Affinage

E2F1

Transcription factor E2F1 · UniProt Q01094

Round 2 corrected
Length
437 aa
Mass
46.9 kDa
Annotated
2026-04-28
130 papers in source corpus 58 papers cited in narrative 53 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

E2F1 is a master transcription factor that integrates cell-cycle progression, apoptosis, DNA repair, autophagy, and metabolic homeostasis by activating or repressing hundreds of target genes in a context-dependent manner. It heterodimerizes with DP1 via heptad repeat domains, binds E2F consensus sequences in promoters of S-phase genes (cyclin E, PCNA, DHFR), DNA repair genes, autophagy genes (LC3, ATG1, DRAM), and metabolic genes (Fasn, PCSK9, Kir6.2, gluconeogenic targets), and is held in an inactive/repressive state by direct pRB binding, which recruits HDAC1 and DNMT1 to silence target loci; sequential CDK4/6- then CDK2-mediated pRB phosphorylation releases E2F1 to activate transcription (PMID:1638635, PMID:8449399, PMID:10499802, PMID:9468139, PMID:10888886). E2F1 protein stability and target-gene specificity are tuned by a network of post-translational modifications—acetylation by P/CAF (activating), deacetylation by HDAC1 and SIRT1 (repressing), ATR-mediated Ser31 phosphorylation (stabilizing and recruiting E2F1 to DNA damage sites for nucleotide excision repair), Set9-mediated K185 methylation coupled with L3MBTL3–CRL4^DCAF5 ubiquitin-dependent degradation (counteracted by LSD1 demethylation), NEDDylation (shifting specificity toward pro-apoptotic targets such as p73), and SUMOylation (enhancing EZH2 promoter occupancy) (PMID:10675335, PMID:24741006, PMID:20603083, PMID:29691401, PMID:23001041, PMID:32816857). E2F1-null mice exhibit defective thymocyte apoptosis and age-dependent aberrant proliferation, and tissue-specific E2F1 loss protects against hepatic steatosis, hypercholesterolemia, and impaired glucose homeostasis, underscoring non-redundant roles for E2F1 in both tumor suppression and systemic metabolism (PMID:8653790, PMID:26619117, PMID:28515357, PMID:29526568).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1992 High

    Cloning of E2F1 as a pRB-binding transcription factor established the direct molecular link between the retinoblastoma tumor suppressor and the E2F transcriptional program that drives cell proliferation.

    Evidence Expression library screening with GST-RB, in vitro/in vivo binding, transcription assays in multiple independent labs

    PMID:1411535 PMID:1531329 PMID:1638634 PMID:1638635

    Open questions at the time
    • No knowledge of which endogenous genes E2F1 regulates beyond viral promoters
    • Mechanism of pRB-mediated repression unknown beyond simple occlusion
  2. 1993 High

    Demonstration that cyclin D–CDK4 phosphorylates pRB to release E2F1 provided the enzymatic mechanism connecting mitogenic signaling to E2F1 activation.

    Evidence In vitro kinase assay with baculovirus-expressed cyclin D/CDK4, co-immunoprecipitation, phosphorylation site mapping

    PMID:8449399

    Open questions at the time
    • Whether CDK2 plays a sequential role was not yet defined
    • Phosphorylation site specificity on pRB not fully mapped
  3. 1994 High

    Identification of the E2F1–DP1 heterodimer and the finding that E2F1 cooperates with p53 for apoptosis and with Ras for oncogenic transformation defined E2F1's dual role as both a proliferative and pro-apoptotic/oncogenic factor.

    Evidence Yeast two-hybrid, co-IP domain mapping (heptad repeats), focus formation assay, nude mouse xenograft, temperature-sensitive p53 cell system

    PMID:7809128 PMID:8170954 PMID:8207796

    Open questions at the time
    • How the cell decides between E2F1-driven proliferation versus apoptosis was unknown
    • Identity of endogenous E2F1 target genes in these programs not established
  4. 1996 High

    E2F1 knockout mice revealed an essential non-redundant role in thymocyte apoptosis and tumor suppression, proving that E2F1 restrains proliferation in vivo rather than solely promoting it.

    Evidence Germline E2F1 knockout mouse, FACS, histology

    PMID:8653790

    Open questions at the time
    • Molecular mechanism of E2F1-dependent apoptosis in thymocytes not identified
    • Whether other E2F family members compensate for proliferative functions unclear
  5. 1998 High

    Discovery that Rb recruits HDAC1 to E2F-responsive promoters and that TRRAP cofactor is required for E2F1 transactivation established active chromatin remodeling as the mechanism underlying both E2F1 repression and activation.

    Evidence Co-IP, in vitro binding, TSA-sensitive chromosomally integrated reporter, transdominant TRRAP mutants and transformation assays

    PMID:9468139 PMID:9468140 PMID:9708738

    Open questions at the time
    • Full composition of the Rb–HDAC repressive complex at E2F targets not known
    • Whether TRRAP recruits HAT activity to E2F1 targets was not yet shown
  6. 1999 High

    Sequential CDK4/6→CDK2 phosphorylation model for pRB inactivation explained how the G1/S switch is implemented in two discrete steps: HDAC displacement followed by E2F1 release.

    Evidence In vitro kinase assays with domain mutants, intramolecular interaction mapping, cell-based assays

    PMID:10499802

    Open questions at the time
    • In vivo validation of sequential model in physiological cell cycle not performed
    • Whether mono-phosphorylated pRB retains other repressive functions on E2F1 targets unknown
  7. 2000 High

    Identification of P/CAF-mediated acetylation as an activating PTM on E2F1 and DNMT1 as an Rb–E2F1 complex component added epigenetic regulatory layers (histone acetylation and DNA methylation) to E2F1-dependent transcription.

    Evidence In vitro acetylation, mutagenesis, protein stability assays; co-purification of DNMT1–Rb–E2F1–HDAC1 complex with promoter repression assays

    PMID:10675335 PMID:10888886

    Open questions at the time
    • Specific acetylation sites on E2F1 identified but physiological acetylation dynamics during cell cycle not resolved
    • Whether DNMT1-mediated methylation at E2F targets is stable or reversible unclear
  8. 2002 High

    Genome-wide ChIP-chip revealed ~127 E2F1-bound promoters spanning DNA repair, checkpoint, and chromatin assembly genes, vastly expanding the E2F1 regulon beyond classical S-phase targets.

    Evidence ChIP coupled with DNA microarray in synchronized cells; validated in E2F1-null mice with non-consensus site identification

    PMID:11799067 PMID:11904439

    Open questions at the time
    • Functional consequence of E2F1 binding at many newly identified targets not individually tested
    • E2F1-specific versus shared E2F-family binding not fully resolved
  9. 2005 High

    Discovery that c-Myc–induced miR-17-5p/miR-20a post-transcriptionally represses E2F1 revealed a feedback circuit that fine-tunes E2F1 protein levels independently of pRB.

    Evidence c-Myc ChIP at miR-17-92 locus, luciferase reporter with miRNA target sites, Western blot

    PMID:15944709

    Open questions at the time
    • Physiological importance of miRNA-mediated E2F1 regulation in specific tissues not assessed
    • Whether other miRNAs similarly target E2F1 not systematically explored
  10. 2008 High

    E2F1 was shown to directly activate autophagy genes (LC3, ATG1, DRAM) and to antagonize β-catenin/TCF signaling (relieved by CDK8 phosphorylation), broadening E2F1 function beyond cell cycle into autophagy and Wnt pathway cross-talk.

    Evidence ChIP at autophagy gene promoters, autophagy flux measurement, siRNA; genetic epistasis and Drosophila model for β-catenin axis

    PMID:18408756 PMID:18794899

    Open questions at the time
    • Whether E2F1-driven autophagy is pro-survival or pro-death in specific contexts unresolved
    • CDK8 phosphorylation site on E2F1 was mapped later (Ser375)
  11. 2010 High

    Identification of Set9 methylation at K185 (destabilizing, coupled to ubiquitination) and LSD1 demethylation (stabilizing) established lysine methylation as a degradation signal for E2F1 and revealed cross-talk between methylation, acetylation, and phosphorylation PTMs.

    Evidence In vitro methylation assay, site-directed mutagenesis (K185R), ubiquitination assay, apoptosis readout

    PMID:20603083

    Open questions at the time
    • E3 ubiquitin ligase recognizing methylated E2F1 not identified at this point
    • Cell-cycle dynamics of K185 methylation not measured
  12. 2011 High

    DNA damage generates two mutually exclusive PTM-defined pools of E2F1—phospho-Ser364/pRB-bound and phospho-Ser31/acetylated/pRB-free—both required at pro-apoptotic promoters, explaining how E2F1 integrates damage signaling into the apoptotic decision.

    Evidence Phospho-specific antibodies, co-IP, ChIP at apoptotic gene promoters, mutagenesis, apoptosis assay

    PMID:22184068

    Open questions at the time
    • Kinases responsible for Ser364 phosphorylation in the damage context not fully resolved (MK2 later implicated)
    • How the two E2F1 pools cooperate at the same promoter mechanistically unclear
  13. 2014 High

    ATR-mediated Ser31 phosphorylation was shown in knock-in mice (S29A) to be essential for E2F1 recruitment to UV damage sites and nucleotide excision repair, directly linking E2F1 to DNA repair beyond transcription.

    Evidence Knock-in S29A mouse model, DNA repair assays, UV carcinogenesis model, ChIP at damage sites

    PMID:24741006

    Open questions at the time
    • Whether E2F1 functions at damage sites through transcription-independent mechanisms or via local transcription activation not distinguished
    • Repair role in double-strand break repair not addressed
  14. 2015 High

    ChIP-Seq in hepatocytes and metabolic phenotyping of E2f1 KO mice established E2F1 as a direct transcriptional regulator of lipogenesis (Fasn), gluconeogenesis, and cholesterol metabolism (PCSK9, Kir6.2), positioning the CDK4/pRB/E2F1 axis as a central metabolic node.

    Evidence ChIP-Seq, E2f1 KO mice in NAFLD and diabetes models, insulin secretion and LDL uptake assays

    PMID:19597485 PMID:26619117 PMID:28515357 PMID:29526568

    Open questions at the time
    • Tissue-specific transcriptional programs of E2F1 in adipose and muscle not systematically profiled
    • Whether metabolic E2F1 targets overlap or are distinct from proliferative targets genome-wide not fully resolved
  15. 2018 High

    The methylation-dependent E2F1 degradation pathway was completed: L3MBTL3 recognizes methylated E2F1 and recruits CRL4^DCAF5 E3 ligase for proteasomal degradation, while LSD1 demethylation protects E2F1—closing the gap from the 2010 Set9/LSD1 discovery.

    Evidence In vitro methylation and ubiquitination reconstitution, L3MBTL3 binding assay, L3MBTL3 KO mouse

    PMID:29691401

    Open questions at the time
    • Whether this degradation pathway operates at specific cell-cycle phases or in response to specific signals not determined
    • Relative contribution of L3MBTL3–CRL4 versus APC/C–Cdc20 versus SCF-mediated pathways to total E2F1 turnover unknown
  16. 2020 Medium

    SUMOylation was shown to enhance E2F1 occupancy at the EZH2 promoter, linking SUMO modification to epigenetic reprogramming through the E2F1–EZH2–H3K27me3 axis.

    Evidence ChIP with SAE2 siRNA and SUMO inhibitor treatment, reporter assays

    PMID:32816857

    Open questions at the time
    • SUMOylation sites on E2F1 not mapped
    • Whether SUMOylation affects E2F1 binding at other loci or is EZH2-specific not tested
    • Independent replication needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the combinatorial PTM code on E2F1 (phosphorylation, acetylation, methylation, NEDDylation, SUMOylation) is read in real time to select specific target-gene programs (proliferation vs. apoptosis vs. metabolism vs. DNA repair) remains an open question.
  • No structural model of E2F1 with PTMs resolved
  • Single-cell-level dynamics of E2F1 PTM switching not measured
  • Systematic mapping of PTM-dependent interactome changes lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 7
Localization
GO:0005634 nucleus 4 GO:0005730 nucleolus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-1640170 Cell Cycle 6 R-HSA-5357801 Programmed Cell Death 5 R-HSA-4839726 Chromatin organization 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 2 R-HSA-9612973 Autophagy 2
Partners
CDK5HDAC1KAP1PCAFRB1SIRT1TFDP1TRRAP
Complex memberships
E2F1–DP1 heterodimerPontin/Reptin chromatin-remodeling complex (E2F1-recruited)Rb–E2F1–HDAC1–DNMT1 repressive complex

Evidence

Reading pass · 53 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 E2F1 (RBAP-1/RBP3) was cloned as a protein that directly binds the retinoblastoma protein (pRB) pocket domain, binds E2F DNA recognition sequences, and transactivates the adenovirus E2 promoter; pRB interaction inhibits E2F1 transcriptional activity. Expression library screening with GST-RB fusion protein, in vitro and in vivo binding assays, transcription assays Cell / Genes & development High 1411535 1531329 1638634 1638635
1993 Cyclin D–CDK4 complexes phosphorylate pRB, causing its dissociation from E2F1 and thereby releasing E2F1 to activate transcription. In vitro kinase assay with baculovirus-expressed proteins, co-immunoprecipitation, pRB phosphorylation site mapping Genes & development High 8449399
1994 E2F1 forms a heterodimer with DP1 via hydrophobic heptad repeat domains (E2F1 aa 206–283 interacts with DP1 aa 196–245); the adenovirus E4 protein interacts with the DP1 subunit of this heterodimer to stabilize the complex on the E2 promoter. Yeast two-hybrid assay, co-transfection/co-immunoprecipitation in SAOS-2 cells, domain deletion mapping Journal of virology High 8207796
1994 E2F1, particularly in combination with DP1, cooperates with activated Ras to transform primary rat embryo fibroblasts and induce tumor formation in nude mice, demonstrating oncogenic capacity when deregulated. Focus formation assay, soft agar colony formation, nude mouse xenograft Proceedings of the National Academy of Sciences of the United States of America High 7809128
1994 Wild-type p53 cooperates with E2F1 to induce rapid apoptosis; coexpression of E2F1 with wild-type p53 (but not mutant p53) causes cell death, linking the Rb-E2F1 and p53 pathways. Temperature-sensitive p53 cell line, transfection, cell viability assay Proceedings of the National Academy of Sciences of the United States of America High 8170954
1994 Mouse E2F1 mRNA levels are cell-cycle regulated and correlate with transcriptional activation of growth-regulated promoters (dhfr, thymidine kinase, DNA polymerase alpha) but not others (thymidylate synthase, c-myc), indicating promoter selectivity. Cloning, Northern blot, promoter-reporter transfection assay, cell-cycle synchronization Molecular and cellular biology Medium 8114719
1995 E2F1 directly activates cyclin E gene transcription through E2F binding sites in the cyclin E promoter, establishing a positive feedback loop that drives G1/S progression. Adenovirus-mediated E2F1 overexpression, promoter-reporter assay, endogenous cyclin E mRNA measurement Proceedings of the National Academy of Sciences of the United States of America High 8618861
1996 E2F1 knockout mice develop normally but exhibit a stage-specific defect in thymocyte apoptosis (excess mature T cells) and, with age, aberrant cell proliferation, demonstrating in vivo roles for E2F1 in apoptosis and proliferation suppression. Germline knockout mouse, FACS, histology Cell High 8653790
1996 The human E2F1 gene contains seven exons and maps to chromosome 20q11; structural characterization reveals splice sites and regulatory elements governing cell-cycle-dependent mRNA accumulation. Genomic cloning, FISH, sequencing Gene Medium 8964493
1998 Rb recruits HDAC1 to E2F-responsive promoters through its pocket domain; Rb–HDAC1 complex represses E2F1-dependent transcription (e.g., cyclin E), and inhibition of deacetylase activity with TSA relieves this repression. Co-immunoprecipitation, in vitro binding, chromosomally integrated reporter assay, TSA treatment Nature High 9468139 9468140
1998 TRRAP (an ATM-related protein) directly interacts with the E2F1 transactivation domain and is required for E2F1- and c-Myc-mediated oncogenic transformation. Co-immunoprecipitation, transdominant mutants, antisense RNA, transformation assay Cell High 9708738
1999 Sequential Cdk4/6-initiated and Cdk2-mediated phosphorylation of pRB progressively disrupts pRB pocket structure: initial Cdk4/6 phosphorylation at the C-terminal region displaces HDAC, and subsequent Cdk2 phosphorylation of the pocket disrupts E2F1 binding near the G1/S boundary. In vitro kinase assay, intramolecular interaction mapping, transfection Cell High 10499802
2000 DNMT1 co-purifies with Rb, E2F1, and HDAC1 and cooperates with Rb to repress transcription from E2F-binding-site-containing promoters, linking DNA methylation with the Rb-E2F1 repressive complex. Co-purification, co-immunoprecipitation, promoter-reporter repression assay Nature genetics High 10888886
2000 P/CAF (and to a lesser extent p300/CBP) acetylates E2F1 in vitro and in vivo at lysine residues adjacent to the DNA-binding domain; acetylation increases E2F1 DNA-binding ability, transcriptional activation, and protein half-life, while the Rb-associated HDAC can reverse this modification. In vitro acetylation assay, intracellular acetylation detection, reporter assay, protein stability measurement The EMBO journal High 10675335
2000 Overexpression of E2F1 alone in post-mitotic cortical neurons is sufficient to induce apoptosis (caspase-3 activation, DNA fragmentation); neurons from E2F1−/− mice are resistant to staurosporine-induced apoptosis. Adenoviral overexpression, caspase-3 activity assay, DNA fragmentation, E2F1 KO neurons Journal of neurochemistry High 10854251
2001 ARF physically interacts with E2F1 and inhibits its transcriptional activity in a manner requiring MDM2; ARF also relocalizes free E2F1 to the nucleolus and promotes its proteolysis, but the E2F1/DP1 heterodimer is refractory to these effects. Co-immunoprecipitation, reporter assay, immunofluorescence, siRNA/overexpression Oncogene / Molecular and cellular biology High 11314038 12446760
2002 Genome-wide ChIP reveals that E2F1 (along with E2F4) binds promoters of ~127 genes expressed during cell cycle entry, including genes for DNA repair, checkpoint control, chromatin assembly, and the mitotic spindle, greatly expanding the known E2F1 target gene network. Chromatin immunoprecipitation coupled with DNA microarray (ChIP-chip) Genes & development High 11799067
2002 ChIP analysis in E2F1-null mice identified E2F1-specific target gene promoters that contain a non-consensus E2F binding element selectively occupied by E2F1 but not other E2F family members in asynchronously growing cells. Oligonucleotide microarray on E2F1 KO mice, ChIP Proceedings of the National Academy of Sciences of the United States of America High 11904439
2003 Rb mediates senescence-associated heterochromatic foci (SAHF) formation and stable repression of E2F1 target genes (e.g., cyclin A, PCNA) by recruiting heterochromatin proteins to E2F-responsive promoters during cellular senescence. Immunofluorescence, ChIP, Rb pathway perturbation Cell High 12809602
2005 c-Myc transcriptionally activates the miR-17-92 cluster; miR-17-5p and miR-20a within this cluster post-transcriptionally repress E2F1 translation, forming a regulatory circuit where c-Myc simultaneously activates E2F1 transcription and limits its translation. Chromatin immunoprecipitation (c-Myc binding), luciferase reporter with miRNA target sites, Western blot Nature High 15944709
2005 The Dnmt-1 promoter contains conserved E2F consensus binding sites; it is regulated by the pRb/E2F pathway, and in Rb−/− cells Dnmt-1 expression is aberrantly elevated and cell-cycle regulation of Dnmt-1 is lost. Promoter analysis, reporter assay, ChIP, Rb−/− cell lines Cancer research Medium 15867357
2006 E2F1 induces SirT1 expression at the transcriptional level; SirT1 in turn binds to and deacetylates E2F1, inhibiting its transcriptional and apoptotic functions, forming a negative feedback loop that modulates cellular sensitivity to DNA damage. Reporter assay, co-immunoprecipitation, siRNA knockdown, apoptosis assay Nature cell biology High 16892051
2007 KAP1 corepressor binds E2F1 independently of pRb, stimulates formation of the E2F1–HDAC1 complex, inhibits E2F1 acetylation, and represses E2F1 transcriptional and apoptotic functions; KAP1 depletion in pRb-deficient cells increases E2F1 acetylation and sensitizes cells to DNA damage-induced apoptosis. Co-immunoprecipitation, acetylation assay, reporter assay, siRNA knockdown The Journal of biological chemistry High 17704056
2008 E2F1 directly activates transcription of autophagy genes LC3, ATG1, and DRAM (binding confirmed by ChIP at their promoters), and E2F1 activation enhances autophagy; reducing endogenous E2F1 inhibits DNA damage-induced autophagy. ChIP, reporter assay, autophagy flux measurement, siRNA knockdown Oncogene High 18408756
2008 E2F1 potently inhibits beta-catenin/TCF-dependent transcription independently of APC/GSK3, contributing to E2F1-induced apoptosis; CDK8 phosphorylates E2F1 to relieve this repression and protect beta-catenin activity in colorectal cancer cells. Reporter assay, siRNA, genetic epistasis, Drosophila model Nature High 18794899
2009 CDK4-pRB-E2F1 pathway directly regulates Kir6.2 (K_ATP channel subunit) expression in pancreatic beta cells; E2F1 binds the Kir6.2 promoter in vivo (by ChIP from tissue), and E2F1 deficiency impairs insulin secretion and causes glucose intolerance reversed by Kir6.2 re-expression. ChIP from tissue, genetic KO, adenoviral rescue, glucose tolerance test, insulin secretion assay Nature cell biology High 19597485
2009 E2F1 induces EZH2 expression, which in turn suppresses the E2F1 pro-apoptotic target Bim via histone methylation, constituting a fail-safe mechanism that dampens E2F1-dependent apoptosis in tumors. siRNA, reporter assay, ChIP, apoptosis assay Cell death and differentiation Medium 19893569
2010 Cdk5 (bound to p35, but not requiring kinase activity) forms a complex with E2F1 that excludes the DP1 cofactor, thereby preventing E2F1 binding to cell-cycle gene promoters and suppressing neuronal cell cycle re-entry. Co-immunoprecipitation, ChIP, kinase-dead mutant, p35/p39/p25 substitution experiments The Journal of neuroscience High 20392944
2010 Set9 methyltransferase methylates E2F1 at lysine-185, preventing its accumulation and pro-apoptotic activity (p73 induction) during DNA damage; LSD1 demethylase removes this mark to stabilize E2F1. Methylation at K185 inhibits distant acetylation and phosphorylation while stimulating ubiquitination and degradation. In vitro methylation assay, site-directed mutagenesis, ubiquitination assay, apoptosis assay Molecular cell High 20603083
2010 APC/C(Cdc20) ubiquitylates E2F1 and targets it for proteasomal degradation in prometaphase; DP1 co-expression protects E2F1 from this degradation, revealing a novel cell-cycle mechanism for controlling free E2F1 levels. Ectopic expression of Cdh1/Cdc20, siRNA Cdc20 knockdown, cell synchronization, stability assay Cell cycle Medium 20948288
2010 RB binding to E2F is required for autophagy induction; E2F1 antagonizes RB-induced autophagy, driving apoptosis instead. Downregulation of E2F1 results in high levels of autophagy. siRNA, autophagy marker assay, Rb mutant constructs Cancer research Medium 20807803
2011 DNA damage creates two mutually exclusive populations of E2F1 distinguished by post-translational modification: phospho-Ser364 E2F1 (found in complex with pRB) and phospho-Ser31/acetylated E2F1 (pRB-free). Both populations are present at pro-apoptotic gene promoters and both are required for maximal apoptosis induction. Phospho-specific antibodies, co-immunoprecipitation, ChIP, mutagenesis, apoptosis assay Molecular and cellular biology High 22184068
2011 E2F1 (but not E2F2 or E2F3) mediates an ATM-dependent DNA damage response during HCMV infection, promoting gamma-H2AX accumulation and being required for efficient viral replication. siRNA knockdown (E2F1/2/3 specifically), gamma-H2AX assay, viral titer measurement PLoS pathogens Medium 21589897
2012 CDK8 phosphorylates E2F1 at serine 375 in vitro and in cells; this phosphorylation is required for E2F1 interaction with CDK8 and inactivates E2F1 transcriptional activation without affecting its DNA binding or DP1 interaction, thereby relieving beta-catenin/TCF repression by E2F1. In vitro kinase assay, site-directed mutagenesis (S375A), reporter assay, co-immunoprecipitation Oncogene High 22945643
2012 NEDDylation of E2F1 suppresses its transactivation of pro-apoptotic target p73 (but not proliferative target E2F2); deNEDDylation by SENP8 switches E2F1 specificity toward apoptotic targets by promoting interaction with the cofactor Microcephalin 1. NEDD8 conjugation assay, SENP8 overexpression/knockdown, reporter assay, co-immunoprecipitation Oncogene Medium 23001041
2012 Rb selectively represses a subset of E2F1 target genes during senescence through a novel TAAC DNA element present in senescence-inhibited promoters (PCNA, CCNA2); this element is required for Rb recruitment but not for E2F1 protein binding. Promoter sequence comparison, ChIP, mutagenesis of TAAC element, reporter assay The Journal of biological chemistry Medium 22955272
2014 E2F1 directly activates miR-224/miR-452 cluster (through GABRE gene transactivation), which targets the metastasis suppressor TXNIP. TXNIP normally provides feedback inhibition of E2F1; the E2F1–miR-224/452–TXNIP axis drives EMT and invasion in melanoma. ChIP, reporter assay, miRNA overexpression/knockdown, in vivo metastasis model EMBO reports High 25341426
2014 In response to UV radiation, ATR kinase phosphorylates E2F1 at serine 29 (mouse; Ser31 in human), stabilizing E2F1 and recruiting it to sites of DNA damage to directly stimulate nucleotide excision repair; knock-in S29A mice show impaired DNA repair and increased UV-induced carcinogenesis. Knock-in mouse model (S29A), DNA repair assay, UV carcinogenesis model, ChIP at damage sites Cancer research High 24741006
2014 p38 MAPK–MK2 axis regulates E2F1 induction by epirubicin; MK2 directly phosphorylates E2F1 at Ser-364 in vitro, and this phosphorylation contributes to E2F1 induction and subsequent FOXM1 expression driving drug resistance. In vitro phosphorylation assay, pharmacologic inhibitors, siRNA, KO MEFs Molecular cancer research Medium 22802261
2015 POH1 deubiquitylase binds to and deubiquitylates E2F1, stabilizing the protein and enhancing downstream pro-survival signaling (Survivin, FOXM1); conditional Poh1 KO reduces E2F1 expression in primary liver cells. Co-immunoprecipitation, in vivo ubiquitination assay, conditional KO mouse, tumor xenograft Nature communications High 26510456
2015 E2F1 directly binds promoters of key lipogenic genes (including Fasn) and regulates glycolysis and de novo fatty acid synthesis in hepatocytes via the CDK4/pRB pathway; E2f1 deletion abrogates hepatic steatosis in NAFLD mouse models. ChIP-Seq, E2f1 KO mouse, insulin stimulation experiments, lipogenesis assay The Journal of clinical investigation High 26619117
2015 Accumulating E2F1 during Rb-family inactivation progressively recruits a Pontin/Reptin chromatin-remodeling complex to E2F target gene loci, opening chromatin and amplifying the E2f transcriptional response including activation of Warburg-effect genes. ChIP, co-immunoprecipitation, mouse liver cancer model Nature communications Medium 26639898
2015 Cezanne deubiquitylase regulates E2F1 protein stability; E2F1 directly binds the HIF2α (EPAS1) promoter and transactivates it, so Cezanne controls HIF2α expression through E2F1 stabilization. siRNA knockdown, reporter assay, co-immunoprecipitation, E2F1 rescue experiment Journal of cell science Medium 26148512
2015 E2F1 downregulation during ER stress is mediated by two UPR sensors: ATF6 directly interacts with the E2F1 promoter to suppress it, while IRE1 acts through E2F7 and Xbp-1; E2F1 decline is required for ER stress-induced apoptosis. Reporter assay, ChIP (ATF6 at E2F1 promoter), siRNA, apoptosis assay Journal of cell science Medium 25616897
2017 E2F1 directly binds and transactivates the PCSK9 promoter (confirmed by ChIP-Seq and reporter assay); E2f1 deletion reduces PCSK9 expression and increases LDLR-mediated LDL uptake in hepatocytes, linking E2F1 to cholesterol homeostasis. ChIP-Seq, promoter reporter assay, E2f1 KO mouse, LDL uptake assay JCI insight High 28515357
2017 PI3Kδ activation in response to mRNA translation stress (triggered by EBV EBNA1) induces E2F1 mRNA translation, leading to c-Myc activation and cell proliferation; PI3Kδ inhibition (Idelalisib) suppresses this E2F1 induction. PI3Kδ inhibitor treatment, polysome profiling, siRNA, cell proliferation assay Nature communications Medium 29235459
2017 RB loss (as opposed to functional RB inactivation) causes E2F1 cistrome expansion and altered DNA-binding specificity, activating protumorigenic transcriptional networks distinct from those produced by RB inactivation. ChIP-Seq in patient-derived and cell line models, cell-free DNA analysis from patients The Journal of clinical investigation High 29202480
2018 Methylated E2F1 (at a conserved methylation motif) is bound by L3MBTL3, which recruits CRL4DCAF5 ubiquitin ligase to degrade E2F1; LSD1 demethylase prevents this degradation, establishing methylation-dependent proteolysis as a regulatory mechanism. In vitro methylation, ubiquitination assay, L3MBTL3 binding assay, mouse L3MBTL3 KO Nature communications High 29691401
2018 SET/I2PP2A suppresses PP2A-B56 activity; PP2A-B56 subunit interacts with E2F1 to reduce its protein levels; SET knockdown decreases E2F1 and suppresses cancer cell stemness, establishing a SET/PP2A/E2F1 axis. Co-immunoprecipitation, pharmacologic PP2A activation (OP449), Western blot, stemness assays Molecular cancer research Medium 29330298
2018 E2F1 promotes hepatic gluconeogenesis via direct transcriptional regulation through the CDK4-RB1-E2F1 pathway; E2f1 deletion or pharmacological inhibition improves glucose homeostasis in diabetic mouse models. Primary hepatocyte E2F1 overexpression/KO, pyruvate tolerance test, genetic mouse models of diabetes Molecular metabolism High 29526568
2018 PTEN (phosphorylation-deficient PTEN-4A) localizes to the nucleus where it physically interacts with E2F1 (via its C2 domain) and associates with E2F1-bound chromatin to suppress E2F1-mediated transcription of cell cycle genes. Co-immunoprecipitation, ChIP, deletion mutants, nuclear fractionation Cell cycle Medium 29108454
2020 SUMOylation enhances E2F1 binding to the EZH2 promoter, promoting EZH2 transcription; inhibition of SUMOylation (by SAE2 knockdown or pharmacologic inhibition) reduces E2F1 occupancy at the EZH2 promoter, decreasing EZH2 mRNA and H3K27me3 levels. ChIP, reporter assay, SAE2 siRNA, SUMO inhibitor treatment Cancer research Medium 32816857
2022 In Drosophila, small upstream open reading frames (uORFs) in the E2f1 mRNA 5'UTR limit translation and cell proliferation; EGFR and TOR signaling pathways enhance E2f1 translation, with TOR bypassing uORF-mediated repression, revealing translational control as a key regulatory mechanism for E2F1 activity. Transgenic Drosophila with mutant 5'UTR, genetic epistasis with TOR/EGFR pathway mutants, cell proliferation assay Proceedings of the National Academy of Sciences of the United States of America Medium 35074910

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2308 15944709
2003 Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 1823 12809602
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
1992 E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science (New York, N.Y.) 1539 1411535
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1993 Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes & development 1214 8449399
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1998 Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 1041 9468139
2013 DNA-binding specificities of human transcription factors. Cell 995 23332764
2002 E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes & development 957 11799067
2017 Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science (New York, N.Y.) 934 28473536
1994 p53 and E2F-1 cooperate to mediate apoptosis. Proceedings of the National Academy of Sciences of the United States of America 855 8170954
1992 Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties. Cell 853 1638635
1999 Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 848 10499802
1998 Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 780 9468140
2000 DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nature genetics 755 10888886
2008 E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer cell 737 18328430
1996 E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 708 8653790
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2003 The BRCT domain is a phospho-protein binding domain. Science (New York, N.Y.) 698 14576433
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1992 A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F. Cell 654 1638634
2016 Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nature medicine 607 26928463
2010 An atlas of combinatorial transcriptional regulation in mouse and man. Cell 573 20211142
2000 Regulation of E2F1 activity by acetylation. The EMBO journal 570 10675335
1992 The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F. Genes & development 569 1531329
1998 The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell 561 9708738
1995 Regulation of the cyclin E gene by transcription factor E2F1. Proceedings of the National Academy of Sciences of the United States of America 559 8618861
2001 The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. The Journal of biological chemistry 555 11278247
2003 BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science (New York, N.Y.) 552 14576432
2006 Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nature cell biology 372 16892051
2010 Lysine methylation regulates E2F1-induced cell death. Molecular cell 297 20603083
2008 E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature 262 18794899
1994 Oncogenic capacity of the E2F1 gene. Proceedings of the National Academy of Sciences of the United States of America 255 7809128
2008 E2F1 regulates autophagy and the transcription of autophagy genes. Oncogene 216 18408756
2011 Transcriptional and nontranscriptional functions of E2F1 in response to DNA damage. Cancer research 148 22180494
2001 Human ARF binds E2F1 and inhibits its transcriptional activity. Oncogene 148 11314038
2005 Regulation of DNA methyltransferase 1 by the pRb/E2F1 pathway. Cancer research 140 15867357
2012 The dark side of E2F1: in transit beyond apoptosis. Cancer research 133 22298593
2002 The identification of E2F1-specific target genes. Proceedings of the National Academy of Sciences of the United States of America 129 11904439
2001 E2F-1 induced apoptosis. Apoptosis : an international journal on programmed cell death 119 11388666
2009 The CDK4-pRB-E2F1 pathway controls insulin secretion. Nature cell biology 111 19597485
2015 E2F1 mediates sustained lipogenesis and contributes to hepatic steatosis. The Journal of clinical investigation 107 26619117
2009 Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression. Cell death and differentiation 106 19893569
2010 The RB-E2F1 pathway regulates autophagy. Cancer research 102 20807803
2009 E2F1 in melanoma progression and metastasis. Journal of the National Cancer Institute 101 20026813
2015 POH1 deubiquitylates and stabilizes E2F1 to promote tumour formation. Nature communications 98 26510456
2000 The transcription factor E2F1 modulates apoptosis of neurons. Journal of neurochemistry 97 10854251
2015 To live or let die - complexity within the E2F1 pathway. Molecular & cellular oncology 96 27308406
2008 A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa. Investigative ophthalmology & visual science 91 19074801
2019 ECT2/PSMD14/PTTG1 axis promotes the proliferation of glioma through stabilizing E2F1. Neuro-oncology 90 30590814
1994 Cloning, chromosomal location, and characterization of mouse E2F1. Molecular and cellular biology 84 8114719
2020 A comprehensive review of the roles of E2F1 in colon cancer. American journal of cancer research 83 32266089
2010 Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 20392944
2000 The paradox of E2F1: oncogene and tumor suppressor gene. Molecular carcinogenesis 82 10708476
2017 Differential impact of RB status on E2F1 reprogramming in human cancer. The Journal of clinical investigation 79 29202480
2004 Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice. The Journal of clinical investigation 79 15146237
2007 Regulation of E2F1 function by the nuclear corepressor KAP1. The Journal of biological chemistry 78 17704056
2014 E2F1 induces miR-224/452 expression to drive EMT through TXNIP downregulation. EMBO reports 74 25341426
2021 Exosomal miRNA-205 promotes breast cancer chemoresistance and tumorigenesis through E2F1. Aging 67 34292880
2003 Evolving intricacies and implications of E2F1 regulation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 67 12665469
2014 Transcription addiction: can we garner the Yin and Yang functions of E2F1 for cancer therapy? Cell death & disease 64 25101673
2012 CDK8 regulates E2F1 transcriptional activity through S375 phosphorylation. Oncogene 61 22945643
2002 Differential regulation of E2F1, DP1, and the E2F1/DP1 complex by ARF. Molecular and cellular biology 61 12446760
2015 Cezanne regulates E2F1-dependent HIF2α expression. Journal of cell science 60 26148512
2015 Redeployment of Myc and E2f1-3 drives Rb-deficient cell cycles. Nature cell biology 60 26192440
2009 The E2F family and the role of E2F1 in apoptosis. The international journal of biochemistry & cell biology 60 19539777
2011 An E2F1-mediated DNA damage response contributes to the replication of human cytomegalovirus. PLoS pathogens 59 21589897
2000 Thymidylate synthase expression correlates closely with E2F1 expression in colon cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 59 10914714
2009 Cdh1 regulates cell cycle through modulating the claspin/Chk1 and the Rb/E2F1 pathways. Molecular biology of the cell 58 19477924
2010 Cell proliferation in the absence of E2F1-3. Developmental biology 57 21185283
2015 Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression. Nature communications 53 26639898
2018 Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4DCAF5 ubiquitin ligase. Nature communications 52 29691401
2021 E2F1: Cause and Consequence of DNA Replication Stress. Frontiers in molecular biosciences 50 33665206
2015 Downregulation of E2F1 during ER stress is required to induce apoptosis. Journal of cell science 50 25616897
2011 DNA damage signals through differentially modified E2F1 molecules to induce apoptosis. Molecular and cellular biology 50 22184068
2022 E2F1-mediated AUF1 upregulation promotes HCC development and enhances drug resistance via stabilization of AKR1B10. Cancer science 49 35178834
2012 The p38 MAPK-MK2 axis regulates E2F1 and FOXM1 expression after epirubicin treatment. Molecular cancer research : MCR 49 22802261
1999 Regulation of the G1/S transition phase in mesangial cells by E2F1. Kidney international 49 10504464
2018 CDCA3 mediates p21-dependent proliferation by regulating E2F1 expression in colorectal cancer. International journal of oncology 48 30226575
2017 E2F1 inhibits circulating cholesterol clearance by regulating Pcsk9 expression in the liver. JCI insight 47 28515357
2014 MiR-136 targets E2F1 to reverse cisplatin chemosensitivity in glioma cells. Journal of neuro-oncology 47 25139024
2010 APC/C(Cdc20) targets E2F1 for degradation in prometaphase. Cell cycle (Georgetown, Tex.) 47 20948288
2015 RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression. Oncogene 46 26234677
2005 Chronic inflammation promotes retinoblastoma protein hyperphosphorylation and E2F1 activation. Cancer research 45 16230367
2018 Stemness Is Enhanced in Gastric Cancer by a SET/PP2A/E2F1 Axis. Molecular cancer research : MCR 44 29330298
2017 EGFR Induces E2F1-Mediated Corticotroph Tumorigenesis. Journal of the Endocrine Society 44 29264472
2012 NEDDylation controls the target specificity of E2F1 and apoptosis induction. Oncogene 44 23001041
2018 SET7/9 promotes hepatocellular carcinoma progression through regulation of E2F1. Oncology reports 42 30106440
2021 CHPF promotes gastric cancer tumorigenesis through the activation of E2F1. Cell death & disease 38 34564711
2017 E2F1 silencing inhibits migration and invasion of osteosarcoma cells via regulating DDR1 expression. International journal of oncology 38 29039472
2014 E2F1 suppresses cardiac neovascularization by down-regulating VEGF and PlGF expression. Cardiovascular research 38 25341896
2010 Transcription factor E2F1 suppresses dendritic cell maturation. Journal of immunology (Baltimore, Md. : 1950) 38 20421650
2015 MicroRNA-320 inhibits cell proliferation in glioma by targeting E2F1. Molecular medicine reports 36 25901521
2010 Estrogen receptor regulates E2F1 expression to mediate tamoxifen resistance. Molecular cancer research : MCR 34 20215421
2018 E2F1 inhibition mediates cell death of metastatic melanoma. Cell death & disease 33 29743521
2018 PTEN Physically Interacts with and Regulates E2F1-mediated Transcription in Lung Cancer. Cell cycle (Georgetown, Tex.) 31 29108454
2014 E2F1 responds to ultraviolet radiation by directly stimulating DNA repair and suppressing carcinogenesis. Cancer research 31 24741006
1997 Targeting E2F1-DNA complexes with microgonotropen DNA binding agents. Proceedings of the National Academy of Sciences of the United States of America 31 9096302
1994 Interacting domains of E2F1, DP1, and the adenovirus E4 protein. Journal of virology 31 8207796
2022 NCAPD2 promotes breast cancer progression through E2F1 transcriptional regulation of CDK1. Cancer science 30 35348268
2019 YY1 promotes colorectal cancer proliferation through the miR-526b-3p/E2F1 axis. American journal of cancer research 30 31911854
2015 E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution. Cell death and differentiation 30 25656653
2014 Tristetraprolin regulates prostate cancer cell growth through suppression of E2F1. Journal of microbiology and biotechnology 30 24150491
2024 CircMYBL2 facilitates hepatocellular carcinoma progression by regulating E2F1 expression. Oncology research 28 38827325
2017 A novel lncRNA, GASL1, inhibits cell proliferation and restricts E2F1 activity. Oncotarget 28 28423601
2017 Regulation of E2F1 Transcription Factor by Ubiquitin Conjugation. International journal of molecular sciences 28 29048367
2015 E2F1 and E2F2 induction in response to DNA damage preserves genomic stability in neuronal cells. Cell cycle (Georgetown, Tex.) 28 25892555
2009 Regulation of E2F1-induced apoptosis by the nucleolar protein RRP1B. The Journal of biological chemistry 28 20040599
2023 LncRNA AGPG Confers Endocrine Resistance in Breast Cancer by Promoting E2F1 Activity. Cancer research 27 37463119
2021 Double-targeting CDCA8 and E2F1 inhibits the growth and migration of malignant glioma. Cell death & disease 26 33542211
2018 HMGA1/E2F1 axis and NFkB pathways regulate LPS progression and trabectedin resistance. Oncogene 26 29980789
2017 PI3Kδ activates E2F1 synthesis in response to mRNA translation stress. Nature communications 26 29235459
2022 Ribosomal protein L5 (RPL5)/ E2F transcription factor 1 (E2F1) signaling suppresses breast cancer progression via regulating endoplasmic reticulum stress and autophagy. Bioengineered 25 35293275
2018 E2F1 promotes hepatic gluconeogenesis and contributes to hyperglycemia during diabetes. Molecular metabolism 25 29526568
2022 Translational control of E2f1 regulates the Drosophila cell cycle. Proceedings of the National Academy of Sciences of the United States of America 23 35074910
2021 Up-regulation of MELK by E2F1 promotes the proliferation in cervical cancer cells. International journal of biological sciences 23 34671205
2020 E2F1-activated SPIN1 promotes tumor growth via a MDM2-p21-E2F1 feedback loop in gastric cancer. Molecular oncology 23 32767629
2020 SUMOylation of E2F1 Regulates Expression of EZH2. Cancer research 23 32816857
2015 E2F1 controls germ cell apoptosis during the first wave of spermatogenesis. Andrology 23 26311345
1996 Structure and partial genomic sequence of the human E2F1 gene. Gene 22 8964493
1995 Regulation of transcription by E2F1/DP1. Journal of cell science. Supplement 22 8655653
2023 Exosomes Derived from E2F1-/- Adipose-Derived Stem Cells Promote Skin Wound Healing via miR-130b-5p/TGFBR3 Axis. International journal of nanomedicine 21 37941530
2014 RORα binds to E2F1 to inhibit cell proliferation and regulate mammary gland branching morphogenesis. Molecular and cellular biology 21 24891616
2010 MEF/ELF4 transactivation by E2F1 is inhibited by p53. Nucleic acids research 21 20805247
2012 The retinoblastoma protein selectively represses E2F1 targets via a TAAC DNA element during cellular senescence. The Journal of biological chemistry 20 22955272
2007 TFDP3 inhibits E2F1-induced, p53-mediated apoptosis. Biochemical and biophysical research communications 20 17632080