E2F1 (E2F transcription factor 1)

2008-12-01   Michael Zachariadis , Vassilios G Gorgoulis 

University of Athens, Faculty of Medicine, Department of Anatomy, Greece (MZ); Department of Histology, Embryology, Molecular Carcinogenesis Group, Greece (VGG)

Identity

HGNC
LOCATION
20q11.22
LOCUSID
ALIAS
E2F-1,RBAP1,RBBP3,RBP3
FUSION GENES

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.

Proteins

Atlas Image
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

    Bibliography

    Pubmed IDLast YearTitleAuthors
    76473121995Transcriptional control by E2F.Adams PD et al
    89433161996Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors.Adams PD et al
    183342812008E2F1 in gliomas: a paradigm of oncogene addiction.Alonso MM et al
    179071532007Gene amplification is a relatively frequent event leading to ZBTB7A (Pokemon) overexpression in non-small cell lung cancer.Apostolopoulou K et al
    155383802004The E2F family: specific functions and overlapping interests.Attwooll C et al
    145263892004Life and death decisions by E2F-1.Bell LA et al
    127268572003Emerging roles for E2F: beyond the G1/S transition and DNA replication.Cam H et al
    91221751997Regulation of E2F through ubiquitin-proteasome-dependent degradation: stabilization by the pRB tumor suppressor protein.Campanero MR et al
    92813031997Transcription factors and the down-regulation of G1/S boundary genes in human diploid fibroblasts during senescence.Chen KY et al
    83212041993Cell cycle analysis of E2F in primary human T cells reveals novel E2F complexes and biochemically distinct forms of free E2F.Chittenden T et al
    156621162004Opposing roles of E2Fs in cell proliferation and death.Crosby ME et al
    171006002006Distinct and Overlapping Roles for E2F Family Members in Transcription, Proliferation and Apoptosis.DeGregori J et al
    179088032008E2F-1 overexpression correlates with decreased proliferation and better prognosis in adenocarcinomas of Barrett oesophagus.Evangelou K et al
    83461961993E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product.Flemington EK et al
    146964192003Chromosome arm 20q gains and other genomic alterations in esophageal squamous cell carcinoma, as analyzed by comparative genomic hybridization and fluorescence in situ hybridization.Fujita Y et al
    183588292008E2F1 contributes to the transcriptional activation of the KIR3DL1 gene.Gao XN et al
    123546232002E2F1 pathways to apoptosis.Ginsberg D et al
    122378732002Transcription factor E2F-1 acts as a growth-promoting factor and is associated with adverse prognosis in non-small cell lung carcinomas.Gorgoulis VG et al
    129549802003Specificity in the activation and control of transcription factor E2F-dependent apoptosis.Hallstrom TC et al
    84132491993Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein.Helin K et al
    95296021998Regulation of cell proliferation by the E2F transcription factors.Helin K et al
    182949582008TGFbeta-mediated formation of pRb-E2F complexes in human myeloid leukemia cells.Hu XT et al
    105044641999Regulation of the G1/S transition phase in mesangial cells by E2F1.Inoshita S et al
    171005992006Putting the Oncogenic and Tumor Suppressive Activities of E2F into Context.Johnson DG et al
    184403232008Regulation of the human mitotic centromere-associated kinesin (MCAK) promoter by the transcription factors Sp1 and E2F1.Jun DY et al
    154663992004Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1.Karakaidos P et al
    183029372008Identification of E2F1 as a positive transcriptional regulator for delta-catenin.Kim K et al
    151076042004Role of E2F1 in apoptosis: a case study in feedback loops.Knezevic D et al
    124145102002Proliferation, but not apoptosis, is associated with distinct beta-catenin expression patterns in non-small-cell lung carcinomas: relationship with adenomatous polyposis coli and G(1)-to S-phase cell-cycle regulators.Kotsinas A et al
    167391122006Centrosome abnormalities are frequently observed in non-small-cell lung cancer and are associated with aneuploidy and cyclin E overexpression.Koutsami MK et al
    82488031993Binding to DNA and the retinoblastoma gene product promoted by complex formation of different E2F family members.Krek W et al
    79173371994DP and E2F proteins: components of a heterodimeric transcription factor implicated in cell cycle control.La Thangue NB et al
    78805341994DP and E2F proteins: coordinating transcription with cell cycle progression.Lam EW et al
    125027412002Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor.Lee C et al
    185248512008The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis.Marlowe JL et al
    112743642001p19ARF targets certain E2F species for degradation.Martelli F et al
    105598581999Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation.Marti A et al
    92714261997Induction of S-phase entry by E2F transcription factors depends on their nuclear localization.Müller H et al
    126654692003Evolving intricacies and implications of E2F1 regulation.Mundle SD et al
    79353801994Transcription of the E2F-1 gene is rendered cell cycle dependent by E2F DNA-binding sites within its promoter.Neuman E et al
    89644931996Structure and partial genomic sequence of the human E2F1 gene.Neuman E et al
    79330661994Mutually exclusive interaction of the adenovirus E4-6/7 protein and the retinoblastoma gene product with internal domains of E2F-1 and DP-1.O'Connor RJ et al
    112454322001Phosphorylation- and Skp1-independent in vitro ubiquitination of E2F1 by multiple ROC-cullin ligases.Ohta T et al
    154674442004Regulation in S phase by E2F.Pardee AB et al
    113886662001E2F-1 induced apoptosis.Phillips AC et al
    174884752007E2F1 death pathways as targets for cancer therapy.Pützer BM et al
    151902062004Life, death and E2F: linking proliferation control and DNA damage signaling via E2F1.Rogoff HA et al
    163600382005Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release.Rubin SM et al
    77749101995Amplification of the E2F1 transcription factor gene in the HEL erythroleukemia cell line.Saito M et al
    185067482008Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: potential role in progression.Scotto L et al
    14480921992Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F.Shan B et al
    93750221997E2F transcription factor action, regulation and possible role in human cancer.Sladek TL et al
    84414011993A protein synthesis-dependent increase in E2F1 mRNA correlates with growth regulation of the dihydrofolate reductase promoter.Slansky JE et al
    152797952004The emerging role of E2F-1 in the DNA damage response and checkpoint control.Stevens C et al
    118237942002Sibling rivalry in the E2F family.Trimarchi JM et al
    171782082007Implication of the transcription factor E2F-1 in the modulation of neuronal apoptosis.Verdaguer E et al
    180038342007E2F1 works as a cell cycle suppressor in mature neurons.Wang L et al
    125986542003Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation.Xiao B et al
    102143481999Balancing proliferation and apoptosis in vivo: the Goldilocks theory of E2F/DP action.Yamasaki L et al
    152219332004Distinct expression patterns of the transcription factor E2F-1 in relation to tumour growth parameters in common human carcinomas.Zacharatos P et al
    100907231999Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP.Zheng N et al
    172227862007Rb loss causes cancer by driving mitosis mad.van Deursen JM et al

    Other Information

    Locus ID:

    NCBI: 1869
    MIM: 189971
    HGNC: 3113
    Ensembl: ENSG00000101412

    Variants:

    dbSNP: 1869
    ClinVar: 1869
    TCGA: ENSG00000101412
    COSMIC: E2F1

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000101412ENST00000343380Q01094

    Expression (GTEx)

    0
    5
    10
    15
    20
    25
    30
    35
    40
    45
    50

    Pathways

    PathwaySourceExternal ID
    Cell cycleKEGGko04110
    Pancreatic cancerKEGGko05212
    GliomaKEGGko05214
    Prostate cancerKEGGko05215
    MelanomaKEGGko05218
    Bladder cancerKEGGko05219
    Chronic myeloid leukemiaKEGGko05220
    Small cell lung cancerKEGGko05222
    Non-small cell lung cancerKEGGko05223
    Cell cycleKEGGhsa04110
    Pathways in cancerKEGGhsa05200
    Pancreatic cancerKEGGhsa05212
    GliomaKEGGhsa05214
    Prostate cancerKEGGhsa05215
    MelanomaKEGGhsa05218
    Bladder cancerKEGGhsa05219
    Chronic myeloid leukemiaKEGGhsa05220
    Small cell lung cancerKEGGhsa05222
    Non-small cell lung cancerKEGGhsa05223
    HTLV-I infectionKEGGko05166
    HTLV-I infectionKEGGhsa05166
    Hepatitis BKEGGhsa05161
    MicroRNAs in cancerKEGGhsa05206
    MicroRNAs in cancerKEGGko05206
    Cell cycle - G1/S transitionKEGGhsa_M00692
    Cell cycle - G1/S transitionKEGGM00692
    Signal TransductionREACTOMER-HSA-162582
    Signaling by NOTCHREACTOMER-HSA-157118
    Pre-NOTCH Expression and ProcessingREACTOMER-HSA-1912422
    Pre-NOTCH Transcription and TranslationREACTOMER-HSA-1912408
    Gene ExpressionREACTOMER-HSA-74160
    Generic Transcription PathwayREACTOMER-HSA-212436
    Transcriptional Regulation by TP53REACTOMER-HSA-3700989
    Cell CycleREACTOMER-HSA-1640170
    Cell Cycle, MitoticREACTOMER-HSA-69278
    Mitotic G1-G1/S phasesREACTOMER-HSA-453279
    G0 and Early G1REACTOMER-HSA-1538133
    G1 PhaseREACTOMER-HSA-69236
    Cyclin D associated events in G1REACTOMER-HSA-69231
    G1/S TransitionREACTOMER-HSA-69206
    G1/S-Specific TranscriptionREACTOMER-HSA-69205
    E2F mediated regulation of DNA replicationREACTOMER-HSA-113510
    Inhibition of replication initiation of damaged DNA by RB1/E2F1REACTOMER-HSA-113501
    Regulation of DNA replicationREACTOMER-HSA-69304
    Association of licensing factors with the pre-replicative complexREACTOMER-HSA-69298
    Mitotic G2-G2/M phasesREACTOMER-HSA-453274
    G2 PhaseREACTOMER-HSA-68911
    M/G1 TransitionREACTOMER-HSA-68874
    DNA Replication Pre-InitiationREACTOMER-HSA-69002
    Assembly of the pre-replicative complexREACTOMER-HSA-68867
    CDC6 association with the ORC:origin complexREACTOMER-HSA-68689
    DNA ReplicationREACTOMER-HSA-69306
    Programmed Cell DeathREACTOMER-HSA-5357801
    ApoptosisREACTOMER-HSA-109581
    Intrinsic Pathway for ApoptosisREACTOMER-HSA-109606
    Activation of BH3-only proteinsREACTOMER-HSA-114452
    Activation of NOXA and translocation to mitochondriaREACTOMER-HSA-111448
    Activation of PUMA and translocation to mitochondriaREACTOMER-HSA-139915
    Cellular responses to stressREACTOMER-HSA-2262752
    Cellular SenescenceREACTOMER-HSA-2559583
    Oncogene Induced SenescenceREACTOMER-HSA-2559585
    Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580
    TP53 Regulates Transcription of Cell Cycle GenesREACTOMER-HSA-6791312
    TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle ArrestREACTOMER-HSA-6804116
    Endocrine resistanceKEGGko01522
    Endocrine resistanceKEGGhsa01522
    Breast cancerKEGGko05224
    Breast cancerKEGGhsa05224
    Mitophagy - animalKEGGko04137
    Mitophagy - animalKEGGhsa04137

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    159447092005c-Myc-regulated microRNAs modulate E2F1 expression.1081
    128096022003Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.715
    183284302008E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer.348
    171352492007An E2F/miR-20a autoregulatory feedback loop.238
    153068142004Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control.204
    269284632016Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer.190
    168920512006Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage.160
    127174392003Chk2 activates E2F-1 in response to DNA damage.141
    200290462010Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia.129
    123890322002Direct coupling of the cell cycle and cell death machinery by E2F.126

    Citation

    Michael Zachariadis ; Vassilios G Gorgoulis

    E2F1 (E2F transcription factor 1)

    Atlas Genet Cytogenet Oncol Haematol. 2008-12-01

    Online version: http://atlasgeneticsoncology.org/gene/40382/e2f1id40382ch20q11