E2F1 (E2F transcription factor 1)

2008-12-01 Michael Zachariadis , Vassilios G Gorgoulis Affiliation

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

Identity

HGNC

E2F1

LOCATION

20q11.22

LOCUSID

1869

ALIAS

E2F-1,RBAP1,RBBP3,RBP3

FUSION GENES

Show Gene Fusions

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

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 p14^ARF 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 p45^skp2-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

Note

In non-small cell lung carcinomas (NSCLCs) E2F1 is significantly increased due to aberrant pRB status. In these cases the elevated levels of E2F1 are positively associated with the tumour growth index whereas apoptosis is not influenced as deregulation of the P53-MDM2 regulatory loop is a common phenomenon in NSCLC. Breast, thyroid and pancreatic cancer, seem to follow this same scenario, where aberrations in the pRB pathway coupled with defective P53 status, enhance E2F1 levels promoting tumor growth. In all these cases, the higher levels of E2F1 are also correlated with poorer outcome. Nevertheless, in other cases, like colon cancer, and diffuse large B-cell lymphomas the more aggressive disease is linked to lower E2F1 expression, as E2F1 in these cases acts as an oncosuppressor, enhancing apoptosis. Likewise, in adenocarcinomas of Barrett oesophagus E2F1 expression is negatively associated with tumor progression and positively with patient survival. In the case of transitional cell bladder carcinomas (TCCs) the findings are controversial. In one series of invasive bladder tumors E2F1 seems to play a tumor suppressive role, while in another series of superficial low-grade TCCs E2F1 is positively correlated with proliferation, but not with apoptosis. This discrepancy seems to lie in the type of TCC examined and the molecular characteristics of the tissue.
The most usual genetic alteration of the E2F1 gene is amplification, as has been reported in several leukemic (e.g. the HEL human erythroleukemia cell line) and melanoma cell lines. The gene has also been found amplified in various esophageal, colorectal, cervical and ovarian cancers, as well as in lymph node metastases of melanoma, and is often linked to chromosome 20q gains in these entities. Importantly, in esophageal squamous cell carcinomas, the 20q gains and the amplification of the E2F1 gene are linked with greater aggressiveness and poorer prognosis.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
7647312	1995	Transcriptional control by E2F.	Adams PD et al
8943316	1996	Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors.	Adams PD et al
18334281	2008	E2F1 in gliomas: a paradigm of oncogene addiction.	Alonso MM et al
17907153	2007	Gene amplification is a relatively frequent event leading to ZBTB7A (Pokemon) overexpression in non-small cell lung cancer.	Apostolopoulou K et al
15538380	2004	The E2F family: specific functions and overlapping interests.	Attwooll C et al
14526389	2004	Life and death decisions by E2F-1.	Bell LA et al
12726857	2003	Emerging roles for E2F: beyond the G1/S transition and DNA replication.	Cam H et al
9122175	1997	Regulation of E2F through ubiquitin-proteasome-dependent degradation: stabilization by the pRB tumor suppressor protein.	Campanero MR et al
9281303	1997	Transcription factors and the down-regulation of G1/S boundary genes in human diploid fibroblasts during senescence.	Chen KY et al
8321204	1993	Cell cycle analysis of E2F in primary human T cells reveals novel E2F complexes and biochemically distinct forms of free E2F.	Chittenden T et al
15662116	2004	Opposing roles of E2Fs in cell proliferation and death.	Crosby ME et al
17100600	2006	Distinct and Overlapping Roles for E2F Family Members in Transcription, Proliferation and Apoptosis.	DeGregori J et al
17908803	2008	E2F-1 overexpression correlates with decreased proliferation and better prognosis in adenocarcinomas of Barrett oesophagus.	Evangelou K et al
8346196	1993	E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product.	Flemington EK et al
14696419	2003	Chromosome 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
18358829	2008	E2F1 contributes to the transcriptional activation of the KIR3DL1 gene.	Gao XN et al
12354623	2002	E2F1 pathways to apoptosis.	Ginsberg D et al
12237873	2002	Transcription 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
12954980	2003	Specificity in the activation and control of transcription factor E2F-dependent apoptosis.	Hallstrom TC et al
8413249	1993	Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein.	Helin K et al
9529602	1998	Regulation of cell proliferation by the E2F transcription factors.	Helin K et al
18294958	2008	TGFbeta-mediated formation of pRb-E2F complexes in human myeloid leukemia cells.	Hu XT et al
10504464	1999	Regulation of the G1/S transition phase in mesangial cells by E2F1.	Inoshita S et al
17100599	2006	Putting the Oncogenic and Tumor Suppressive Activities of E2F into Context.	Johnson DG et al
18440323	2008	Regulation of the human mitotic centromere-associated kinesin (MCAK) promoter by the transcription factors Sp1 and E2F1.	Jun DY et al
15466399	2004	Overexpression 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
18302937	2008	Identification of E2F1 as a positive transcriptional regulator for delta-catenin.	Kim K et al
15107604	2004	Role of E2F1 in apoptosis: a case study in feedback loops.	Knezevic D et al
12414510	2002	Proliferation, 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
16739112	2006	Centrosome abnormalities are frequently observed in non-small-cell lung cancer and are associated with aneuploidy and cyclin E overexpression.	Koutsami MK et al
8248803	1993	Binding to DNA and the retinoblastoma gene product promoted by complex formation of different E2F family members.	Krek W et al
7917337	1994	DP and E2F proteins: components of a heterodimeric transcription factor implicated in cell cycle control.	La Thangue NB et al
7880534	1994	DP and E2F proteins: coordinating transcription with cell cycle progression.	Lam EW et al
12502741	2002	Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor.	Lee C et al
18524851	2008	The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis.	Marlowe JL et al
11274364	2001	p19ARF targets certain E2F species for degradation.	Martelli F et al
10559858	1999	Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation.	Marti A et al
9271426	1997	Induction of S-phase entry by E2F transcription factors depends on their nuclear localization.	Müller H et al
12665469	2003	Evolving intricacies and implications of E2F1 regulation.	Mundle SD et al
7935380	1994	Transcription of the E2F-1 gene is rendered cell cycle dependent by E2F DNA-binding sites within its promoter.	Neuman E et al
8964493	1996	Structure and partial genomic sequence of the human E2F1 gene.	Neuman E et al
7933066	1994	Mutually 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
11245432	2001	Phosphorylation- and Skp1-independent in vitro ubiquitination of E2F1 by multiple ROC-cullin ligases.	Ohta T et al
15467444	2004	Regulation in S phase by E2F.	Pardee AB et al
11388666	2001	E2F-1 induced apoptosis.	Phillips AC et al
17488475	2007	E2F1 death pathways as targets for cancer therapy.	Pützer BM et al
15190206	2004	Life, death and E2F: linking proliferation control and DNA damage signaling via E2F1.	Rogoff HA et al
16360038	2005	Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release.	Rubin SM et al
7774910	1995	Amplification of the E2F1 transcription factor gene in the HEL erythroleukemia cell line.	Saito M et al
18506748	2008	Identification 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
1448092	1992	Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F.	Shan B et al
9375022	1997	E2F transcription factor action, regulation and possible role in human cancer.	Sladek TL et al
8441401	1993	A protein synthesis-dependent increase in E2F1 mRNA correlates with growth regulation of the dihydrofolate reductase promoter.	Slansky JE et al
15279795	2004	The emerging role of E2F-1 in the DNA damage response and checkpoint control.	Stevens C et al
11823794	2002	Sibling rivalry in the E2F family.	Trimarchi JM et al
17178208	2007	Implication of the transcription factor E2F-1 in the modulation of neuronal apoptosis.	Verdaguer E et al
18003834	2007	E2F1 works as a cell cycle suppressor in mature neurons.	Wang L et al
12598654	2003	Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation.	Xiao B et al
10214348	1999	Balancing proliferation and apoptosis in vivo: the Goldilocks theory of E2F/DP action.	Yamasaki L et al
15221933	2004	Distinct expression patterns of the transcription factor E2F-1 in relation to tumour growth parameters in common human carcinomas.	Zacharatos P et al
10090723	1999	Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP.	Zheng N et al
17222786	2007	Rb 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 ID	Transcript ID	Uniprot
ENSG00000101412	ENST00000343380	Q01094

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
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Transcriptional Regulation by TP53	REACTOME	R-HSA-3700989
Cell Cycle	REACTOME	R-HSA-1640170
Cell Cycle, Mitotic	REACTOME	R-HSA-69278
Mitotic G1-G1/S phases	REACTOME	R-HSA-453279
G0 and Early G1	REACTOME	R-HSA-1538133
G1 Phase	REACTOME	R-HSA-69236
Cyclin D associated events in G1	REACTOME	R-HSA-69231
G1/S Transition	REACTOME	R-HSA-69206
G1/S-Specific Transcription	REACTOME	R-HSA-69205
E2F mediated regulation of DNA replication	REACTOME	R-HSA-113510
Inhibition of replication initiation of damaged DNA by RB1/E2F1	REACTOME	R-HSA-113501
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
Programmed Cell Death	REACTOME	R-HSA-5357801
Apoptosis	REACTOME	R-HSA-109581
Intrinsic Pathway for Apoptosis	REACTOME	R-HSA-109606
Activation of BH3-only proteins	REACTOME	R-HSA-114452
Activation of NOXA and translocation to mitochondria	REACTOME	R-HSA-111448
Activation of PUMA and translocation to mitochondria	REACTOME	R-HSA-139915
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
TP53 Regulates Transcription of Cell Cycle Genes	REACTOME	R-HSA-6791312
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	REACTOME	R-HSA-6804116
Endocrine resistance	KEGG	ko01522
Endocrine resistance	KEGG	hsa01522
Breast cancer	KEGG	ko05224
Breast cancer	KEGG	hsa05224
Mitophagy - animal	KEGG	ko04137
Mitophagy - animal	KEGG	hsa04137

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
36168932	2024	E2F1 induced neuroblastoma cell migration and invasion via activation of CENPE/FOXM1 signaling pathway.	1
37824372	2024	Transcription Factor E2F1 Enhances Hepatocellular Carcinoma Cell Proliferation and Stemness by Activating GINS1.	1
37992567	2024	NEIL3 promotes cell proliferation of ccRCC via the cyclin D1-Rb-E2F1 feedback loop regulation.	0
38182895	2024	DLGAP5 triggers proliferation and metastasis of bladder cancer by stabilizing E2F1 via USP11.	0
38242392	2024	Analysis of E2F1 single-nucleotide polymorphisms reveals deleterious non-synonymous substitutions that disrupt E2F1-RB protein interaction in cancer.	1
38360622	2024	The association of E2F1 and E2F2 single nucleotide polymorphisms with laryngeal squamous cell carcinoma pathomorphological features.	0
38378679	2024	Hsa_circ_0007990 promotes breast cancer growth via inhibiting YBX1 protein degradation to activate E2F1 transcription.	0
38386202	2024	E2F1 Mediates Traumatic Brain Injury and Regulates BDNF-AS to Promote the Progression of Alzheimer's Disease.	0
38424195	2024	RNA m(5)C modification upregulates E2F1 expression in a manner dependent on YBX1 phase separation and promotes tumor progression in ovarian cancer.	0
38783241	2024	New link between RNH1 and E2F1: regulates the development of lung adenocarcinoma.	1
38978058	2024	CDCA5 accelerates progression of breast cancer by promoting the binding of E2F1 and FOXM1.	0
36168932	2024	E2F1 induced neuroblastoma cell migration and invasion via activation of CENPE/FOXM1 signaling pathway.	1
37824372	2024	Transcription Factor E2F1 Enhances Hepatocellular Carcinoma Cell Proliferation and Stemness by Activating GINS1.	1
37992567	2024	NEIL3 promotes cell proliferation of ccRCC via the cyclin D1-Rb-E2F1 feedback loop regulation.	0
38182895	2024	DLGAP5 triggers proliferation and metastasis of bladder cancer by stabilizing E2F1 via USP11.	0

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/e2f1-(e2f-transcription-factor-1)