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E2F1 (E2F transcription factor 1)

Written2008-12Michael Zachariadis, Vassilios G Gorgoulis
University of Athens, Faculty of Medicine, Department of Anatomy, Greece (MZ); Department of Histology, Embryology, Molecular Carcinogenesis Group, Greece (VGG)

(Note : for Links provided by Atlas : click)

Identity

Other namesE2F-1
OTTHUMP00000030661
PBR3
RBAP-1
RBAP1
RBBP-3
RBBP3
RBP3
HGNC (Hugo) E2F1
LocusID (NCBI) 1869
Atlas_Id 40382
Location 20q11.22  [Link to chromosome band 20q11]
Location_base_pair Starts at 32263292 and ends at 32274210 bp from pter ( according to hg19-Feb_2009)  [Mapping E2F1.png]
Local_order - C20orf114 31334.602 20q11.21 chromosome 20 open reading frame 114
- CDK5RAP1 31410.306 20pter-q11.23 CDK5 regulatory subunit associated protein 1
- CBFA2T2 31613.832 20q11 core-binding factor, runt domain, alpha subunit 2; translocated to, 2
- E2F1 31727.150 20q11.2 E2F transcription factor 1
- ASIP 32311.832 20q11.2-q12 agouti signaling protein, nonagouti homolog (mouse)
- ITCH 32414.745 20q11.22-q11.23 itchy homolog E3 ubiquitin protein ligase (mouse)
- DYNLRB1 32567.865 20q11.21 dynein, light chain, roadblock-type 1
Fusion genes
(updated 2016)
E2F1 (20q11.22) / E2F1 (20q11.22)E2F1 (20q11.22) / ESR1 (6q25.1)E2F1 (20q11.22) / RDH11 (14q24.1)

DNA/RNA

Note Start: 31,727,147 bp from pter
End: 31,737,871 bp from pter
Size: 10,725 bases
Orientation: minus strand
Transcription The gene is comprised of 7 exons, building one main transcript of 2506 bps.
Pseudogene Non known pseudogenes.

Protein

 
  Schematic representation of human E2F1, depicting conserved domains and post-translational modification sites (see description for details).
Description Length: 437 aa, molecular weight: 46920 Da.
The protein contains a number of conserved domains, including a cyclin A binding domain (aa 67-108); a nuclear localization signal (NLS, aa 85-91); a helix-loop-helix DNA binding domain (aa 120-191); a heptad repeat (aa 201-243), which mediates homo/hetero dimerization; a marked box (245-317), which is implicated in the E2F/DP and E2F/E4 ORF 6/7 interaction, and is also essential for the apoptotic activity of E2F1; and a transactivation domain (aa 368-437) containing the pRB binding domain (aa 409-426). The E2F1 protein molecule is subject to a number of post-translational modifications, including phosphorylation by cyclin D / CDK4 / CDK6 at serine residues 332 and 337, which stabilizes E2F1 and prevents its binding to pRB regardless of its phosphorylation status; acetylation of lysine residues 117, 120, and 125 by the factor acetyltransferase (FAT) complex CBP/p/CAF, which enhances DNA binding and stabilizes E2F1 further; phosphorylation by cyclin A / CDK2 at serine residue 375, which reduces DNA binding; and phosphorylation at serine residues 31 and 364 by ATM/ATR and CHK2 kinases, respectively, in response to DNA damage, which stabilizes E2F1 and promotes its apoptotic activity.
Expression E2F1 is expressed in all actively proliferating tissues in a cell-cycle specific manner. It is expressed mainly at late G1 and G1/S transition, and its mRNA is absent or low during the rest of the cell cycle.
Localisation E2F1 is constitutively nuclear, due to a Nuclear Localization Signal (NLS) located around aa 90.
Function E2F1 represents a controversial player in cell cycle control, exhibiting a dual behavior, sometimes acting as a tumor-suppressor and others as an oncogene. E2F1 exerts transcriptional control over the cell cycle, induces apoptosis via distinct pathways, and participates in DNA damage response and checkpoint.

  • Transcriptional control
    E2F1 belongs to the E2F family of transcription factors, coordinating the expression of key genes involved in cell cycle regulation and progression. It is active during the G1 to S transition, and thus its target genes, which include regulatory elements of the cell cycle, such as CDC2, CDC25A and cyclin E, and essential components of DNA replication machinery, including DHFR, and DNA polymerase alpha, are expressed in a cell cycle dependent manner (i.e. only in late G1 and early S phase of the cell cycle). E2F1 recognizes and binds to specific DNA sequences (5'-TTTSSCGS-3', where S = C/G) that lie within the promoter of target genes, in the form of functional heterodimers with members of the DP family of transcription factors.

  • Apoptosis
    E2F1 can induce apoptosis via distinct P53-dependent and independent pathways.
    The P53-independent pathways involve the p53 homolog P73 and APAF1, which are both transcriptionally controlled by E2F1. Transcriptional activation of P73 by E2F1 may lead to the activation of P53-responsive target genes, while induction of APAF1 transcription leads to activation of the caspase cascade. Ultimately, both pathways lead to cell death by apoptosis. Moreover, E2F1 is implicated in the upregulation of the pro-apoptotic members of the BCL2 family, but also in the downregulation of anti-apoptotic signals, by inhibiting NF-kB activity, thereby enhancing also apoptosis.
    There are many pathways linking E2F1 to P53-dependent apoptosis. The main mechanism involves direct transcriptional activation of the p14ARF tumor suppressor gene by E2F1. ARF sequesters MDM2 away from P53, leading consequently to P53 stabilization and activation. Nevertheless, ARF overexpression may lead to E2F1 downregulation, as ARF targets the latter for proteasomal degradation through p45skp2-dependent pathways. On the other hand, E2F1 can induce P53-dependent apoptosis in the absence of ARF. For instance, E2F1 can interact directly with P53 through the cyclin A-binding domain of E2F1, enhancing its apoptotic activity in response to DNA damage. Additionally, some reports argue that E2F1 uses the ATM pathway in order to activate both P53 and CHK2. Finally, E2F1 can augment the apoptotic capacity of P53 by enhancing the transcription of pro-apoptotic P53 cofactors such as P53-ASPP1, ASPP2, JMY and TP53INP1.

  • DNA Damage Response
    In response to DNA damage, E2F1 is upregulated through phosporylation-mediated stabilization. E2F1 is phosphorylated at S31 by ATM/ATR kinases and at S364 by CHK2 kinase, which are all integral components of the DNA damage signaling pathway. These phosphorylations interfere with the ARF/SKP2- and MDM2-dependent degradation of E2F1, thus stabilizing the latter by decreasing its turnover rate. In response to IR or other agents that cause DNA double strand breaks, phosphorylation by ATM/ATR seems to prime E2F1 for acetylation at specific lysine residues. These acetylations are a prerequisite for the targeting of the P73 gene promoter by E2F1, which ultimately leads to apoptosis (see above paragraph). UV radiation does not trigger E2F1 acetylation and apoptosis. Instead, E2F1 seems to play a role in DNA repair and cell survival, either directly at the sites of DNA repair or through modulation of DNA repair genes that are under its transcriptional control.
  • Homology Shares lesser or greater homology with other members of the E2F family (E2F2, E2F3, E2F4, E2F5, E2F6) and with the DP family of transcription factors ( DP1, DP2).

    Mutations

    Note No known mutations.

    Implicated in

    Note
    Note Due to its pivotal and multifunctional role in cell cycle control, E2F1 is expected to be a significant player in carcinogenesis. Nevertheless, its paradoxical behavior, i.e. acting as an oncogene or a tumor suppressor depending on the cell context, renders its characterization and study challenging. Moreover, deregulation of E2F1 in cancer is often attributed to upstream alterations, in the pRB pathway that mainly regulates E2F function, and not to genetic mutations of its gene. The E2F1 paradox is quite evident in the various in vitro cellular systems and in vivo animal models that have been employed in order to study E2F1 function in cancer. Excess of E2F1 may promote proliferation, but at the same time it may also enhance apoptosis, and there are examples where overexpression or lack of E2F1 has both positive and negative effects on tumorigenesis. The delicate balance between growth and death seems to depend on the level of E2F1 deregulation, but also on the cell context background.
    In non-small cell lung carcinomas (NSCLCs) E2F1 is significantly increased due to aberrant pRB status. In these cases the elevated levels of E2F1 are positively associated with the tumour growth index whereas apoptosis is not influenced as deregulation of the P53-MDM2 regulatory loop is a common phenomenon in NSCLC. Breast, thyroid and pancreatic cancer, seem to follow this same scenario, where aberrations in the pRB pathway coupled with defective P53 status, enhance E2F1 levels promoting tumor growth. In all these cases, the higher levels of E2F1 are also correlated with poorer outcome. Nevertheless, in other cases, like colon cancer, and diffuse large B-cell lymphomas the more aggressive disease is linked to lower E2F1 expression, as E2F1 in these cases acts as an oncosuppressor, enhancing apoptosis. Likewise, in adenocarcinomas of Barrett oesophagus E2F1 expression is negatively associated with tumor progression and positively with patient survival. In the case of transitional cell bladder carcinomas (TCCs) the findings are controversial. In one series of invasive bladder tumors E2F1 seems to play a tumor suppressive role, while in another series of superficial low-grade TCCs E2F1 is positively correlated with proliferation, but not with apoptosis. This discrepancy seems to lie in the type of TCC examined and the molecular characteristics of the tissue.
    The most usual genetic alteration of the E2F1 gene is amplification, as has been reported in several leukemic (e.g. the HEL human erythroleukemia cell line) and melanoma cell lines. The gene has also been found amplified in various esophageal, colorectal, cervical and ovarian cancers, as well as in lymph node metastases of melanoma, and is often linked to chromosome 20q gains in these entities. Importantly, in esophageal squamous cell carcinomas, the 20q gains and the amplification of the E2F1 gene are linked with greater aggressiveness and poorer prognosis.
      

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    Citation

    This paper should be referenced as such :
    Zachariadis, M ; Gorgoulis, VG
    E2F1 (E2F transcription factor 1)
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(11):812-816.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/E2F1ID40382ch20q11.html


    Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 0 ]
      Head and neck: Retinoblastoma

    External links

    Nomenclature
    HGNC (Hugo)E2F1   3113
    Cards
    AtlasE2F1ID40382ch20q11
    Entrez_Gene (NCBI)E2F1  1869  E2F transcription factor 1
    AliasesE2F-1; RBAP1; RBBP3; RBP3
    GeneCards (Weizmann)E2F1
    Ensembl hg19 (Hinxton)ENSG00000101412 [Gene_View]  chr20:32263292-32274210 [Contig_View]  E2F1 [Vega]
    Ensembl hg38 (Hinxton)ENSG00000101412 [Gene_View]  chr20:32263292-32274210 [Contig_View]  E2F1 [Vega]
    ICGC DataPortalENSG00000101412
    TCGA cBioPortalE2F1
    AceView (NCBI)E2F1
    Genatlas (Paris)E2F1
    WikiGenes1869
    SOURCE (Princeton)E2F1
    Genomic and cartography
    GoldenPath hg19 (UCSC)E2F1  -     chr20:32263292-32274210 -  20q11   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)E2F1  -     20q11   [Description]    (hg38-Dec_2013)
    EnsemblE2F1 - 20q11 [CytoView hg19]  E2F1 - 20q11 [CytoView hg38]
    Mapping of homologs : NCBIE2F1 [Mapview hg19]  E2F1 [Mapview hg38]
    OMIM189971   
    Gene and transcription
    Genbank (Entrez)AF086380 BC005098 BC050369 BC058902 M96577
    RefSeq transcript (Entrez)NM_005225
    RefSeq genomic (Entrez)NC_000020 NC_018931 NT_011362 NW_004929418
    Consensus coding sequences : CCDS (NCBI)E2F1
    Cluster EST : UnigeneHs.654393 [ NCBI ]
    CGAP (NCI)Hs.654393
    Alternative Splicing GalleryENSG00000101412
    Gene ExpressionE2F1 [ NCBI-GEO ]   E2F1 [ EBI - ARRAY_EXPRESS ]   E2F1 [ SEEK ]   E2F1 [ MEM ]
    Gene Expression Viewer (FireBrowse)E2F1 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)1869
    GTEX Portal (Tissue expression)E2F1
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ01094 (Uniprot)
    NextProtQ01094  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ01094
    Splice isoforms : SwissVarQ01094 (Swissvar)
    PhosPhoSitePlusQ01094
    Domains : Interpro (EBI)E2F    E2F_CC-MB    E2F_WHTH_DNA-bd_dom    WHTH_DNA-bd_dom   
    Domain families : Pfam (Sanger)E2F_CC-MB (PF16421)    E2F_TDP (PF02319)   
    Domain families : Pfam (NCBI)pfam16421    pfam02319   
    DMDM Disease mutations1869
    Blocks (Seattle)E2F1
    PDB (SRS)1H24    1O9K    2AZE   
    PDB (PDBSum)1H24    1O9K    2AZE   
    PDB (IMB)1H24    1O9K    2AZE   
    PDB (RSDB)1H24    1O9K    2AZE   
    Structural Biology KnowledgeBase1H24    1O9K    2AZE   
    SCOP (Structural Classification of Proteins)1H24    1O9K    2AZE   
    CATH (Classification of proteins structures)1H24    1O9K    2AZE   
    SuperfamilyQ01094
    Human Protein AtlasENSG00000101412
    Peptide AtlasQ01094
    HPRD01806
    IPIIPI00005630   IPI00816797   IPI00884010   
    Protein Interaction databases
    DIP (DOE-UCLA)Q01094
    IntAct (EBI)Q01094
    FunCoupENSG00000101412
    BioGRIDE2F1
    STRING (EMBL)E2F1
    ZODIACE2F1
    Ontologies - Pathways
    QuickGOQ01094
    Ontology : AmiGODNA damage checkpoint  negative regulation of transcription from RNA polymerase II promoter  nuclear chromatin  core promoter binding  DNA binding  DNA binding  transcription factor activity, sequence-specific DNA binding  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleoplasm  mitochondrion  transcription, DNA-templated  regulation of transcription, DNA-templated  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  spermatogenesis  transcription factor binding  intrinsic apoptotic signaling pathway in response to DNA damage  positive regulation of gene expression  protein kinase binding  forebrain development  Rb-E2F complex  anoikis  negative regulation of DNA binding  sequence-specific DNA binding  negative regulation of fat cell differentiation  negative regulation of transcription, DNA-templated  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of fibroblast proliferation  mRNA stabilization  negative regulation of fat cell proliferation  cellular response to fatty acid  cellular response to hypoxia  cellular response to xenobiotic stimulus  negative regulation of transcription involved in G1/S transition of mitotic cell cycle  intrinsic apoptotic signaling pathway by p53 class mediator  positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway  lens fiber cell apoptotic process  cellular response to nerve growth factor stimulus  regulation of G1/S transition of mitotic cell cycle  
    Ontology : EGO-EBIDNA damage checkpoint  negative regulation of transcription from RNA polymerase II promoter  nuclear chromatin  core promoter binding  DNA binding  DNA binding  transcription factor activity, sequence-specific DNA binding  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleoplasm  mitochondrion  transcription, DNA-templated  regulation of transcription, DNA-templated  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  spermatogenesis  transcription factor binding  intrinsic apoptotic signaling pathway in response to DNA damage  positive regulation of gene expression  protein kinase binding  forebrain development  Rb-E2F complex  anoikis  negative regulation of DNA binding  sequence-specific DNA binding  negative regulation of fat cell differentiation  negative regulation of transcription, DNA-templated  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of fibroblast proliferation  mRNA stabilization  negative regulation of fat cell proliferation  cellular response to fatty acid  cellular response to hypoxia  cellular response to xenobiotic stimulus  negative regulation of transcription involved in G1/S transition of mitotic cell cycle  intrinsic apoptotic signaling pathway by p53 class mediator  positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway  lens fiber cell apoptotic process  cellular response to nerve growth factor stimulus  regulation of G1/S transition of mitotic cell cycle  
    Pathways : BIOCARTACyclins and Cell Cycle Regulation [Genes]    Influence of Ras and Rho proteins on G1 to S Transition [Genes]    IL-2 Receptor Beta Chain in T cell Activation [Genes]    Cyclin E Destruction Pathway [Genes]    Regulation of p27 Phosphorylation during Cell Cycle Progression [Genes]    p53 Signaling Pathway [Genes]    METS affect on Macrophage Differentiation [Genes]    Tumor Suppressor Arf Inhibits Ribosomal Biogenesis [Genes]    Cell Cycle: G1/S Check Point [Genes]    E2F1 Destruction Pathway [Genes]   
    Pathways : KEGGCell cycle    Hepatitis B    HTLV-I infection    Pathways in cancer    MicroRNAs in cancer    Pancreatic cancer    Glioma    Prostate cancer    Melanoma    Bladder cancer    Chronic myeloid leukemia    Small cell lung cancer    Non-small cell lung cancer   
    REACTOMEQ01094 [protein]
    REACTOME PathwaysR-HSA-113510 E2F mediated regulation of DNA replication [pathway]
    REACTOME PathwaysR-HSA-1538133 G0 and Early G1 [pathway]
    REACTOME PathwaysR-HSA-2559585 Oncogene Induced Senescence [pathway]
    REACTOME PathwaysR-HSA-68689 CDC6 association with the ORC:origin complex [pathway]
    REACTOME PathwaysR-HSA-111448 Activation of NOXA and translocation to mitochondria [pathway]
    REACTOME PathwaysR-HSA-69231 Cyclin D associated events in G1 [pathway]
    REACTOME PathwaysR-HSA-1912408 Pre-NOTCH Transcription and Translation [pathway]
    REACTOME PathwaysR-HSA-2559580 Oxidative Stress Induced Senescence [pathway]
    REACTOME PathwaysR-HSA-68911 G2 Phase [pathway]
    REACTOME PathwaysR-HSA-69205 G1/S-Specific Transcription [pathway]
    REACTOME PathwaysR-HSA-139915 Activation of PUMA and translocation to mitochondria [pathway]
    REACTOME PathwaysR-HSA-69298 Association of licensing factors with the pre-replicative complex [pathway]
    REACTOME PathwaysR-HSA-113501 Inhibition of replication initiation of damaged DNA by RB1/E2F1 [pathway]
    NDEx NetworkE2F1
    Atlas of Cancer Signalling NetworkE2F1
    Wikipedia pathwaysE2F1
    Orthology - Evolution
    OrthoDB1869
    GeneTree (enSembl)ENSG00000101412
    Phylogenetic Trees/Animal Genes : TreeFamE2F1
    Homologs : HomoloGeneE2F1
    Homology/Alignments : Family Browser (UCSC)E2F1
    Gene fusions - Rearrangements
    Polymorphisms : SNP, variants
    NCBI Variation ViewerE2F1 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)E2F1
    dbVarE2F1
    ClinVarE2F1
    1000_GenomesE2F1 
    Exome Variant ServerE2F1
    ExAC (Exome Aggregation Consortium)E2F1 (select the gene name)
    Genetic variants : HAPMAP1869
    Genomic Variants (DGV)E2F1 [DGVbeta]
    Mutations
    ICGC Data PortalE2F1 
    TCGA Data PortalE2F1 
    Broad Tumor PortalE2F1
    OASIS PortalE2F1 [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICE2F1 
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    BioMutasearch E2F1
    DgiDB (Drug Gene Interaction Database)E2F1
    DoCM (Curated mutations)E2F1 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)E2F1 (select a term)
    intoGenE2F1
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
    Diseases
    DECIPHER (Syndromes)20:32263292-32274210  ENSG00000101412
    CONAN: Copy Number AnalysisE2F1 
    Mutations and Diseases : HGMDE2F1
    OMIM189971   
    MedgenE2F1
    Genetic Testing Registry E2F1
    NextProtQ01094 [Medical]
    TSGene1869
    GENETestsE2F1
    Huge Navigator E2F1 [HugePedia]
    snp3D : Map Gene to Disease1869
    BioCentury BCIQE2F1
    ClinGenE2F1
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD1869
    Chemical/Pharm GKB GenePA152
    Clinical trialE2F1
    Miscellaneous
    canSAR (ICR)E2F1 (select the gene name)
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineE2F1
    EVEXE2F1
    GoPubMedE2F1
    iHOPE2F1
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Mon Sep 19 19:26:11 CEST 2016

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