E2F3 (E2F transcription factor 3)

2005-07-01   Roderick AF MacLeod  , Stefan Nagel  

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

Atlas Image
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

Atlas Image
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
Atlas Image
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

Atlas Image
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.

Article Bibliography

Pubmed IDLast YearTitleAuthors
107793532000Complex transcriptional regulatory mechanisms control expression of the E2F3 locus.Adams MR et al
151752422004Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics.Aslanian A et al
104022521999Upregulation of E2F transcription factors in chemically induced mouse skin tumors.Balasubramanian S et al
109185892000A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts.Berns K et al
100684621999Neural precursor cells differentiating in the absence of Rb exhibit delayed terminal mitosis and deregulated E2F 1 and 3 activity.Callaghan DA et al
108238962000CpG methylation as a mechanism for the regulation of E2F activity.Campanero MR et al
119099602002Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo.Cloud JE et al
93763161997Expression patterns of the E2F family of transcription factors during mouse nervous system development.Dagnino L et al
120208002002The genetics of the E2F family of transcription factors: shared functions and unique roles.DeGregori J et al
92070761997Distinct roles for E2F proteins in cell growth control and apoptosis.DeGregori J et al
157184992005Divergent siblings: E2F2 and E2F4 but not E2F1 and E2F3 induce DNA synthesis in cardiomyocytes without activation of apoptosis.Ebelt H et al
147162982004Amplification and overexpression of E2F3 in human bladder cancer.Feber A et al
95464301998E2F-3 accumulation is regulated by polypeptide stability.Flores AM et al
151848672004Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome.Foster CS et al
150144472004Combinatorial gene control involving E2F and E Box family members.Giangrande PH et al
151770202004E2F3-a novel repressor of the ARF/p53 pathway.Ginsberg D et al
107274622000Deregulated E2F transcriptional activity in autonomously growing melanoma cells.Halaban R et al
129549802003Specificity in the activation and control of transcription factor E2F-dependent apoptosis.Hallstrom TC et al
109185992000Identification of E2F-3B, an alternative form of E2F-3 lacking a conserved N-terminal region.He Y et al
88469211996Differential effects of cdk2 and cdk3 on the control of pRb and E2F function during G1 exit.Hofmann F et al
127545112003Gene expression phenotypic models that predict the activity of oncogenic pathways.Huang E et al
107335292000E2f3 is critical for normal cellular proliferation.Humbert PO et al
152719872004Aberrant regulation of survivin by the RB/E2F family of proteins.Jiang Y et al
92425061997E2F as a regulator of keratinocyte proliferation: implications for skin tumor development.Jones SJ et al
159768202005E2F1 is crucial for E2F-dependent apoptosis.Lazzerini Denchi E et al
82469961993The retinoblastoma protein binds to a family of E2F transcription factors.Lees JA et al
96790571998E2F3 activity is regulated during the cell cycle and is required for the induction of S phase.Leone G et al
107793522000Identification of a novel E2F3 product suggests a mechanism for determining specificity of repression by Rb proteins.Leone G et al
115113642001Myc requires distinct E2F activities to induce S phase and apoptosis.Leone G et al
86226491996Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression.Lukas J et al
111599082001E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis.Müller H et al
129029772003Inhibition of cell proliferation and induction of apoptosis by novel tetravalent peptides inhibiting DNA binding of E2F.Montigiani S et al
157727022005HLXB9 activates IL6 in Hodgkin lymphoma cell lines and is regulated by PI3K signalling involving E2F3.Nagel S et al
151223262004E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer.Oeggerli M et al
151583362004Mitoinhibitory 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
118839352002Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.Parisi T et al
118219562002E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis.Polager S et al
127268602003Inactivation of E2F3 results in centrosome amplification.Saavedra HI et al
124114952002Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function.Schlisio S et al
94383891998E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation.Strom DK et al
102254401999Expression of the E2F family in human gastrointestinal carcinomas.Suzuki T et al
107667372000Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression.Takahashi Y et al
124792702002Inhibition 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
106196031999Differential regulation of E2F transcription factors by p53 tumor suppressor protein.Vaishnav YN et al
127825932003Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors.Veltman JA et al
117198082001The E2F1-3 transcription factors are essential for cellular proliferation.Wu L et al
158763502005Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer.Wu Q et al
78779821995Multiple members of the E2F transcription factor family are the products of oncogenes.Xu G et al
155102132004E2Fs link the control of G1/S and G2/M transcription.Zhu W et al
125546972003Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression.Zhu Y et al
129444802003E2F3 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
112301462001E2F3 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 IDTranscript IDUniprot
ENSG00000112242ENST00000346618O00716
ENSG00000112242ENST00000535432O00716
ENSG00000112242ENST00000613242A0A087X0B6

Expression (GTEx)

0
5
10
15
20
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

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
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G1 PhaseREACTOMER-HSA-69236
Cyclin D associated events in G1REACTOMER-HSA-69231
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
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oncogene Induced SenescenceREACTOMER-HSA-2559585
Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580
Endocrine resistanceKEGGko01522
Endocrine resistanceKEGGhsa01522
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224

References

Pubmed IDYearTitleCitations
377756192024MiR-210-3p enhances intermittent hypoxia-induced tumor progression via inhibition of E2F3.2
381941582024Transcription factor E2F3 activates CDC25B to regulate DNA damage and promote mitoxantrone resistance in stomach adenocarcinoma.0
383809572024FTO promotes the progression of retinoblastoma through YTHDF2-dependent N6-methyladenosine modification in E2F3.0
377756192024MiR-210-3p enhances intermittent hypoxia-induced tumor progression via inhibition of E2F3.2
381941582024Transcription factor E2F3 activates CDC25B to regulate DNA damage and promote mitoxantrone resistance in stomach adenocarcinoma.0
383809572024FTO promotes the progression of retinoblastoma through YTHDF2-dependent N6-methyladenosine modification in E2F3.0
361620092023Interaction of E2F3a and CASP8AP2 Regulates Histone Expression and Chemosensitivity of Leukemic Cells.0
367382822023CircKRT14 upregulates E2F3 by interacting with miR-1256 to act as an oncogenic factor in esophageal cancer.0
372873692023Circ_001422 aggravates osteosarcoma progression through targeting miR-497-5p/E2F3 axis.0
374999292023E2F3 induces DNA damage repair, stem-like properties and therapy resistance in breast cancer.0
361620092023Interaction of E2F3a and CASP8AP2 Regulates Histone Expression and Chemosensitivity of Leukemic Cells.0
367382822023CircKRT14 upregulates E2F3 by interacting with miR-1256 to act as an oncogenic factor in esophageal cancer.0
372873692023Circ_001422 aggravates osteosarcoma progression through targeting miR-497-5p/E2F3 axis.0
374999292023E2F3 induces DNA damage repair, stem-like properties and therapy resistance in breast cancer.0
344182322022Long noncoding RNA plasmacytoma variant translocation 1 promotes progression of colorectal cancer by sponging microRNA-152-3p and regulating E2F3/MAPK8 signaling.13

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/css/tumors-explorer/gene-fusions-explorer/