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E2F4 (E2F transcription factor 4, p107/p130-binding)

Written2012-03Marie-Christine Paquin, Nathalie Rivard
CIHR Team on Digestive Epithelium, Departement d'Anatomie et Biologie Cellulaire, Faculte de Medecine et des Sciences de la Sante, Universite de Sherbrooke, Sherbrooke, QC, Canada

(Note : for Links provided by Atlas : click)

Identity

Alias_namesE2F transcription factor 4
Alias_symbol (synonym)E2F-4
Other alias
HGNC (Hugo) E2F4
LocusID (NCBI) 1874
Atlas_Id 40385
Location 16q22.1  [Link to chromosome band 16q22]
Location_base_pair Starts at 67226068 and ends at 67232821 bp from pter ( according to hg19-Feb_2009)  [Mapping E2F4.png]
Fusion genes
(updated 2016)
APOA2 (1q23.3) / E2F4 (16q22.1)E2F4 (16q22.1) / RPL14 (3p22.1)RPL14 (3p22.1) / E2F4 (16q22.1)
SIPA1L1 (14q24.2) / E2F4 (16q22.1)

DNA/RNA

Description E2F4 gene spans 6753 base pairs.
Transcription E2F4 gene produces 1 transcript of 2100 bp that counts 10 exons.

Exon/Intron
Start
End
Length (bp)
5' upstream
Exon 1
67,226,068
67,226,265
198
Intron 1-2
67,226,266
67,226,663
398
Exon 2
67,226,664
67,226,773
110
Intron 2-3
67,226,774
67,226,911
138
Exon 3
67,226,912
67,227,073
162
Intron 3-4
67,227,074
67,227,374
301
Exon 4
67,227,375
67,227,418
44
Intron 4-5
67,227,419
67,228,300
882
Exon 5
67,228,301
67,228,362
62
Intron 5-6
67,228,363
67,228,588
226
Exon 6
67,228,589
67,228,883
295
Intron 6-7
67,228,884
67,229,684
801
Exon 7
67,229,685
67,229,909
225
Intron 7-8
67,229,910
67,231,501
1592
Exon 8
67,231,502
67,231,549
48
Intron 8-9
67,231,550
67,231,769
220
Exon 9
67,231,770
67,231,814
45
Intron 9-10
67,231,815
67,231,910
96
Exon 10
67,231,911
67,232,821
911
3' downstream
Table adapted from Ensembl.
Pseudogene E2F4P1 (E2F Transcription Factor 4, p107/p130-binding pseudogene 1).
Location: 6p21.2 (39521587-39522719).

Protein

 
  Adapted from Sardet et al., 1995; Magae et al., 1996; Zheng et al., 1999; Scime et al., 2008.
DNA BD: Originally viewed as a basic helix-loop-helix DNA-binding motif (Kaelin et al., 1992; Cress et al., 1993), however the crystal structure of E2F-4/DP2 dimer binding to DNA revealed a winged-helix DNA-binding motif (Zheng et al., 1999).
Dimerization Domain: Dimerization with DP proteins is required for proper E2F DNA binding and transactivation capacity. The Leuzine Zipper (100-128) and the Marked Box both contribute to DP dimerization (Kaelin et al., 1992; Chen et al., 2009). E2F transcription factors can bind DNA as homodimers although to a much lesser extent than heterodimers (Huber et al., 1993).
Transactivation Domain: The transactivation domain mediates interaction with transcriptional machinery, co-activators and chromatin-remodeling proteins (Emili and Ingles, 1995; Trouche and Kouzarides, 1996; Pearson and Greenblatt, 1997; McMahon et al., 1998; Ross et al., 1999; Vandel and Kouzarides, 1999; Martinez-Balbas et al., 2000; Marzio et al., 2000; Lang et al., 2001; Louie et al., 2004; Taubert et al., 2004) and includes the Pocket Protein Binding Domain. E2F4 interacts with p130/RBL2, p107/RBL1 and to a lesser extent with pRb/RB1 (Beijersbergen et al., 1994; Ginsberg et al., 1994; Ikeda et al., 1996; Moberg et al., 1996; Li et al., 1997). Association of E2F4 with Rb protein family members (particularly p130/RBL2) prevents activation of E2F target genes and triggers their repression by recruiting transcriptional repression machinery (Zhang and Dean, 2001; Frolov and Dyson, 2004; Litovchick et al., 2007). E2F4 is the only E2F possessing a stretch of 13 consecutive serine residues in its transactivation domain (Sardet et al., 1995).
Numerous publications infer that E2F4 is a phosphorylated protein (Beijersbergen et al., 1994; Ginsberg et al., 1994; Vairo et al., 1995; Gaubatz et al., 2001; Popov et al., 2005; Scime et al., 2008) although only a few have identified specific phosphorylation sites: T14 and S16 are phosphorylated residues (Van Hoof et al., 2009); S281 and S285 are phosphorylated by IKKα and IKKβ and enhance E2F4 nuclear localization and DNA-binding of the E2F4/p130 complex in human primary fibroblasts (Araki et al., 2008); S384 is phosphorylated in the DREAM or MMB complexes (Litovchick et al., 2011).
Description The E2F4 coding sequence yields a 413-amino acid protein predicting a molecular weight of 44 kDa. However, E2F4 migrates as an heterogeneous set of bands between 57-64 kDa which are associated with extensive phosphorylations (Beijersbergen et al., 1994; Ginsberg et al., 1994; Vairo et al., 1995; Gaubatz et al., 2001; Popov et al., 2005; Araki et al., 2008; Scime et al., 2008; Van Hoof et al., 2009; Litovchick et al., 2011).
Unlike E2F1, E2F2 and E2F3, which exhibit a cyclin A binding domain at their N-terminus, E2F4 has a truncated N-terminus and therefore does not harbor this domain (Beijersbergen et al., 1994; Sardet et al., 1995). The full E2F transcriptional activity requires its heterodimerization with a DP partner, although E2F transcription factors have been reported to bind DNA as homodimers (Bandara et al., 1993; Helin et al., 1993b; Huber et al., 1993; Krek et al., 1993). The DNA-binding domain of E2F4 was originally viewed as a helix-loop-helix DNA-binding motif (Kaelin et al., 1992; Cress et al., 1993). However, the crystal structure of E2F4-DP2 dimer by Zheng et al. rather reveals a structure related to the winged-helix DNA-binding motif. E2F4 and its DP partner bind to the E2F-consensus DNA sequence TTTC/GC/GCGC/G (Nevins, 1992; Slansky et al., 1993) by means of a conserved Arg-Arg-Xxx-Tyr-Asp sequence (Zheng et al., 1999). Binding specificity of E2F transcription factors to different target gene promoters is affected by the DNA sequence itself, E2F transcription factors, DP partners as well as other factors (Karlseder et al., 1996; Lin et al., 1996; Shin et al., 1996; Wells et al., 1997; Le Cam et al., 1999; Chen et al., 2002; Schlisio et al., 2002; Araki et al., 2003; Giangrande et al., 2003; Giangrande et al., 2004; Zhu et al., 2004).
The transactivation domain of E2F transcription factors, including E2F4, mediates target gene transcription through two distinct mechanisms: 1- by recruiting general transcription machinery such as TBP/TFIID, TFIIA and TFIIH which promote RNA pol II pre-initiation complex (PIC) assembly (Hagemeier et al., 1993; Emili and Ingles, 1995; Pearson and Greenblatt, 1997; Ross et al., 1999; Vandel and Kouzarides., 1999) and 2- by relaxing chromatin structure at promoters by interacting with histone acetyltransferases (HAT) such as Tip60 (Taubert et al., 2004), p300/CBP (Trouche and Kouzarides, 1996; Trouche et al., 1996; Martinez-Balbas et al., 2000; Marzio et al., 2000) and PCAF/GCN5 (Martinez-Balbas et al., 2000; Marzio et al., 2000; Lang et al., 2001). The transactivation domain also includes a pocket protein interacting domain. E2F4 interacts primarily with p130/RBL2, p107/RBL1 and to a lesser extent with Rb/RB1 (Beijersbergen et al., 1994; Ginsberg et al., 1994; Ikeda et al., 1996; Moberg et al., 1996; Li et al., 1997). Pocket proteins modulate E2F transcription factor activity via two different mechanisms: 1- by preventing general transcription machinery and chromatin-remodeling protein recruitment (Helin et al., 1992; Flemington et al., 1993; Hagemeier et al., 1993; Helin et al., 1993a; Pearson and Greenblatt., 1997) and 2- by actively repressing gene transcription (Harbour and Dean, 2000; Singh et al., 2010). In fact, pocket proteins have been shown to recruit histone deacetylase enzymes (HDACs) (Brehm et al., 1998; Luo et al., 1998; Dahiya et al., 2000), the histone methyltransferase SUV39H1 (Nielsen et al., 2001; Vandel et al., 2001), SWI/SNF family members (BRG1, Brm) (Dunaief et al., 1994; Singh et al., 1995; Strobeck et al., 2000; Zhang et al., 2000; Iakova et al., 2003), the Sin3B repressor complex (via RBP1 and SAP30) (David et al., 2008; Grandinetti and David., 2008) and the ErbB3 binding protein Ebp1 (Zhang et al., 2003), all of which contribute to chromatin compaction and thus, to transcriptional repression (Kouzarides, 2007).
During quiescence, E2F transcription factors are sequestered by hypophosphorylated forms of pocket proteins (pRb, p130 and p107) which prevent the activation of their target genes. Upon G1 progression, cyclin-dependent kinases (cdk)-cyclin complexes are activated and phosphorylate pocket proteins leading to the release of E2F transcription factors. Indeed, activation of cdk4 and cdk6, in association with cyclin D, leads to partial inactivation of Rb-like proteins. Further phosphorylation by cyclin E/cdk2 complex is required for total pocket protein inactivation and full release of E2F transcription factors. Thereafter, genes required for DNA synthesis and cell cycle progression are induced, allowing cells to enter S-phase and pursue their cell cycle (Cobrinik, 2005; Malumbres and Barbacid, 2009).
In addition to pocket protein-mediated regulation, E2F4 is also controlled by other mechanisms such as phosphorylation, antisenses (Yochum et al., 2007), reactive oxygen species (Kim and Lee, 2010), cofactors and mainly by its subcellular localization. Indeed, E2F4 protein levels are not significantly modulated during cell cycle progression; however, its nuclear localization is tightly regulated (Lindeman et al., 1997; Verona et al., 1997; Deschenes et al., 2004) (see below). Furthermore, many studies have reported E2F4 phosphorylation but only a few have associated these phosphorylation events with a specific function (Beijersbergen et al., 1994; Ginsberg et al., 1994; Vairo et al., 1995; Gaubatz et al., 2001; Popov et al., 2005; Araki et al., 2008; Scime et al., 2008; Van Hoof et al., 2009; Litovchick et al., 2011). For example, Araki et al., 2008 showed that E2F4 phosphorylation by IKKα and/or IKKβ leads to increased binding of the E2F4/p130 complex to DNA in TIG-3 human primary fibroblasts.
Finally, Balciunaite et al., 2005 suggested that in early G1, both p107 and p130 are absent of certain repressed E2F4 target promoters, suggesting that another repression mechanism must be implicated. Moreover, Rayman et al., 2002 reported that pocket proteins are not required for mSin3B recruitment to certain E2F-regulated promoters reinforcing the notion of a pocket protein-independent repression mechanism. Indeed, E2F4 can also recruit Host cell factor-1 (HCF-1), an important cell cycle regulator, which brings Sin3/HDAC complexes to E2F target gene promoters, repressing their transcription independently of pocket proteins (Tyagi et al., 2007).
Expression In adult mouse tissues, Rempel et al. proposed that E2F4 is particularly abundant in hematopoietic tissues (i.e. thymus, spleen and bone marrow) and in the gut, in comparison to the heart, kidney, liver, brain and muscle (Rempel et al., 2000). However, other publications reported an ubiquitous expression of E2F4 (Gill and Hamel, 2000; D'Souza et al., 2001). Furthermore, it was suggested that E2F4 accounts for the vast majority of E2F cellular activity (Moberg et al., 1996; Puri et al., 1997). Of note, E2F4 expression changes according to cellular status. During external epithelium formation, E2F4 transcripts are detectable in 11,5-day post coitum (dpc) embryos in all cells of the ectoderm. In 13,5-dpc embryos, the proliferating undifferentiated epithelial cells show strong E2F4 expression. At 18,5-dpc, proliferating basal cell layers of the primitive epidermis express abundant E2F4 transcripts whereas the suprabasal cell layers display negligible E2F4 signals (Dagnino et al., 1997b). During intestinal morphogenesis, E2F4 expression is high in the intervillus epithelium and almost absent in the non proliferating villus tips and in the underlying mesenchyme (Dagnino et al., 1997b). E2F4 transcripts are widespread in the central and peripheral developing nervous systems. In the developing brain, E2F4 is ubiquitously expressed with the highest levels detected in ventricular and subventricular zones (Dagnino et al., 1997a; Ruzhynsky et al., 2007).
Localisation E2F4 exhibits a CRM1-dependent bipartite nuclear export signal (NES) which mediates its export to the cytoplasm. The two elements of E2F4 NES are referred to as NES1 (residues 61 to 70) and NES2 (residues 91 to 100) (Gaubatz et al., 2001). Therefore, E2F4 relies on other proteins to reach the nucleus, such as DP2 (Magae et al., 1996; Verona et al., 1997; Puri et al., 1998) or pocket proteins (Verona et al., 1997; Gaubatz et al., 2001; Apostolova et al., 2002; Rayman et al., 2002). Studies have shown that nuclear E2F4, triggered by the addition of an ectopic NLS or co-expression with DP2, is transcriptionally active and can induce DNA synthesis (Lindeman et al., 1997; Muller et al., 1997; Verona et al., 1997; Puri et al., 1998; Gill and Hamel, 2000). Of note, Apostolova et al. suggested that E2F4 may also travel to the nucleus on its own (Apostolova et al., 2002).
A number of studies have highlighted the importance of regulating the subcellular localization of E2F4 (Magae et al., 1996; Lindeman et al., 1997; Muller et al., 1997; Verona et al., 1997; Puri et al., 1997; Puri et al., 1998; Gill and Hamel, 2000; Deschenes et al., 2004). In immortalized fibroblasts and certain cancer cells, E2F4 is expressed in the nucleus of quiescent cells and as cells progress through G1 and enter the S phase, E2F4 translocates to the cytoplasm (Lindeman et al., 1997; Muller et al., 1997; Verona et al., 1997). In addition, overexpression of E2F4 in certain asynchronously growing cancer cells or fibroblasts revealed that E2F4 is primarily expressed in the cytoplasm (Magae et al., 1996; Lindeman et al., 1997; Muller et al., 1997; Verona et al., 1997). By contrast, endogenous E2F4 is found in the nucleus of proliferating basal epidermal cells (Paramio et al., 2000), proliferating intestinal crypt cells (Deschenes et al., 2004) and proliferating cardiomyocytes (van Amerongen et al., 2009). Likewise, overexpression of E2F4 in mice epidermis under the K5 promoter leads to E2F4 expression in the nucleus of cycling keratinocytes in the basal cell layer and the hair follicle resulting in hyperplasia and increased tumor formation in a mouse skin model of multistage carcinogenesis (Wang et al., 2000). Moreover, endogenous E2F4 is observed in the nucleus of many differentiated cells including ciliated epithelial cells (Danielian et al., 2007), myotubes (Puri et al., 1997; Puri et al., 1998) and neurons (Persengiev et al., 1999). Overall, these results suggest that E2F4 can act as either an activator or an inhibitor of transcription, proliferation and differentiation. Therefore, E2F4 localization control must be tightly regulated in a timely and restricted manner.
Function The main characterized function of E2F transcription factors is the regulation of the cell cycle. E2F factors induce a number of genes required for DNA synthesis, including dihydrofolate reductase, thymidine kinase, DNA polymerase α, and for cell cycle progression, including cyclin A, cyclin E, c-myc, E2F and cdc2, to name a few (Stevens and La Thangue, 2003; Tsantoulis and Gorgoulis, 2005). In quiescent fibroblasts and certain cancer cells, E2F4 (mainly in complex with p130) binds to DNA and contributes to active repression of E2F target genes preventing cell cycle progression (DeGregori, 2002; Trimarchi and Lees, 2002; Cam et al., 2004). Upon G1 phase progression, E2F4 translocates to the cytoplasm while E2F1-3a transactivates genes required for S phase entry (Takahashi et al., 2000; Rayman et al., 2002; Trimarchi and Lees, 2002). However, no detectable defect either in cell cycle regulation or target gene expression was identified in E2F4-/- mouse embryonic cells, suggesting its compensation by other E2F members (Humbert et al., 2000; Rempel et al., 2000; Landsberg et al., 2003). Accordingly, dual loss of E2F4 and E2F5 impairs pocket protein-mediated cell cycle exit (Gaubatz et al., 2000).
Interestingly, loss of p107 and p130 triggers a massive E2F4 relocalization to the cytoplasm accompanied by a hyperacetylation of nucleosomes proximal to E2F binding sites, producing an important de-repression of E2F target genes (Rayman et al., 2002). Indeed, during quiescence, E2F4/p130 or E2F4/p107 complexes are associated with E2F-responsive genes and repress their transcription (Takahashi et al., 2000; Wells et al., 2000; Rayman et al., 2002). Recent data also implicate E2F4 as part of a multiprotein complex referred to as the DREAM complex (DP, RB-like, E2F4 and MuvB). In fact, the DREAM complex binds to the promoters of more than 800 cell cycle-regulated genes during quiescence and favors their repression (Litovchick et al., 2007; Schmit et al., 2007). This E2F4 repressing effect is also observed during cell cycle arrest associated with aging and differentiation. For example, in aging mice, reduced proliferation of hepatocytes is accompanied by the association of Brm1/C/EBPα/E2F4/Rb repressive complex to E2F target genes (Iakova et al., 2003). In keratinocytes, E2F4 in complex with p130 recruits HDAC1 and represses Cdc25A, correlating with cell cycle arrest (Iavarone and Massague, 1999).
In keeping with the above concept, (Grandinetti and David, 2008) proposed the following model. Upon entry into quiescence, repression of E2F responsive genes responsible for cell cycle progression is initiated by the recruitment of E2F4/5 bound to a Rb-like protein (pRb, p130, p107) to target promoters. Sin3B recruitment to the pocket protein is then brought by Retinoblastoma Binding protein 1 (RBP1) and Sin3 Associated Protein 30 (SAP30) adaptor proteins. Thereafter, Sin3B recruits HDACs, which desacetylate histones, and RBP2, a histone demethylase responsible for demethylation of histones on lysine 4. All of these events promote nucleosome assembly rendering chromatin less permissive to transcription. Upon permanent cell cycle withdrawal (terminal differentiation or senescence), further recruitment of SUV39H1 enables methylation of histones on lysine 9 creating docking sites for HP1 protein and thus driving heterochromatinization and stable repression of E2F target genes (Narita et al., 2003; Grandinetti and David, 2008).
Although E2F4 has been particularly described as a repressor of both transcription and cell cycle progression (Vairo et al., 1995; Muller et al., 1997; Rayman et al., 2002), several studies have reported other roles such as 1- its binding to E2F-responsive elements as a pocket protein-free E2F during S phase, 2- its capacity to induce E2F target genes and 3- its implication in proliferation. Hence, these studies suggest that E2F4 can also act as a transcriptional activator (Verona et al., 1997; Wells et al., 1997; Ross et al., 1999; Lang et al., 2001; Garneau et al., 2009; van Amerongen et al., 2009). For example, studies carried out by Lo et al., 2011 demonstrated that the majority of E2F4 binding sites are located proximal to transcription start sites. There, E2F4 has been shown to stabilize TFIID/TFIIA complex thereby preventing Rb repressor effect and promoting PIC assembly (Ross et al., 1999). E2F4 can recruit the potent acetyltransferase GCN5 and the cofactor TRRAP which promote E2F4 transcriptional activity (Lang et al., 2001). Host cell factor-1 also interacts with E2F4 and plays both co-activator (Knez et al., 2006) or co-repressor (Tyagi et al., 2007) roles in the regulation of E2F4-controlled promoters. Accordingly, forced expression of nuclear E2F4 promotes S-phase entry into cardiomyocytes (Ebelt et al., 2005; van Amerongen et al., 2009). Moreover, nuclear E2F4 expression is associated with proliferation of rapid renewing tissues such as bone marrow (Kinross et al., 2006; Zhang et al., 2010), digestive tract (Rempel et al., 2000; Garneau et al., 2009) and skin (Wang et al., 2000; Wang et al., 2001).
Many in vivo and in vitro studies have led to the identification of numerous roles of E2F4 in different cellular processes such as nervous system development, intestinal homeostasis, bone development, myogenesis, adipogenesis and erythropoiesis, to name a few. E2F4 gene deletion in mice leads to important neonatal lethality due to chronic rhinitis and increased susceptibility to opportunistic infections (Humbert et al., 2000). Many factors contribute to the observed neonatal lethality in these mice. First, ciliated cells are absent from the entire airway epithelium and are replaced by mucin-secreting cells, creating a mucus overflow in the nasal cavities allowing microbial colonization (Danielian et al., 2007). Secondly, sonic hedgehog (Shh) signaling is dysregulated which impairs eye patterning, self-renewal capacity of neural progenitor cells and ventral telencephalic structure formation during brain development (Ruzhynsky et al., 2007; Ruzhynsky et al., 2009; Swiss and Casaccia, 2010). Studies also highlighted E2F4 requirement for proper bone development, especially for calvarial ossification (Humbert et al., 2000; Miller et al., 2010). These generated craniofacial defects are thought to contribute to the aberrant accumulation of proteinaceous secretions in nasal cavities leading to lethality (Humbert et al., 2000). Thirdly, recall proliferation of CD8+ T-lymphocytes, which participate in viral infections control, is impaired (Bancos et al., 2009).
Aside from its role during brain development, implication of E2F4 in neuronal differentiation has been strengthened by in vitro studies using the pheochromocytoma line (PC-12 cells), which show reduced neuronal differentiation following E2F4 depletion and accelerated NGF-induced neuronal maturation with E2F4 overexpression (Persengiev et al., 1999). Other laboratories have also documented a role for E2F4 in repressing adipocyte differentiation independently of its cell cycle regulation properties but through PPARγ repression, a primordial factor in adipogenesis (Fajas et al., 2002; Landsberg et al., 2003; Tseng et al., 2005).
E2F4 also appears to play a critical role in rapid renewing tissues. In the gut, E2F4 is highly and preferentially expressed in the nucleus of proliferative cells (Dagnino et al., 1997b; Deschenes et al., 2004; Garneau et al., 2009). Loss of E2F4 in the small intestine results in a significant decline in proliferative zones (crypts) and a shortening and a reduction in the number of intestinal villi (Rempel et al., 2000). The role of E2F4 in maintaining intestinal homeostasis is also reinforced by the fact that it is overexpressed in the nucleus of colorectal cancer cells, contributing to hyperproliferation (Mady et al., 2002; Garneau et al., 2007; Garneau et al., 2009). In human and mouse epidermis, E2F4 is expressed in the basal and the immediately suprabasal cells, fading in upper cell layers (Dagnino et al., 1997b; Paramio et al., 2000; Wang et al., 2000; D'Souza et al., 2001). Although E2F4 has been reported to contribute to cell cycle arrest and differentiation in keratinocytes (Iavarone and Massague., 1999; Paramio et al., 2000), overexpressed E2F4 increases keratinocyte proliferation leading to hyperplasia and to an increased response to a two-step skin carcinogenesis assay (Wang et al., 2000; Wang et al., 2001). Finally, E2F4-deficient mice display a marked macrocytic anemia caused by impaired cell cycle progression and proliferation of fetal erythroid precursors also accompanied by maturation defects in multiple other hematopoietic lineages (Rempel et al., 2000; Kinross et al., 2006; Zhang et al., 2010).
In addition to the roles identified in proliferation, differentiation and development, other unconventional functions have been attributed to E2F4. Indeed, E2F4 binds various genes having functions in mitochondrial biogenesis, metabolism, cytoskeleton and mRNA processing (Cam et al., 2004). Moreover, E2F4 is thought to regulate the expression of certain miRNAs (Lee et al., 2011), control DNA repair (Ren et al., 2002; DuPree et al., 2004; Bindra and Glazer, 2007; Crosby et al., 2007; Dominguez-Brauer et al., 2009; Hegan et al., 2010; Lee et al., 2011), control survival in certain specific cell contexts (Chang et al., 2000; Wang et al., 2000; Ebelt et al., 2005; Garneau et al., 2007; Yang et al., 2008; Lee et al., 2011) as well as regulate aging and senescence (Iakova et al., 2003; Litovchick et al., 2011; Martin et al., 2011). Lastly, although the majority of E2F4 binding sites are located near transcription start sites and contribute to direct activation or repression of transcription (Lee et al., 2011; Lo et al., 2011), many sites are frequently localized more than 20 kb away from any annotated transcription start sites, suggesting that E2F4 can also act as a long-range transcriptional regulator (Lee et al., 2011).
Homology E2F4 is more related to E2F5 (69% identity, 80% similarity) than E2F1-3 (between 36% and 40% identity, between 52% and 60% similarity) (Sardet et al., 1995). In the E2F4 DNA-binding domain, residues mediating contact with DNA are conserved throughout the E2F transcription factor family (Zheng et al., 1999). Seventy-five percent of the DP interaction interface is identical within E2F transcription factors family (Zheng et al., 1999) and the pocket protein interaction domain of E2F4 has 48% homology with the Rb-interacting domain of E2F1 (Beijersbergen et al., 1994).

Implicated in

Note
  
Entity Colorectal cancer
Note Summary: Mutation (AGC repeat) (Yoshitaka et al., 1996; Souza et al., 1997; Ikeda et al., 1998; Moriyama et al., 2002); Increased expression (Mady et al., 2002; Garneau et al., 2009).

Many studies have reported the presence of mutations in E2F4 AGC trinucleotide repeats in colorectal cancer bearing microsatellite instability (MSI). The more frequent mutations observed are the deletion or the addition of a trinucleotide AGC and the deletion of 7 trinucleotides (Yoshitaka et al., 1996; Souza et al., 1997; Ikeda et al., 1998; Moriyama et al., 2002). Furthermore, Takashima et al., 2001, studied the impact of E2F4 mutations and observed an increase in nuclear expression, in transcriptional activity as well as in proliferation rate of fibroblasts overexpressing these mutants.

  
  
Entity Gastric carcinoma
Note Summary: Mutation (AGC repeat) (Kim et al., 1999; Ogata et al., 2001).

Kim et al., 1999, analyzed 56 gastric adenomas and 167 gastric carcinomas and found that frameshift mutations in E2F4 were more frequent in gastric adenomas than in carcinomas.

  
  
Entity Bladder cancer
Note Summary: Amplification of chromosome arm 16q (Yu et al., 2001).

Comparative genomic hybridization (CGH) analysis revealed amplifications of chromosome arm 16q in 6/12 human transitional cell carcinoma (TCC) lines (more frequent in low-grade tumors) (Yu et al., 2001).

  
  
Entity Hepatocellular carcinoma (HCC)
Note Summary: LOH on chromosome 16 (Sakai et al., 1992).

Using restriction fragment length polymorphism (RFLP) analysis on sixty-eight HCC specimens and their corresponding non-tumor liver tissues, a loss of heterozygosity was frequently observed on chromosome 16: specifically the MT2 locus at 16q21-22.1 (15%) and the HP locus at 16q22.1-22.2 (39%) (Sakai et al., 1992).

  
  
Entity Breast cancer
Note Summary: Deletion of chromosome arm 16q22 or LOH (Dorion-Bonnet et al., 1995; Iida et al., 1997; Cleton-Jansen et al., 2001); Decreased expression (Ho et al., 2001); Increased nuclear expression (Rakha et al., 2004; Rakha et al., 2005).

Loss of chromosomal material at 16q22.1 is one of the most frequent genetic aberrations found in breast carcinogenesis suggesting the presence of a tumor suppressor gene (TSG) at this region (Dorion-Bonnet et al., 1995; Iida et al., 1997; Cleton-Jansen et al., 2001). E2F4 is one of the candidate genes localized in this region and therefore was analyzed in different studies.
Ho et al., 2001, studied E2F4 protein expression in 10 primary breast carcinomas and 10 metastatic nodal tissues. The authors found a lower E2F4 protein expression in 7/10 primary breast carcinomas and in all (10/10) metastatic nodal tissues when compared to corresponding normal breast tissues. No tumor-specific mutation was detected, but polymorphisms were identified in the polyserine tract of E2F4 (3/11). Ho et al., 2001, further suggested that E2F4 is likely to function as a tumor suppressor in breast cancer.
Another group published two complementary and more in-depth studies arguing against the role of E2F4 as a TSG in breast cancer. Indeed, Rakha et al., 2005, used a Multiplex Amplifiable Probe Hybridization (MAPH) method to measure DNA copy-number at chromosome arm 16q22.1 in forty-nine invasive lobular, low-grade invasive ductal or tubular breast carcinoma samples. No correlation was detected between the expression of E2F4 with its gene's copy number. Likewise, no significant loss or decrease in E2F4 protein levels was observed in malignant tissues. However, the authors did describe a correlation between increased nuclear expression of E2F4 and tumors with higher histological grade and positive lymph node disease whereas E2F4 was expressed in both the nuclei and cytoplasm in normal mammary epithelial cells, thus suggesting an oncogenic rather than a tumor suppressor role for this factor in breast cancer. The same group (Rakha et al., 2004) also analyzed 265 breast carcinomas for E2F4 protein expression and found a correlation between increased nuclear expression of E2F4 and indicators of poor prognosis including larger tumor size, grade 3 lesions, lymph node stage and poorer Nottingham prognostic index group. Increased E2F4 expression was also seen in association with the development of recurrent disease, distant metastasis and poorer outcome including poorer overall survival time and shorter disease-free interval.

  
  
Entity Prostate cancer
Note Summary: Increased expression (Waghray et al., 2001).

Using serial analysis of gene expression (SAGE), Waghray et al., 2001, found that E2F4 was overexpressed by more than five-fold in prostate tumor tissues compared to the normal surrounding tissues. Immunohistochemistry analysis further revealed strong E2F4 staining in epithelial cells of tumor glands as opposed to weak to no staining in normal glands.

  
  
Entity Hematological malignancies
Note Summary: Mutation (AGC repeat) (Komatsu et al., 2000).

Komatsu et al., 2000, analyzed nine childhood acute lymphoblastic leukemia (ALL) samples, five acute myelocytic leukemia (AML) samples and ten adult T-cell leukemia (ATL) samples: frameshift mutations were found in E2F4 trinucleotide AGC repeats in 20% of ATL samples (3 AGC codon insertions) and in 11% of childhood ALL samples (6 AGC codon deletions).

  

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EMBO J. 2002 Nov 1;21(21):5775-86.
PMID 12411495
 
LINC, a human complex that is related to pRB-containing complexes in invertebrates regulates the expression of G2/M genes.
Schmit F, Korenjak M, Mannefeld M, Schmitt K, Franke C, von Eyss B, Gagrica S, Hanel F, Brehm A, Gaubatz S.
Cell Cycle. 2007 Aug 1;6(15):1903-13. Epub 2007 May 25.
PMID 17671431
 
Cyclin D1/cdk4 can interact with E2F4/DP1 and disrupts its DNA-binding capacity.
Scime A, Li L, Ciavarra G, Whyte P.
J Cell Physiol. 2008 Mar;214(3):568-81.
PMID 17894419
 
The N-terminal region of E2F-1 is required for transcriptional activation of a new class of target promoter.
Shin EK, Tevosian SG, Yee AS.
J Biol Chem. 1996 May 24;271(21):12261-8.
PMID 8647824
 
A role for retinoblastoma protein in potentiating transcriptional activation by the glucocorticoid receptor.
Singh P, Coe J, Hong W.
Nature. 1995 Apr 6;374(6522):562-5.
PMID 7700385
 
Small molecule regulators of Rb-E2F pathway as modulators of transcription.
Singh S, Johnson J, Chellappan S.
Biochim Biophys Acta. 2010 Oct-Dec;1799(10-12):788-94. Epub 2010 Jul 15. (REVIEW)
PMID 20637913
 
A protein synthesis-dependent increase in E2F1 mRNA correlates with growth regulation of the dihydrofolate reductase promoter.
Slansky JE, Li Y, Kaelin WG, Farnham PJ.
Mol Cell Biol. 1993 Mar;13(3):1610-8.
PMID 8441401
 
Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors.
Souza RF, Yin J, Smolinski KN, Zou TT, Wang S, Shi YQ, Rhyu MG, Cottrell J, Abraham JM, Biden K, Simms L, Leggett B, Bova GS, Frank T, Powell SM, Sugimura H, Young J, Harpaz N, Shimizu K, Matsubara N, Meltzer SJ.
Cancer Res. 1997 Jun 15;57(12):2350-3.
PMID 9192806
 
E2F and cell cycle control: a double-edged sword.
Stevens C, La Thangue NB.
Arch Biochem Biophys. 2003 Apr 15;412(2):157-69. (REVIEW)
PMID 12667479
 
BRG-1 is required for RB-mediated cell cycle arrest.
Strobeck MW, Knudsen KE, Fribourg AF, DeCristofaro MF, Weissman BE, Imbalzano AN, Knudsen ES.
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7748-53.
PMID 10884406
 
Cell-context specific role of the E2F/Rb pathway in development and disease.
Swiss VA, Casaccia P.
Glia. 2010 Mar;58(4):377-90. (REVIEW)
PMID 19795505
 
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 Dev. 2000 Apr 1;14(7):804-16.
PMID 10766737
 
Effect of naturally occurring E2F-4 alterations on transcriptional activation and proliferation in transfected cells.
Takashima H, Matsumoto Y, Matsubara N, Shirakawa Y, Kawashima R, Tanino M, Ito S, Isozaki H, Ouchida M, Meltzer SJ, Shimizu K, Tanaka N.
Lab Invest. 2001 Nov;81(11):1565-73.
PMID 11706064
 
E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1.
Taubert S, Gorrini C, Frank SR, Parisi T, Fuchs M, Chan HM, Livingston DM, Amati B.
Mol Cell Biol. 2004 May;24(10):4546-56.
PMID 15121871
 
Sibling rivalry in the E2F family.
Trimarchi JM, Lees JA.
Nat Rev Mol Cell Biol. 2002 Jan;3(1):11-20. (REVIEW)
PMID 11823794
 
The CBP co-activator stimulates E2F1/DP1 activity.
Trouche D, Cook A, Kouzarides T.
Nucleic Acids Res. 1996 Nov 1;24(21):4139-45.
PMID 8932363
 
E2F1 and E1A(12S) have a homologous activation domain regulated by RB and CBP.
Trouche D, Kouzarides T.
Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1439-42.
PMID 8643650
 
Involvement of E2F transcription factor family in cancer.
Tsantoulis PK, Gorgoulis VG.
Eur J Cancer. 2005 Nov;41(16):2403-14. Epub 2005 Oct 5. (REVIEW)
PMID 16213134
 
Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin.
Tseng YH, Butte AJ, Kokkotou E, Yechoor VK, Taniguchi CM, Kriauciunas KM, Cypess AM, Niinobe M, Yoshikawa K, Patti ME, Kahn CR.
Nat Cell Biol. 2005 Jun;7(6):601-11. Epub 2005 May 15.
PMID 15895078
 
E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases.
Tyagi S, Chabes AL, Wysocka J, Herr W.
Mol Cell. 2007 Jul 6;27(1):107-19.
PMID 17612494
 
Functional interaction between E2F-4 and p130: evidence for distinct mechanisms underlying growth suppression by different retinoblastoma protein family members.
Vairo G, Livingston DM, Ginsberg D.
Genes Dev. 1995 Apr 1;9(7):869-81.
PMID 7705662
 
Phosphorylation dynamics during early differentiation of human embryonic stem cells.
Van Hoof D, Munoz J, Braam SR, Pinkse MW, Linding R, Heck AJ, Mummery CL, Krijgsveld J.
Cell Stem Cell. 2009 Aug 7;5(2):214-26.
PMID 19664995
 
Residues phosphorylated by TFIIH are required for E2F-1 degradation during S-phase.
Vandel L, Kouzarides T.
EMBO J. 1999 Aug 2;18(15):4280-91.
PMID 10428966
 
Transcriptional repression by the retinoblastoma protein through the recruitment of a histone methyltransferase.
Vandel L, Nicolas E, Vaute O, Ferreira R, Ait-Si-Ali S, Trouche D.
Mol Cell Biol. 2001 Oct;21(19):6484-94.
PMID 11533237
 
2F activity is regulated by cell cycle-dependent changes in subcellular localization.
Verona R, Moberg K, Estes S, Starz M, Vernon JP, Lees JA.
Mol Cell Biol. 1997 Dec;17(12):7268-82.
PMID 9372959
 
Identification of differentially expressed genes by serial analysis of gene expression in human prostate cancer.
Waghray A, Schober M, Feroze F, Yao F, Virgin J, Chen YQ.
Cancer Res. 2001 May 15;61(10):4283-6.
PMID 11358857
 
Deregulated expression of DP1 induces epidermal proliferation and enhances skin carcinogenesis.
Wang D, Russell J, Xu H, Johnson DG.
Mol Carcinog. 2001 Jun;31(2):90-100.
PMID 11429786
 
Target gene specificity of E2F and pocket protein family members in living cells.
Wells J, Boyd KE, Fry CJ, Bartley SM, Farnham PJ.
Mol Cell Biol. 2000 Aug;20(16):5797-807.
PMID 10913163
 
Accumulation of E2F-4.DP-1 DNA binding complexes correlates with induction of dhfr gene expression during the G1 to S phase transition.
Wells JM, Illenye S, Magae J, Wu CL, Heintz NH.
J Biol Chem. 1997 Feb 14;272(7):4483-92.
PMID 9020173
 
Rb/E2F4 and Smad2/3 link survivin to TGF-beta-induced apoptosis and tumor progression.
Yang J, Song K, Krebs TL, Jackson MW, Danielpour D.
Oncogene. 2008 Sep 11;27(40):5326-38. Epub 2008 May 26.
PMID 18504435
 
An antisense transcript induced by Wnt/beta-catenin signaling decreases E2F4.
Yochum GS, Cleland R, McWeeney S, Goodman RH.
J Biol Chem. 2007 Jan 12;282(2):871-8. Epub 2006 Nov 22.
PMID 17121828
 
Mutations of E2F-4 trinucleotide repeats in colorectal cancer with microsatellite instability.
Yoshitaka T, Matsubara N, Ikeda M, Tanino M, Hanafusa H, Tanaka N, Shimizu K.
Biochem Biophys Res Commun. 1996 Oct 14;227(2):553-7.
PMID 8878551
 
Detection of chromosomal alterations in bladder cancer by comparative genomic hybridization.
Yu DS, Hsieh DS, Chang SY.
BJU Int. 2001 Jun;87(9):889-93.
PMID 11412232
 
Rb-mediated chromatin structure regulation and transcriptional repression.
Zhang HS, Dean DC.
Oncogene. 2001 May 28;20(24):3134-8. (REVIEW)
PMID 11420730
 
Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF.
Zhang HS, Gavin M, Dahiya A, Postigo AA, Ma D, Luo RX, Harbour JW, Dean DC.
Cell. 2000 Mar 31;101(1):79-89.
PMID 10778858
 
pRB and E2F4 play distinct cell-intrinsic roles in fetal erythropoiesis.
Zhang J, Lee EY, Liu Y, Berman SD, Lodish HF, Lees JA.
Cell Cycle. 2010 Jan 15;9(2):371-6. Epub 2010 Jan 29.
PMID 20023434
 
Repression of E2F1-mediated transcription by the ErbB3 binding protein Ebp1 involves histone deacetylases.
Zhang Y, Woodford N, Xia X, Hamburger AW.
Nucleic Acids Res. 2003 Apr 15;31(8):2168-77.
PMID 12682367
 
Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP.
Zheng N, Fraenkel E, Pabo CO, Pavletich NP.
Genes Dev. 1999 Mar 15;13(6):666-74.
PMID 10090723
 
E2Fs link the control of G1/S and G2/M transcription.
Zhu W, Giangrande PH, Nevins JR.
EMBO J. 2004 Nov 24;23(23):4615-26. Epub 2004 Oct 28.
PMID 15510213
 
E2F4 is required for cardiomyocyte proliferation.
van Amerongen MJ, Diehl F, Novoyatleva T, Patra C, Engel FB.
Cardiovasc Res. 2010 Apr 1;86(1):92-102. Epub 2009 Dec 2.
PMID 19955219
 

Citation

This paper should be referenced as such :
Paquin, MC ; Rivard, N
E2F4 (E2F transcription factor 4, p107/p130-binding)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(8):529-539.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/E2F4ID40385ch16q22.html


External links

Nomenclature
HGNC (Hugo)E2F4   3118
Cards
AtlasE2F4ID40385ch16q22
Entrez_Gene (NCBI)E2F4  1874  E2F transcription factor 4
AliasesE2F-4
GeneCards (Weizmann)E2F4
Ensembl hg19 (Hinxton)ENSG00000205250 [Gene_View]  chr16:67226068-67232821 [Contig_View]  E2F4 [Vega]
Ensembl hg38 (Hinxton)ENSG00000205250 [Gene_View]  chr16:67226068-67232821 [Contig_View]  E2F4 [Vega]
ICGC DataPortalENSG00000205250
TCGA cBioPortalE2F4
AceView (NCBI)E2F4
Genatlas (Paris)E2F4
WikiGenes1874
SOURCE (Princeton)E2F4
Genetics Home Reference (NIH)E2F4
Genomic and cartography
GoldenPath hg19 (UCSC)E2F4  -     chr16:67226068-67232821 +  16q22.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)E2F4  -     16q22.1   [Description]    (hg38-Dec_2013)
EnsemblE2F4 - 16q22.1 [CytoView hg19]  E2F4 - 16q22.1 [CytoView hg38]
Mapping of homologs : NCBIE2F4 [Mapview hg19]  E2F4 [Mapview hg38]
OMIM600659   
Gene and transcription
Genbank (Entrez)AB451292 AB451425 BC021050 BC031071 BC033180
RefSeq transcript (Entrez)NM_001950
RefSeq genomic (Entrez)NC_000016 NC_018927 NT_010498 NW_004929402
Consensus coding sequences : CCDS (NCBI)E2F4
Cluster EST : UnigeneHs.108371 [ NCBI ]
CGAP (NCI)Hs.108371
Alternative Splicing GalleryENSG00000205250
Gene ExpressionE2F4 [ NCBI-GEO ]   E2F4 [ EBI - ARRAY_EXPRESS ]   E2F4 [ SEEK ]   E2F4 [ MEM ]
Gene Expression Viewer (FireBrowse)E2F4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1874
GTEX Portal (Tissue expression)E2F4
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ16254   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ16254  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ16254
Splice isoforms : SwissVarQ16254
PhosPhoSitePlusQ16254
Domains : Interpro (EBI)E2F    E2F4    E2F_CC-MB    E2F_WHTH_DNA-bd_dom    WHTH_DNA-bd_dom   
Domain families : Pfam (Sanger)E2F_CC-MB (PF16421)    E2F_TDP (PF02319)   
Domain families : Pfam (NCBI)pfam16421    pfam02319   
Conserved Domain (NCBI)E2F4
DMDM Disease mutations1874
Blocks (Seattle)E2F4
PDB (SRS)1CF7   
PDB (PDBSum)1CF7   
PDB (IMB)1CF7   
PDB (RSDB)1CF7   
Structural Biology KnowledgeBase1CF7   
SCOP (Structural Classification of Proteins)1CF7   
CATH (Classification of proteins structures)1CF7   
SuperfamilyQ16254
Human Protein AtlasENSG00000205250
Peptide AtlasQ16254
HPRD02806
IPIIPI00292880   
Protein Interaction databases
DIP (DOE-UCLA)Q16254
IntAct (EBI)Q16254
FunCoupENSG00000205250
BioGRIDE2F4
STRING (EMBL)E2F4
ZODIACE2F4
Ontologies - Pathways
QuickGOQ16254
Ontology : AmiGOregulation of transcription involved in G1/S transition of mitotic cell cycle  nuclear chromatin  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  epithelial cell development  DNA binding  transcription factor activity, sequence-specific DNA binding  protein binding  nucleoplasm  nucleoplasm  transcription factor complex  transcription from RNA polymerase II promoter  cell volume homeostasis  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  blood circulation  transcription factor binding  organ morphogenesis  protein domain specific binding  regulation of cell proliferation  motile cilium assembly  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  centriole assembly  multi-ciliated epithelial cell differentiation  
Ontology : EGO-EBIregulation of transcription involved in G1/S transition of mitotic cell cycle  nuclear chromatin  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  epithelial cell development  DNA binding  transcription factor activity, sequence-specific DNA binding  protein binding  nucleoplasm  nucleoplasm  transcription factor complex  transcription from RNA polymerase II promoter  cell volume homeostasis  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  blood circulation  transcription factor binding  organ morphogenesis  protein domain specific binding  regulation of cell proliferation  motile cilium assembly  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  centriole assembly  multi-ciliated epithelial cell differentiation  
Pathways : BIOCARTAMETS affect on Macrophage Differentiation [Genes]   
Pathways : KEGGCell cycle    TGF-beta signaling pathway   
REACTOMEQ16254 [protein]
REACTOME Pathways1538133 [pathway]   2173796 [pathway]   6804114 [pathway]   69231 [pathway]   
NDEx NetworkE2F4
Atlas of Cancer Signalling NetworkE2F4
Wikipedia pathwaysE2F4
Orthology - Evolution
OrthoDB1874
GeneTree (enSembl)ENSG00000205250
Phylogenetic Trees/Animal Genes : TreeFamE2F4
HOVERGENQ16254
HOGENOMQ16254
Homologs : HomoloGeneE2F4
Homology/Alignments : Family Browser (UCSC)E2F4
Gene fusions - Rearrangements
Fusion Cancer (Beijing)APOA2 [1q23.3]  -  E2F4 [16q22.1]  [FUSC002260]
Fusion Cancer (Beijing)E2F4 [16q22.1]  -  RPL14 [3p22.1]  [FUSC000406]  [FUSC000406]  [FUSC000406]  [FUSC000406]  [FUSC000406]  [FUSC000406]  [FUSC000406]
Fusion Cancer (Beijing)RPL14 [3p22.1]  -  E2F4 [16q22.1]  [FUSC000219]  [FUSC000219]  [FUSC000219]  [FUSC000219]  [FUSC000219]  [FUSC000219]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerE2F4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)E2F4
dbVarE2F4
ClinVarE2F4
1000_GenomesE2F4 
Exome Variant ServerE2F4
ExAC (Exome Aggregation Consortium)E2F4 (select the gene name)
Genetic variants : HAPMAP1874
Genomic Variants (DGV)E2F4 [DGVbeta]
DECIPHER (Syndromes)16:67226068-67232821  ENSG00000205250
CONAN: Copy Number AnalysisE2F4 
Mutations
ICGC Data PortalE2F4 
TCGA Data PortalE2F4 
Broad Tumor PortalE2F4
OASIS PortalE2F4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICE2F4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDE2F4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch E2F4
DgiDB (Drug Gene Interaction Database)E2F4
DoCM (Curated mutations)E2F4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)E2F4 (select a term)
intoGenE2F4
NCG5 (London)E2F4
Cancer3DE2F4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM600659   
Orphanet
MedgenE2F4
Genetic Testing Registry E2F4
NextProtQ16254 [Medical]
TSGene1874
GENETestsE2F4
Huge Navigator E2F4 [HugePedia]
snp3D : Map Gene to Disease1874
BioCentury BCIQE2F4
ClinGenE2F4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1874
Chemical/Pharm GKB GenePA27576
Clinical trialE2F4
Miscellaneous
canSAR (ICR)E2F4 (select the gene name)
Probes
Litterature
PubMed113 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineE2F4
EVEXE2F4
GoPubMedE2F4
iHOPE2F4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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