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E2F3 (E2F transcription factor 3)

Identity

Other namesE2F-3
KIAA0075
Y10479
HGNC (Hugo) E2F3
LocusID (NCBI) 1871
Location 6p22.3
Location_base_pair Starts at 20404034 and ends at 20493945 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order tel-OACT1-E2F3-CDKAL1-cen

DNA/RNA

 
  Schematic diagram of the E2F3 gene comprising 7 exons (in blue). Exons 1a or 1b are used alternatively to produce variants E2F3A or E2F3B, respectively. The sizes in base pairs (bp) of exons (above) and introns (below) are shown.
Description The gene has 7 exons (two alternative exons 1) and 6 introns comprising 91545 bp.
Transcription Transcription takes place in a centromeric -> telomeric orientation. The length of the processed mRNA is about 4744 bp. EMBL lists two alternativly spliced forms other than those concerning exons 1a/b.
Pseudogene 2q33-q35, 17q11-q12

Protein

 
  Schematic diagram of E2F3 protein structure. E2F3A is shown in the upper part, E2F3B below. The proteins differ in their N-terminal regions comprising 132 and 6 amino acid residues, respectively. N: nuclear localization sequence, LZ: leucine zipper (blue), RBD: pRB binding domain (light blue). DNA binding domain (yellow), dimerization domain (red), transactivation domain (green). The positions of amino acid residues are indicated.
Description E2F3A comprises 465 amino acid residues (49 kDa), E2F3B comprises 334 amino acid residues.
Expression ubiquitous
Localisation nuclear
Function E2F3 is a sequence-specific transcription factor implicated in cell cycle regulation (S-phase). It is a transcriptional activator for E2F-responsive genes. E2F proteins heterodimerize with DP proteins and are subject to inhibition by binding to the pocket domain of retinoblastoma protein (pRB). Phosphorylation of pRB sets E2F proteins free to regulate their target genes.
Homology E2F transcription factor family consists of E2F-proteins (E2F1-6) and DP-proteins (DP1, DP2).

Mutations

Note Gene mutations have not been described hitherto.
Germinal Not known
Somatic Not known

Implicated in

Entity amp(6)(p22)
Note Medium-to-high-level genomic amplification sometimes resulting in HSR formation and believed to target E2F3 which lies within the common amplified region (see image below). Genomic amplification may not be required for over-expression.
Disease Notably, bladder and prostate cancers.
Prognosis Associated with invasiveness in bladder cancer, and with poor survival in prostate cancer. Circa 33% of primary transitional cell carcinomas of the bladder overexpress nuclear E2F3 protein.
Cytogenetics Presumptive target of genomic amplification at 6p22 in bladder cancer where it effects E2F3 overexpression (as exemplified by the bladder cancer cell lines 5637 and HT-1367). However, E2F3 may not be the only target gene inside the common amplified region.
 
Genomic amplification of E2F3: FISH image shows HT-1376 bladder cancer cell line (DSMZ acc 397) hybridized with a BAC clone (RPMI-99F1) covering the E2F3 locus at 6p22.3. (See breakpoint diagram below for map.) Note high level genomic amplification comprising multiple tandemly repeated copies of E2F3 via formation of an homogeneously staining region (HSR) in a marker chromosome - a hallmark of oncogene activity. Similar findings have been reported in both primary bladder and prostate cancers. Analysis of E2F3 protein has confirmed overexpression in cell lines evidencing genomic amplification, including HT-1376 as well as 5637 (DSMZ acc 35) and TCC-SUP (DSMZ acc 377).
Hybrid/Mutated Gene Not yet reported
  
Entity t(6;9)(p22;p13)
Note Observed in a DLBCL cell line: yet to be described clinically.
Disease Diffuse large B-cell lymphoma (DLBCL).
Prognosis Unknown
Cytogenetics Breakpoint lies upstream of E2F3 and juxtaposes upstream (regulatory) region of PAX5.
See below
Hybrid/Mutated Gene Not yet reported
Oncogenesis E2F3 behaves like a classical oncogene and is subject to upregulation via genomic amplification in bladder and prostate cancers. Upregulated E2F3 stimulates cycle progression and proliferation. E2F3 transcription is induced by MYC and these together conspire to promote G1/S-phase transition. This activity is negatively regulated by binding of the E2F transactivation domain to RB1 or p107. In prostate cancer, oncogenesis directed by E2F3 may be mediated by the polycomb group protein Enhancer of Zeste Homolog gene 2 (EZH2). E2F3 may also activate survivin transcription.
In Hodgkin lymphoma which, though lacking recurrent chromosomal rearrangements at 6p22, shows a pattern of gene dysregulation reminiscent of prostate cancer, E2F3 regulates HLXB9 expression which in turn drives IL-6 expression thought to play a central role in this enigmatic tumor.
E2F3 may also act as a tumor suppressor though the supporting evidence is tentative. Thus, while E2F3 loss results in centrosome defects associated with aneuploidy and promotes metastasis of medullary thyroid carcinoma, E2F3 -/- mice show no excess tumor incidence. Furthermore, loss of E2F3 has been associated with suppression of pituitary tumors.
  

Breakpoints

 
  Figure depicts location of sole E2F3 breakpoint described hitherto, lying approximately 50-150 Kbp upstream of the transcription unit as detected in a complex t(6;9)(p22;p13) in a DLBCL cell line. The upstream region of E2F3 is thus juxtaposed with the upstream regulatory region of PAX5. Figure shows genes flanking E2F3 together with RPCI-11 library clones.

External links

Nomenclature
HGNC (Hugo)E2F3   3115
Entrez_Gene (NCBI)E2F3  1871  E2F transcription factor 3
Cards
AtlasE2F3ID40384ch6p22
GeneCards (Weizmann)E2F3
Ensembl (Hinxton)ENSG00000112242 [Gene_View]  chr6:20404034-20493945 [Contig_View]  E2F3 [Vega]
AceView (NCBI)E2F3
Genatlas (Paris)E2F3
euGene (Indiana)1871
SOURCE (Stanford)NM_001243076 NM_001949
Genomic and cartography
GoldenPath (UCSC)E2F3  -  6p22.3   chr6:20404034-20493945 +  6p22   [Description]    (hg19-Feb_2009)
EnsemblE2F3 - 6p22 [CytoView]
Mapping of homologs : NCBIE2F3 [Mapview]
OMIM600427   
Gene and transcription
Genbank (Entrez)BC016847 BC099908 BC114554 BC156367 BC172526
RefSeq transcript (SRS)NM_001243076 NM_001949
RefSeq transcript (Entrez)NM_001243076 NM_001949
RefSeq genomic (SRS)AC_000138 NC_000006 NG_029591 NT_007592 NW_001838973
RefSeq genomic (Entrez)AC_000138 NC_000006 NG_029591 NT_007592 NW_001838973
Consensus coding sequences : CCDS (NCBI)E2F3
Cluster EST : UnigeneHs.703174 [ SRS ] Hs.703174 [ NCBI ]
Alternative Splicing : Fast-db (Paris)3300
Alternative Splicing GalleryENSG00000112242
Gene ExpressionE2F3 [ NCBI-GEO ]   E2F3 [ EBI - ARRAY_EXPRESS ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO00716 (SRS) O00716 (Uniprot)
With graphics : InterProO00716
Splice isoforms : SwissVarO00716(Swissvar)
Domains : Interpro (SRS)E2F    E2F_TDP    WHTH_trsnscrt_rep_DNA-bd   
Domains : Interpro (EBI)E2F    E2F_TDP    WHTH_trsnscrt_rep_DNA-bd   
Related proteins : CluSTrO00716
Domain families : Pfam (SRS)E2F_TDP (PF02319)   
Domain families : Pfam (Sanger)E2F_TDP (PF02319)   
Domain families : Pfam (NCBI)pfam02319   
Blocks (Seattle)O00716
Human Protein AtlasENSG00000112242
HPRD02693
IPIIPI00743509   IPI00647428   IPI01011332   IPI00386286   
Protein Interaction databases
DIP (DOE-UCLA)O00716
IntAct (EBI)O00716
FunCoupENSG00000112242
REACTOMEE2F3
BioGRIDE2F3
InParanoidO00716
Interologous Interaction database O00716
Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)E2F3
SNP (GeneSNP Utah)E2F3
SNP : HGBaseE2F3
Genetic variants : HAPMAPE2F3
Somatic Mutations in Cancer : COSMICE2F3 
CONAN: Copy Number AnalysisE2F3 
Mutations and Diseases : HGMDE2F3
OMIM600427   
GENETests600427   
Disease Genetic AssociationE2F3
Huge Navigator E2F3 [HugePedia]  E2F3 [HugeCancerGEM]
Genomic VariantsE2F3
snp3D : Map Gene to Disease1871
General knowledge
Homologs : HomoloGeneE2F3
Homology/Alignments : Family Browser (UCSC)E2F3
Phylogenetic Trees/Animal Genes : TreeFamE2F3
Chemical/Protein Interactions : CTD1871
Chemical/Pharm GKB GenePA27573
Clinical trialE2F3
Cancer Resource (Charite)ENSG00000112242
Ontology : AmiGOG1 phase of mitotic cell cycle  G2 phase of mitotic cell cycle  mitotic cell cycle  core promoter binding  DNA binding  sequence-specific DNA binding transcription factor activity  cyclin-dependent protein kinase activity  protein binding  nucleus  nucleoplasm  transcription factor complex  regulation of transcription, DNA-dependent  transcription initiation from RNA polymerase II promoter  positive regulation of cell proliferation  positive regulation of transcription, DNA-dependent  
Ontology : EGO-EBIG1 phase of mitotic cell cycle  G2 phase of mitotic cell cycle  mitotic cell cycle  core promoter binding  DNA binding  sequence-specific DNA binding transcription factor activity  cyclin-dependent protein kinase activity  protein binding  nucleus  nucleoplasm  transcription factor complex  regulation of transcription, DNA-dependent  transcription initiation from RNA polymerase II promoter  positive regulation of cell proliferation  positive regulation of transcription, DNA-dependent  
Other databases
Probes
Probes : ImagenesE2F3 Related clones (RZPD - Berlin)
Litterature
PubMed61 Pubmed reference(s) in Entrez
PubGeneE2F3
iHOPE2F3

Bibliography

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PMID 9242506
 
E2F-3 accumulation is regulated by polypeptide stability.
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E2F3 activity is regulated during the cell cycle and is required for the induction of S phase.
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E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation.
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PMID 9438389
 
Upregulation of E2F transcription factors in chemically induced mouse skin tumors.
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PMID 10402252
 
Neural precursor cells differentiating in the absence of Rb exhibit delayed terminal mitosis and deregulated E2F 1 and 3 activity.
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PMID 10068462
 
Expression of the E2F family in human gastrointestinal carcinomas.
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PMID 10225440
 
Differential regulation of E2F transcription factors by p53 tumor suppressor protein.
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PMID 10619603
 
Complex transcriptional regulatory mechanisms control expression of the E2F3 locus.
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PMID 10779353
 
A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts.
Berns K, Hijmans EM, Koh E, Daley GQ, Bernards R
Oncogene. 2000 ; 19 (29) : 3330-3334.
PMID 10918589
 
CpG methylation as a mechanism for the regulation of E2F activity.
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Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (12) : 6481-6486.
PMID 10823896
 
Deregulated E2F transcriptional activity in autonomously growing melanoma cells.
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PMID 10727462
 
Identification of E2F-3B, an alternative form of E2F-3 lacking a conserved N-terminal region.
He Y, Armanious MK, Thomas MJ, Cress WD
Oncogene. 2000 ; 19 (30) : 3422-3433.
PMID 10918599
 
E2f3 is critical for normal cellular proliferation.
Humbert PO, Verona R, Trimarchi JM, Rogers C, Dandapani S, Lees JA
Genes & development. 2000 ; 14 (6) : 690-703.
PMID 10733529
 
Identification of a novel E2F3 product suggests a mechanism for determining specificity of repression by Rb proteins.
Leone G, Nuckolls F, Ishida S, Adams M, Sears R, Jakoi L, Miron A, Nevins JR
Molecular and cellular biology. 2000 ; 20 (10) : 3626-3632.
PMID 10779352
 
Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression.
Takahashi Y, Rayman JB, Dynlacht BD
Genes & development. 2000 ; 14 (7) : 804-816.
PMID 10766737
 
Myc requires distinct E2F activities to induce S phase and apoptosis.
Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park CH, Giangrande P, Wu L, Saavedra HI, Field SJ, Thompson MA, Yang H, Fujiwara Y, Greenberg ME, Orkin S, Smith C, Nevins JR
Molecular cell. 2001 ; 8 (1) : 105-113.
PMID 11511364
 
E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis.
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Genes & development. 2001 ; 15 (3) : 267-285.
PMID 11159908
 
The E2F1-3 transcription factors are essential for cellular proliferation.
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Nature. 2001 ; 414 (6862) : 457-462.
PMID 11719808
 
E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos.
Ziebold U, Reza T, Caron A, Lees JA
Genes & development. 2001 ; 15 (4) : 386-391.
PMID 11230146
 
Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo.
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Molecular and cellular biology. 2002 ; 22 (8) : 2663-2672.
PMID 11909960
 
The genetics of the E2F family of transcription factors: shared functions and unique roles.
DeGregori J
Biochimica et biophysica acta. 2002 ; 1602 (2) : 131-150.
PMID 12020800
 
Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.
Parisi T, Pollice A, Di Cristofano A, Calabrˆū V, La Mantia G
Biochemical and biophysical research communications. 2002 ; 291 (5) : 1138-1145.
PMID 11883935
 
E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis.
Polager S, Kalma Y, Berkovich E, Ginsberg D
Oncogene. 2002 ; 21 (3) : 437-446.
PMID 11821956
 
Specificity of E2F1, E2F2, and E2F3 in mediating phenotypes induced by loss of Rb.
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Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 2002 ; 13 (5) : 215-225.
PMID 12065245
 
Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function.
Schlisio S, Halperin T, Vidal M, Nevins JR
The EMBO journal. 2002 ; 21 (21) : 5775-5786.
PMID 12411495
 
Identification of E-box factor TFE3 as a functional partner for the E2F3 transcription factor.
Giangrande PH, Hallstrom TC, Tunyaplin C, Calame K, Nevins JR
Molecular and cellular biology. 2003 ; 23 (11) : 3707-3720.
PMID 12748276
 
Specificity in the activation and control of transcription factor E2F-dependent apoptosis.
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Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (19) : 10848-10853.
PMID 12954980
 
Gene expression phenotypic models that predict the activity of oncogenic pathways.
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Nature genetics. 2003 ; 34 (2) : 226-230.
PMID 12754511
 
Inhibition of cell proliferation and induction of apoptosis by novel tetravalent peptides inhibiting DNA binding of E2F.
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Oncogene. 2003 ; 22 (32) : 4943-4952.
PMID 12902977
 
Inactivation of E2F3 results in centrosome amplification.
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Cancer cell. 2003 ; 3 (4) : 333-346.
PMID 12726860
 
Inhibition of retinoblastoma protein (Rb) phosphorylation at serine sites and an increase in Rb-E2F complex formation by silibinin in androgen-dependent human prostate carcinoma LNCaP cells: role in prostate cancer prevention.
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Molecular cancer therapeutics. 2002 ; 1 (7) : 525-532.
PMID 12479270
 
Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors.
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PMID 12782593
 
Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression.
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PMID 12554697
 
E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas.
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Molecular and cellular biology. 2003 ; 23 (18) : 6542-6552.
PMID 12944480
 
Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics.
Aslanian A, Iaquinta PJ, Verona R, Lees JA
Genes & development. 2004 ; 18 (12) : 1413-1422.
PMID 15175242
 
Amplification and overexpression of E2F3 in human bladder cancer.
Feber A, Clark J, Goodwin G, Dodson AR, Smith PH, Fletcher A, Edwards S, Flohr P, Falconer A, Roe T, Kovacs G, Dennis N, Fisher C, Wooster R, Huddart R, Foster CS, Cooper CS
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PMID 14716298
 
Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome.
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Oncogene. 2004 ; 23 (35) : 5871-5879.
PMID 15184867
 
Combinatorial gene control involving E2F and E Box family members.
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The EMBO journal. 2004 ; 23 (6) : 1336-1347.
PMID 15014447
 
E2F3-a novel repressor of the ARF/p53 pathway.
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Developmental cell. 2004 ; 6 (6) : 742-743.
PMID 15177020
 
Aberrant regulation of survivin by the RB/E2F family of proteins.
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PMID 15271987
 
E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer.
Oeggerli M, Tomovska S, Schraml P, Calvano-Forte D, Schafroth S, Simon R, Gasser T, Mihatsch MJ, Sauter G
Oncogene. 2004 ; 23 (33) : 5616-5623.
PMID 15122326
 
Mitoinhibitory effects of the tumor promoter 2-acetylaminofluorene in rat liver: loss of E2F-1 and E2F-3 expression and cdk 2 kinase activity in late G1.
Ohlson LC, Koroxenidou L, Porsch-Hˆ§llstrˆm I
Journal of hepatology. 2004 ; 40 (6) : 957-962.
PMID 15158336
 
E2Fs link the control of G1/S and G2/M transcription.
Zhu W, Giangrande PH, Nevins JR
The EMBO journal. 2004 ; 23 (23) : 4615-4626.
PMID 15510213
 
Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland.
Lazzerini Denchi E, Attwooll C, Pasini D, Helin K
Molecular and cellular biology. 2005 ; 25 (7) : 2660-2672.
PMID 15767672
 
Divergent siblings: E2F2 and E2F4 but not E2F1 and E2F3 induce DNA synthesis in cardiomyocytes without activation of apoptosis.
Ebelt H, Hufnagel N, Neuhaus P, Neuhaus H, Gajawada P, Simm A, Mˆšller-Werdan U, Werdan K, Braun T
Circulation research. 2005 ; 96 (5) : 509-517.
PMID 15718499
 
HLXB9 activates IL6 in Hodgkin lymphoma cell lines and is regulated by PI3K signalling involving E2F3.
Nagel S, Scherr M, Quentmeier H, Kaufmann M, Zaborski M, Drexler HG, MacLeod RA
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2005 ; 19 (5) : 841-846.
PMID 15772702
 
E2F1 is crucial for E2F-dependent apoptosis.
Lazzerini Denchi E, Helin K
EMBO reports. 2005 ; 6 (7) : 661-668.
PMID 15976820
 
Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer.
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PMID 15876350
 
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Contributor(s)

Written07-2005Roderick AF MacLeod, Stefan Nagel
DSMZ-Deutsche Sammlung von, Mikroorganismen und Zellkulturen, Inhoffenstr. 7B, D-38124 Braunschweig, Germany

Citation

This paper should be referenced as such :
MacLeod RAF, Nagel S . E2F3 (E2F transcription factor 3). Atlas Genet Cytogenet Oncol Haematol. July 2005 .
URL : http://AtlasGeneticsOncology.org/Genes/E2F3ID40384ch6p22.html

This paper is referenced by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/38239/1/07-2005-E2F3ID40384ch6p22.pdf   [ Bibliographic record ]

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