E2F3 (E2F transcription factor 3)

2005-07-01 Roderick AF MacLeod , Stefan Nagel Affiliation

DSMZ-Deutsche Sammlung von, Mikroorganismen und Zellkulturen, Inhoffenstr. 7B, D-38124 Braunschweig, Germany

Identity

HGNC

E2F3

LOCATION

6p22.3

LOCUSID

1871

ALIAS

E2F-3

FUSION GENES

Show Gene Fusions

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

Proteins

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 name

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.

Hybrid gene

Not yet reported

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).

Entity name

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.

Hybrid gene

Not yet reported

See below

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.

Bibliography

Pubmed ID	Last Year	Title	Authors
10779353	2000	Complex transcriptional regulatory mechanisms control expression of the E2F3 locus.	Adams MR et al
15175242	2004	Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics.	Aslanian A et al
10402252	1999	Upregulation of E2F transcription factors in chemically induced mouse skin tumors.	Balasubramanian S et al
10918589	2000	A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts.	Berns K et al
10068462	1999	Neural precursor cells differentiating in the absence of Rb exhibit delayed terminal mitosis and deregulated E2F 1 and 3 activity.	Callaghan DA et al
10823896	2000	CpG methylation as a mechanism for the regulation of E2F activity.	Campanero MR et al
11909960	2002	Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo.	Cloud JE et al
9376316	1997	Expression patterns of the E2F family of transcription factors during mouse nervous system development.	Dagnino L et al
12020800	2002	The genetics of the E2F family of transcription factors: shared functions and unique roles.	DeGregori J et al
9207076	1997	Distinct roles for E2F proteins in cell growth control and apoptosis.	DeGregori J et al
15718499	2005	Divergent siblings: E2F2 and E2F4 but not E2F1 and E2F3 induce DNA synthesis in cardiomyocytes without activation of apoptosis.	Ebelt H et al
14716298	2004	Amplification and overexpression of E2F3 in human bladder cancer.	Feber A et al
9546430	1998	E2F-3 accumulation is regulated by polypeptide stability.	Flores AM et al
15184867	2004	Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome.	Foster CS et al
15014447	2004	Combinatorial gene control involving E2F and E Box family members.	Giangrande PH et al
15177020	2004	E2F3-a novel repressor of the ARF/p53 pathway.	Ginsberg D et al
10727462	2000	Deregulated E2F transcriptional activity in autonomously growing melanoma cells.	Halaban R et al
12954980	2003	Specificity in the activation and control of transcription factor E2F-dependent apoptosis.	Hallstrom TC et al
10918599	2000	Identification of E2F-3B, an alternative form of E2F-3 lacking a conserved N-terminal region.	He Y et al
8846921	1996	Differential effects of cdk2 and cdk3 on the control of pRb and E2F function during G1 exit.	Hofmann F et al
12754511	2003	Gene expression phenotypic models that predict the activity of oncogenic pathways.	Huang E et al
10733529	2000	E2f3 is critical for normal cellular proliferation.	Humbert PO et al
15271987	2004	Aberrant regulation of survivin by the RB/E2F family of proteins.	Jiang Y et al
9242506	1997	E2F as a regulator of keratinocyte proliferation: implications for skin tumor development.	Jones SJ et al
15976820	2005	E2F1 is crucial for E2F-dependent apoptosis.	Lazzerini Denchi E et al
8246996	1993	The retinoblastoma protein binds to a family of E2F transcription factors.	Lees JA et al
9679057	1998	E2F3 activity is regulated during the cell cycle and is required for the induction of S phase.	Leone G et al
10779352	2000	Identification of a novel E2F3 product suggests a mechanism for determining specificity of repression by Rb proteins.	Leone G et al
11511364	2001	Myc requires distinct E2F activities to induce S phase and apoptosis.	Leone G et al
8622649	1996	Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression.	Lukas J et al
11159908	2001	E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis.	Müller H et al
12902977	2003	Inhibition of cell proliferation and induction of apoptosis by novel tetravalent peptides inhibiting DNA binding of E2F.	Montigiani S et al
15772702	2005	HLXB9 activates IL6 in Hodgkin lymphoma cell lines and is regulated by PI3K signalling involving E2F3.	Nagel S et al
15122326	2004	E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer.	Oeggerli M et al
15158336	2004	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 et al
11883935	2002	Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.	Parisi T et al
11821956	2002	E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis.	Polager S et al
12726860	2003	Inactivation of E2F3 results in centrosome amplification.	Saavedra HI et al
12411495	2002	Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function.	Schlisio S et al
9438389	1998	E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation.	Strom DK et al
10225440	1999	Expression of the E2F family in human gastrointestinal carcinomas.	Suzuki T et al
10766737	2000	Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression.	Takahashi Y et al
12479270	2002	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.	Tyagi A et al
10619603	1999	Differential regulation of E2F transcription factors by p53 tumor suppressor protein.	Vaishnav YN et al
12782593	2003	Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors.	Veltman JA et al
11719808	2001	The E2F1-3 transcription factors are essential for cellular proliferation.	Wu L et al
15876350	2005	Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer.	Wu Q et al
7877982	1995	Multiple members of the E2F transcription factor family are the products of oncogenes.	Xu G et al
15510213	2004	E2Fs link the control of G1/S and G2/M transcription.	Zhu W et al
12554697	2003	Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression.	Zhu Y et al
12944480	2003	E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas.	Ziebold U et al
11230146	2001	E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos.	Ziebold U et al

Other Information

Locus ID:

NCBI: 1871
MIM: 600427
HGNC: 3115
Ensembl: ENSG00000112242

Variants:

dbSNP: 1871
ClinVar: 1871
TCGA: ENSG00000112242
COSMIC: E2F3

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000112242	ENST00000346618	O00716
ENSG00000112242	ENST00000535432	O00716
ENSG00000112242	ENST00000613242	A0A087X0B6

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Cell cycle	KEGG	ko04110
Pancreatic cancer	KEGG	ko05212
Glioma	KEGG	ko05214
Prostate cancer	KEGG	ko05215
Melanoma	KEGG	ko05218
Bladder cancer	KEGG	ko05219
Chronic myeloid leukemia	KEGG	ko05220
Small cell lung cancer	KEGG	ko05222
Non-small cell lung cancer	KEGG	ko05223
Cell cycle	KEGG	hsa04110
Pathways in cancer	KEGG	hsa05200
Pancreatic cancer	KEGG	hsa05212
Glioma	KEGG	hsa05214
Prostate cancer	KEGG	hsa05215
Melanoma	KEGG	hsa05218
Bladder cancer	KEGG	hsa05219
Chronic myeloid leukemia	KEGG	hsa05220
Small cell lung cancer	KEGG	hsa05222
Non-small cell lung cancer	KEGG	hsa05223
HTLV-I infection	KEGG	ko05166
HTLV-I infection	KEGG	hsa05166
Hepatitis B	KEGG	hsa05161
MicroRNAs in cancer	KEGG	hsa05206
MicroRNAs in cancer	KEGG	ko05206
Cell cycle - G1/S transition	KEGG	hsa_M00692
Cell cycle - G1/S transition	KEGG	M00692
Signal Transduction	REACTOME	R-HSA-162582
Signaling by NOTCH	REACTOME	R-HSA-157118
Pre-NOTCH Expression and Processing	REACTOME	R-HSA-1912422
Pre-NOTCH Transcription and Translation	REACTOME	R-HSA-1912408
Cell Cycle	REACTOME	R-HSA-1640170
Cell Cycle, Mitotic	REACTOME	R-HSA-69278
Mitotic G1-G1/S phases	REACTOME	R-HSA-453279
G1 Phase	REACTOME	R-HSA-69236
Cyclin D associated events in G1	REACTOME	R-HSA-69231
Regulation of DNA replication	REACTOME	R-HSA-69304
Association of licensing factors with the pre-replicative complex	REACTOME	R-HSA-69298
Mitotic G2-G2/M phases	REACTOME	R-HSA-453274
G2 Phase	REACTOME	R-HSA-68911
M/G1 Transition	REACTOME	R-HSA-68874
DNA Replication Pre-Initiation	REACTOME	R-HSA-69002
Assembly of the pre-replicative complex	REACTOME	R-HSA-68867
CDC6 association with the ORC:origin complex	REACTOME	R-HSA-68689
DNA Replication	REACTOME	R-HSA-69306
Cellular responses to stress	REACTOME	R-HSA-2262752
Cellular Senescence	REACTOME	R-HSA-2559583
Oncogene Induced Senescence	REACTOME	R-HSA-2559585
Oxidative Stress Induced Senescence	REACTOME	R-HSA-2559580
Endocrine resistance	KEGG	ko01522
Endocrine resistance	KEGG	hsa01522
Breast cancer	KEGG	ko05224
Breast cancer	KEGG	hsa05224

References

Pubmed ID	Year	Title	Citations
17135249	2007	An E2F/miR-20a autoregulatory feedback loop.	238
27351135	2016	Long non-coding RNA NEAT1 promotes non-small cell lung cancer progression through regulation of miR-377-3p-E2F3 pathway.	104
20308562	2010	Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds.	99
12411495	2002	Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function.	96
18810376	2009	MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a.	92
21067862	2011	Dysregulation of microRNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells.	69
22345517	2012	Pumilio facilitates miRNA regulation of the E2F3 oncogene.	68
14716298	2004	Amplification and overexpression of E2F3 in human bladder cancer.	51
22139708	2012	MicroRNA-200b reverses chemoresistance of docetaxel-resistant human lung adenocarcinoma cells by targeting E2F3.	48
16180235	2006	Expression analysis of 6p22 genomic gain in retinoblastoma.	47

Citation

Roderick AF MacLeod ; Stefan Nagel

E2F3 (E2F transcription factor 3)

Atlas Genet Cytogenet Oncol Haematol. 2005-07-01

Online version: http://atlasgeneticsoncology.org/gene/40384/e2f3-(e2f-transcription-factor-3)