish & shellfish immunology 27 28610850
2012 Anti-apoptotic function of the E2F transcription factor 4 (E2F4)/p130, a member of retinoblastoma gene family in cardiac myocytes. Journal of molecular and cellular cardiology 27 22985930
2003 N-Acetylcysteine enhances UV-mediated caspase-3 activation, fragmentation of E2F-4, and apoptosis in human C8161 melanoma: inhibition by ectopic Bcl-2 expression. Biochemical pharmacology 27 12754095
1999 Herpes simplex virus induces intracellular redistribution of E2F4 and accumulation of E2F pocket protein complexes. Virology 27 10366563
2007 Cell cycle regulator E2F4 is essential for the development of the ventral telencephalon. The Journal of neuroscience : the official journal of the Society for Neuroscience 26 17537963
2001 Expression of E2F-1 and E2F-4 is reduced in primary and metastatic breast carcinomas. Breast cancer research and treatment 26 11759817
2020 E2F4 functions as a tumour suppressor in acute myeloid leukaemia via inhibition of the MAPK signalling pathway by binding to EZH2. Journal of cellular and molecular medicine 25 31943751
2009 E2F4 and ribonucleotide reductase mediate S-phase arrest in colon cancer cells treated with chlorophyllin. International journal of cancer 25 19585502
2014 Regulation of ischemic neuronal death by E2F4-p130 protein complexes. The Journal of biological chemistry 24 24828495
2002 Physical and functional interaction of HIV-1 Tat with E2F-4, a transcriptional regulator of mammalian cell cycle. The Journal of biological chemistry 24 12055184
2019 Amino Acid Deprivation-Induced Autophagy Requires Upregulation of DIRAS3 through Reduction of E2F1 and E2F4 Transcriptional Repression. Cancers 23 31052266
2003 Stimulation of bovine herpesvirus-1 productive infection by the adenovirus E1A gene and a cell cycle regulatory gene, E2F-4. The Journal of general virology 23 12655094
2002 Differences in DNA binding properties between E2F1 and E2F4 specify repression of the Mcl-1 promoter. Oncogene 22 11896585
2005 Cell cycle-related transformation of the E2F4-p130 repressor complex. Biochemical and biophysical research communications 19 16153605
2015 E2F4 Program Is Predictive of Progression and Intravesical Immunotherapy Efficacy in Bladder Cancer. Molecular cancer research : MCR 18 26032289
2000 Microsatellite instability and alteration of E2F-4 gene in adenosquamous and squamous cell carcinomas of the stomach. Pathology international 18 11012981
2021 E2F4-induced AGAP2-AS1 up-regulation accelerates the progression of colorectal cancer via miR-182-5p/CFL1 axis. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 17 34838479
1997 The predominant E2F complex in human primary haemopoietic cells and in AML blasts contains E2F-4, DP-1 and p130. British journal of haematology 17 9074408
2013 ERK-associated changes in E2F4 phosphorylation, localization and transcriptional activity during mitogenic stimulation in human intestinal epithelial crypt cells. BMC cell biology 16 23919615
2006 Necdin and E2F4 are modulated by rosiglitazone therapy in diabetic human adipose and muscle tissue. Diabetes 16 16505226
2002 Expression of E2F-4 gene in colorectal adenocarcinoma and corresponding covering mucosa: an immunohistochemistry, image analysis, and immunoblot study. Applied immunohistochemistry & molecular morphology : AIMM 16 12373148

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