E2F3 (E2F transcription factor 3)

Identity

Other names	E2F-3
	KIAA0075
	Y10479
Hugo	E2F3
Location	6p22.3
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
Hugo	E2F3
GDB	E2F3
Entrez_Gene	E2F3  1871  E2F transcription factor 3
	Cards
Atlas	E2F3ID40384ch6p22
GeneCards	E2F3
Ensembl	E2F3 [Search_View]   ENSG00000112242 [Gene_View]
Genatlas	E2F3
GeneLynx	E2F3
eGenome	E2F3
euGene	1871
	Genomic and cartography
GoldenPath	E2F3  -  6p22.3   chr6:20510377-20601920 +  6p22   [Description]    (hg18-Mar_2006)
Ensembl	E2F3 - 6p22 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	E2F3
	Gene and transcription
Genbank	BC016847 [ ENTREZ ]
Genbank	BC099908 [ ENTREZ ]
Genbank	BC114554 [ ENTREZ ]
Genbank	BC156367 [ ENTREZ ]
Genbank	CR597993 [ ENTREZ ]
RefSeq	NM_001949 [ SRS ]    NM_001949 [ ENTREZ ]
RefSeq	AC_000049 [ SRS ]    AC_000049 [ ENTREZ ]
RefSeq	NC_000006 [ SRS ]    NC_000006 [ ENTREZ ]
RefSeq	NT_007592 [ SRS ]    NT_007592 [ ENTREZ ]
RefSeq	NW_922984 [ SRS ]    NW_922984 [ ENTREZ ]
AceView	E2F3 AceView - NCBI
Unigene	Hs.703174 [ SRS ]    Hs.703174 [ NCBI ]     HS703174 [ spliceNest ]
Fast-db	3300 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	O00716 [ SRS]    O00716 [ EXPASY ]     O00716 [ INTERPRO ]
Interpro	IPR015633 E2F [ SRS ]    IPR015633 E2F [ EBI ]
Interpro	IPR003316 E2F_TDP [ SRS ]    IPR003316 E2F_TDP [ EBI ]
Interpro	IPR011991 Wing_hlx_DNA_bd [ SRS ]    IPR011991 Wing_hlx_DNA_bd [ EBI ]
CluSTr	O00716
Pfam	PF02319 E2F_TDP [ SRS ]    PF02319 E2F_TDP [ Sanger ]    pfam02319 [ NCBI-CDD ]
Blocks	O00716
HPRD	02693
	Protein Interaction databases
DIP	O00716
IntAct	O00716
	Polymorphism : SNP, mutations, diseases
OMIM	600427    [ map ]
GENECLINICS	600427
SNP	E2F3 [dbSNP-NCBI]
SNP	NM_001949 [SNP-NCI]
SNP	E2F3 [GeneSNPs - Utah]  E2F3] [HGBASE - SRS]
HAPMAP	E2F3 [HAPMAP]
COSMIC	E2F3 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	E2F3
	General knowledge
Family Browser	E2F3 [UCSC Family Browser]
SOURCE	NM_001949
SMD	Hs.703174
SAGE	Hs.703174
GO	transcription factor activity [Amigo]  transcription factor activity
GO	transcription factor activity [Amigo]  transcription factor activity
GO	protein binding [Amigo]  protein binding
GO	nucleus [Amigo]  nucleus
GO	transcription factor complex [Amigo]  transcription factor complex
GO	transcription [Amigo]  transcription
GO	regulation of transcription, DNA-dependent [Amigo]  regulation of transcription, DNA-dependent
GO	transcription initiation from RNA polymerase II promoter [Amigo]  transcription initiation from RNA polymerase II promoter
GO	cell cycle [Amigo]  cell cycle
PubGene	E2F3
TreeFam	E2F3
CTD	1871 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	E2F3 Related clones (RZPD - Berlin)
	PubMed
PubMed	37 Pubmed reference(s) in LocusLink

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A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts.

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PMID 10918589

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PMID 10779352

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Genes & development. 2000 ; 14 (7) : 804-816.

PMID 10766737

Myc requires distinct E2F activities to induce S phase and apoptosis.

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PMID 11511364

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PMID 15014447

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PMID 15177020

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PMID 15122326

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PMID 15158336

E2Fs link the control of G1/S and G2/M transcription.

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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

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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

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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)

Written	07-2005	Roderick 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

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:23:10 2008