Alternative titles; symbols
HGNC Approved Gene Symbol: E2F1
Cytogenetic location: 20q11.22 Genomic coordinates (GRCh38): 20:33,675,477-33,686,385 (from NCBI)
The E2F1 transcription factor is generally dispensable for cell proliferation but is selectively activated in response to specific cues. It can promote proliferation or apoptosis when activated, and is a key downstream target of the RB1 protein (614041). When activated in response to DNA damage, E2F1 drives the expression of proapoptotic genes (summary by Morris et al., 2008).
Many DNA tumor viruses appear to have transforming activity due, in part, to their ability to bind and inactivate the product of the RB1 gene (Nevins, 1992). Several cellular proteins bind RB1, including the transcription factor E2F. E2F was originally identified as a DNA-binding protein essential for E1A-dependent activation of the adenovirus E2 promoter. E2F-binding sites are present in the promoters of many cellular genes whose products are involved in cell proliferation, especially DNA synthesis. Helin et al. (1992) cloned a cDNA encoding E2F1, which they called RBP3. The deduced 437-amino acid E2F1 protein has a calculated molecular mass of 47 kD and contains a nuclear localization signal. Northern blot analysis detected a 3.1-kb transcript that was highly expressed in heart, brain, and placenta and more weakly expressed in skeletal muscle, kidney, and pancreas. Kaelin et al. (1992) independently cloned E2F1, which they called RBAP1.
Lees et al. (1993) identified 2 additional E2F-related cDNAs by low-stringency hybridization. Northern blot analysis showed that both are closely related to E2F1 and have similar properties, although they are expressed at lower levels than E2F1.
By immunohistochemical analysis, Paik et al. (2010) found that E2F1 colocalized with the ribosomal RNA-processing protein RRP1B (610654) in nucleoli and punctate nucleoplasmic foci of several human cell lines.
Neuman et al. (1996) found that the human E2F1 gene is composed of 7 exons and spans approximately 11 kb. Intron 4 does not have consensus 5-prime and 3-prime splice sites. Like the other members of the E2F family, the E2F1 protein contains an N-terminal DNA-binding domain and a C-terminal acidic-amino acid transactivation domain.
By fluorescence in situ hybridization, Neuman et al. (1996) mapped the E2F1 gene to 20q11.2. Using FISH with genomic cosmid probes containing each locus, Lees et al. (1993) mapped the E2F2 gene (600426) to 1p36 and the E2F3 gene (600427) to 6p22.
Independently, Helin et al. (1992) and Kaelin et al. (1992) showed that E2F1 interacted with RB (180200), bound E2F DNA recognition sequences, and could induce gene activation.
A variety of experimental findings point to the transcription factor E2F as a critical determinant of the G1/S-phase transition during the mammalian cell cycle, serving to activate the transcription of a group of genes that encode proteins necessary for DNA replication. In addition, E2F activity appears to be directly regulated by the action of retinoblastoma protein, and indirectly regulated through the action of G1 cyclins and associated kinases. Ohtani et al. (1995) showed that the accumulation of G1 cyclins is regulated by E2F1. E2F binding sites are found in both the cyclin E (123837) and cyclin D1 (168461) promoters. Both promoters are activated by E2F gene products, and at least for cyclin E, the E2F sites contribute to cell cycle-dependent control. They found that the endogenous cyclin E gene is activated following expression of the E2F1 product encoded by a recombinant adenovirus vector. Results were interpreted to suggest the involvement of E2F1 and cyclin E in an autoregulatory loop that governs the accumulation of critical activities affecting the progression of cells through G1.
RB1 inhibits progression from G1 to S phase of the cell cycle and associates with a number of cellular proteins. Zhang et al. (1999) presented evidence that RB1 must normally interact with the E2F family of transcription factors to arrest cells in G1, and that this arrest results from active transcriptional repression by the RB-E2F complex, not from inactivation of E2F. Thus, a major role of E2F in cell cycle regulation is assembly of this repressor complex. Zhang et al. (1999) demonstrated that active repression by the RB1-E2F complex mediates the G1 arrest triggered by transforming growth factor-beta (TGFB; 190180), p16(INK4A) (CDKN2A; 600160), and contact inhibition.
Phillips et al. (1999) showed that E2F1 can induce apoptosis by a death receptor-dependent mechanism, by downregulating TRAF2 (601895) protein levels and inhibiting activation of antiapoptotic signals such as NFKB (see 164011). In this way, independent of p53, E2F1 expression can lead to the sensitization of cells to apoptosis by a number of agents. Deregulation of E2F1 activity occurs in the majority of human tumors, and the authors suggested that the ability of E2F1 to inhibit antiapoptotic signaling may contribute to the enhanced sensitivity of transformed cells to chemotherapeutic agents.
Zhang and Chellappan (1995) stated that E2F factors bind to DNA as homodimers or heterodimers in association with dimerization partners DP1 (189902) or DP2 (602160).
Strong stimulation of the T-cell receptor on cycling peripheral T cells causes their apoptosis by TCR activation-induced cell death (TCR-AICD). Using TUNEL (TdT mediated dUTP nick end labeling) analysis, Lissy et al. (2000) showed that T cells undergoing TCR-AICD induce the p53 (191170)-related gene, TP73 (601990). Introduction of dominant-negative E2F1 or TP73, but not E2F2, E2F4 (600659), or p53, protects cells from TCR-AICD. Primary T cells not expressing E2F1 or TP73 do not undergo TCR-AICD, either. Lissy et al. (2000) concluded that TCR-AICD, which occurs from a late G1 phase cell cycle check point independently of p53, is dependent on E2F1 and TP73.
Sherr (1998) noted in a review that E2F1 induces p53-dependent apoptosis by inducing ARF (CDKN2A), which neutralizes MDM2 (164785) and stabilizes p53. Irwin et al. (2000) found that transient expression of E2F1 causes an accumulation of p73 mRNA, activates the p73 promoter, and increases TP73 protein levels, but does not affect TP63 (603273). TUNEL analysis showed that apoptosis is diminished in E2F1-expressing cells lacking p53 or p73 and nearly undetectable in cells lacking both proteins, suggesting that E2F1 can induce apoptosis in a p53-independent manner through p73.
Furukawa et al. (2002) identified an E2F1-binding element within the promoter region of human APAF1 (602233) and confirmed binding in a chromatin immunoprecipitation assay. They found that E2F1-induced apoptosis was accompanied by caspase-9 (602234) activation and enhanced expression of APAF1 without the cytosolic accumulation of cytochrome c. Overexpression of APAF1 resulted in direct activation of caspase-9 without mitochondrial damage and initiated a caspase cascade.
Nevins (2001) reviewed the role of the Rb/E2F pathway in cell proliferation, cell fate determination, and cancer.
MYC (190080) induces transcription of the E2F1, E2F2, and E2F3 genes. Using primary mouse embryo fibroblasts deleted for individual E2f genes, Leone et al. (2001) showed that MYC-induced S phase and apoptosis requires distinct E2F activities. The ability of Myc to induce S phase was impaired in the absence of either E2f2 or E2f3 but not E2f1 or E2f4. In contrast, the ability of Myc to induce apoptosis was markedly reduced in cells deleted for E2f1 but not E2f2 or E2f3. The authors proposed that the induction of specific E2F activities is an essential component in the MYC pathways that control cell proliferation and cell fate decisions.
Fajas et al. (2002) concluded that the E2F1 and E2F4 proteins play a direct role in the regulation of early adipocyte differentiation. Using electrophoretic mobility shift assays and immunoprecipitation experiments, Fajas et al. (2002) demonstrated that E2F family members bind in vitro and in vivo to the PPARG (601487) promoter. Using a combination of in vitro experiments and in vivo experiments with knockout and chimeric mice, Fajas et al. (2002) demonstrated that the absence of E2F1 impairs adipogenesis. The authors concluded that E2F1 induces PPARG transcription during the early stages of adipogenesis.
De Angelis et al. (2003) showed that human ATF4 (604064) and RBP3 dimerized in vitro and in vivo and that RBP3 enhanced ATF4 transactivating activity. Expression of both proteins increased during differentiation of a mouse myogenic cell line.
Liu et al. (2004) presented evidence that TOPBP1 (607760) recruits BRG1 (SMARCA4; 603254)/BRM (SMARCA2; 600014) to E2F1-responsive promoters to repress the transcriptional activity of E2F1, but not other E2F factors. The inhibition of E2F1 repressed E2F1-dependent apoptosis during S phase and DNA damage. TOPBP1 was also induced by E2F and interacted with E2F1 during G1/S transition. Liu et al. (2004) concluded that E2F1 and TOPBP1 form a feedback regulation to prevent apoptosis during DNA replication.
O'Donnell et al. (2005) showed that c-Myc activates expression of a cluster of 6 miRNAs on human chromosome 13 (see 609415). Chromatin immunoprecipitation experiments showed that c-Myc binds directly to this locus. The transcription factor E2F1 is an additional target of c-Myc that promotes cell cycle progression. O'Donnell et al. (2005) found that expression of E2F1 is negatively regulated by 2 miRNAs in this cluster, miR17-5p (609416) and miR20a (609420). O'Donnell et al. (2005) concluded that their findings expand the known classes of transcripts within the c-Myc target gene network, and reveal a mechanism through which c-Myc simultaneously activates E2F1 transcription and limits its translation, allowing a tightly controlled proliferative signal.
The marked box domain and adjacent region of E2F1 are critical for the specificity of E2F1 apoptosis induction. Using the marked box domain of E2F1 in a yeast 2-hybrid screen of a human thymus cDNA library, Hallstrom and Nevins (2006) identified JAB1 (604850) as an E2F1 binding partner. JAB1 and E2F1 coexpression in rat embryonic fibroblasts synergistically induced apoptosis, coincident with the induction of p53 protein accumulation. In contrast, JAB1 did not synergize with E2F1 to promote cell cycle entry. Cells depleted of JAB1 were deficient for both E2F1-induced apoptosis and induction of p53 accumulation. Hallstrom and Nevins (2006) concluded that JAB1 is an essential cofactor for the apoptotic function of E2F1.
By genomewide mapping of RELA (164014)-bound loci in lipopolysaccharide (LPS)-stimulated monocytes, together with global gene expression profiling, Lim et al. (2007) identified an overrepresentation of the E2F1-binding motif among RELA-bound loci associated with NFKB target genes. Knockdown of endogenous E2F1 impaired the LPS inducibility of the proinflammatory cytokines CCL3 (182283), IL23A (605580), TNF (191160), and IL1B (147720). Sequential chromatin immunoprecipitation and coimmunoprecipitation analysis showed that E2F1 existed as a complex with p50 (164011)/RELA in LPS-stimulated monocytes. Lim et al. (2007) concluded that E2F1 positively regulates a spectrum of NFKB target genes and that E2F1 has a critical role in the TLR4 (603030) pathway.
Morris et al. (2008) demonstrated that E2F1 is a potent and specific inhibitor of beta-catenin (116806)/T cell factor (TCF)-dependent transcription and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC; 611731)/glycogen synthase kinase-3 (GSK3; see 606784)-independent manner, reducing the expression of key beta-catenin targets including c-MYC (190080). This interaction explains why colorectal tumors, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8; 603184), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. Morris et al. (2008) concluded that thus, by retaining RB1 and amplifying CDK8, colorectal tumor cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin.
To address the function of E2F1, E2F2 (600426), and E2F3 (600427) in normal mammalian cells in vivo, Chen et al. (2009) focused on the mouse retina, which is a relatively simple central nervous system component that can be manipulated genetically without compromising viability and has provided considerable insight into development and cancer. The authors showed that unlike fibroblasts, E2f1-, E2f2-, and E2f3-null retinal progenitor cells or activated Muller glia can divide. Chen et al. (2009) attributed this effect to functional interchangeability with Mycn (164840). However, loss of activating E2fs caused downregulation of the p53 (191170) deacetylase Sirt1 (604479), p53 hyperacetylation, and elevated apoptosis, establishing a novel E2f-Sirt1-p53 survival axis in vivo. Chen et al. (2009) concluded that activating E2fs are not universally required for normal mammalian cell division, but have an unexpected prosurvival role in development.
Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles, Chong et al. (2009) examined the effects of E2f1, E2f2, and E2f3 triple deficiency in murine embryonic stem cells, embryos, and small intestines. They showed that in normal dividing progenitor cells, E2f1-3 function as transcriptional activators, but are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1-3 function in a complex with Rb (180200) as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f-responsive targets and ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency. Chong et al. (2009) concluded that their work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.
Gain-of-function mutations in LRRK2 (609007) cause Parkinson disease (PARK8; 607060) characterized by age-dependent degeneration of dopaminergic neurons. Gehrke et al. (2010) found that LRRK2 interacted with the miRNA pathway to regulate protein synthesis. They showed that mRNAs for Drosophila E2f1 and Dp, which had previously been implicated in cell cycle and survival control (Girling et al., 1993), were translationally repressed by the miRNAs Let7 (MIRLET7A1; 605386) and miR184* (613146), respectively. Pathogenic human LRRK2 antagonized Let7 and miR184*, leading to overproduction of E2f1 and Dp, which was critical for LRRK2 pathogenesis. In Drosophila, genetic deletion of Let7, antagomir-mediated blockage of Let7 and miR184* action, transgenic expression of Dp target protector, or replacement of endogenous Dp with a Dp transgene nonresponsive to Let7 each had toxic effects similar to those of pathogenic LRRK2. Conversely, increasing the level of Let7 or miR184* attenuated pathogenic LRRK2 effects. Human LRRK2 associated with Drosophila Argonaute-1 (EIF2C1, or AGO1; 606228) or human Argonaute-2 (EIF2C2, or AGO2; 606229) of the RNA-induced silencing complex (RISC). In aged fly brain, Ago1 protein level was negatively regulated by human LRRK2. Furthermore, pathogenic LRRK2 promoted the association of phosphorylated 4EBP1 (EIF4EPB1; 602223) with human AGO2. Gehrke et al. (2010) concluded that deregulated synthesis of E2F1 and DP caused by miRNA pathway impairment is a key event in LRRK2 pathogenesis, suggesting that novel miRNA-based therapeutic strategies may be useful for Parkinson disease.
Using semiquantitative RT-PCR, Paik et al. (2010) found that overexpression of E2F1, but not other E2F family member, upregulated expression of RRP1B in several human cell lines. Conversely, knockdown of E2F1 reduced RRP1B transcription. RRP1B expression peaked at the G1/S transition in human cell lines and primary foreskin fibroblasts, consistent with E2F1 expression. Truncation analysis coupled with reporter gene assays showed that E2F1 bound and activated the RRP1B promoter at the most proximal E2F site only. RRP1B expression was also elevated following exposure of human cell lines to several DNA-damaging agents. Knockdown of RRP1B decreased apoptosis induced by genotoxic agents or by E2F1 overexpression, but it had no effect on E2F1-regulated cell proliferation. Knockdown of RRP1B reduced the expression of a subset of E2F1-dependent apoptotic genes, including caspase-3 (CASP3; 600636), caspase-7 (CASP7; 601761), and APAF1. Coimmunoprecipitation, protein pull-down, and chromatin immunoprecipitation assays showed that regulation of these genes by RRP1B occurred by direct interaction between RRP1B with E2F1.
By analyzing data from chromatin immunoprecipitation-sequencing and -microarray analyses in mouse embryonic stem cells, Gokhman et al. (2013) identified E2f1 and E2f4 as master regulators of histone gene expression. These 2 factors bound all histone genes examined.
The retinoblastoma tumor suppressor protein is a transcriptional repressor that regulates gene expression by physically associating with transcription factors such as members of the E2F family. To address the function of E2F1 and the RB/E2F1 complex in vivo, Yamasaki et al. (1996) and Field et al. (1996) produced mice homozygous for a nonfunctional E2f1 allele. Both groups found that mice lacking E2f1 are viable and fertile. However, Yamasaki et al. (1996) found that they show testicular atrophy and exocrine gland dysplasia, and develop a broad and unusual spectrum of tumors. Although overexpression of E2F1 in tissue culture cells can stimulate cell proliferation and be oncogenic, loss of E2f1 in mice resulted in tumorigenesis, demonstrating that E2F1 also functions as a tumor suppressor. Field et al. (1996) found that E2f1 -/- mice exhibit a defect in T-lymphocyte development, leading to an excess of mature T cells due to a maturation stage-specific defect in thymocyte apoptosis. They also observed aberrant cell proliferation. Weinberg (1996) suggested that the findings of these 2 groups indicate that E2F1 satisfies the definition of a tumor suppressor gene.
To investigate the requirement for E2F1 function in the cellular and developmental phenotypes caused by homozygous RB1 mutations in the mouse, Tsai et al. (1998) crossed mice homozygous for targeted disruptions of the Rb gene (Jacks et al., 1992) and the E2f1 gene (Yamasaki et al., 1996). Mice mutant for the Rb tumor suppressor gene die in midgestation with defects in erythropoiesis, cell cycle control, and apoptosis. Tsai et al. (1998) showed that embryos mutant for both Rb and its downstream target E2f1 demonstrated significant suppression of apoptosis compared to Rb mutants, implicating E2f1 as a critical mediator of these effects. Upregulation of the p53 pathway, required for cell death in Rb mutants, was also suppressed in the Rb/E2f1 double mutants. However, double mutants had defects in cell cycle regulation and apoptosis in some tissues and died at approximately E17.0 with anemia and defective skeletal muscle and lung development, demonstrating that E2F1 regulation is not the sole function of RB in development.
To study the involvement of E2F1 in p53-dependent apoptosis, Pan et al. (1998) crossed mice with targeted disruption of the E2f1 gene (Yamasaki et al., 1996) with mice harboring a transgene that encodes the first 121 amino acids of the SV40 T antigen (Saenz Robles et al., 1994). Pan et al. (1998) showed that E2f1 signals p53-dependent apoptosis since E2f1 deficiency caused an 80% apoptosis reduction. E2F1 acts upstream of p53 since transcriptional activation of p53 target genes was also impaired. However, E2f1 deficiency did not accelerate tumor growth. Unlike normal cells, tumor cell proliferation was impaired without E2f1, counterbalancing the effect of apoptosis reduction. These studies may explain the apparent paradox that E2F1 can act as both an oncogene and a tumor suppressor in experimental systems.
The Rb tumor suppressor pathway is believed to have a critical role in the control of cellular proliferation by regulating E2F activities. E2F1, E2F2, and E2F3 belong to a subclass of E2F factors thought to act as transcriptional activators important for progression through the G1/S transition. Wu et al. (2001) used a conditional gene targeting approach to demonstrate that combined loss of these 3 E2F factors severely affects E2F target expression and completely abolishes the ability of mouse embryonic fibroblasts to enter S phase, progress through mitosis, and proliferate. Loss of E2F function results in elevation of CIP1 (116899) protein, leading to a decrease in cyclin-dependent kinase activity and Rb phosphorylation. Wu et al. (2001) concluded that these findings suggest a function for this subclass of E2F transcriptional activators in a positive feedback loop, through downmodulation of CIP1, that leads to the inactivation of Rb-dependent repression and S phase entry. By targeting the entire subclass of E2F transcriptional activators, Wu et al. (2001) provided direct genetic evidence for their essential role in cell cycle progression, proliferation, and development. Wu et al. (2001) initially generated and interbred E2f1, E2f2, and E2f3 mutant mice, and found that although mice null for E2f1 and E2f2 were viable and developed to adulthood, mice null for E2f1 and E2f3 or E2f2 and E2f3 died early during embryonic development, at or just before embryonic day 9.5, pointing to a central role for E2F3 in mouse development.
Iglesias et al. (2004) generated mice deficient in both E2f1 and E2f2 (600426). The mice developed nonautoimmune insulin-deficient diabetes and exocrine pancreatic dysfunction characterized by endocrine and exocrine cell dysplasia and a reduction in the number and size of acini and islets, which were replaced by ductal structures and adipose tissue. Mutant pancreatic cells exhibited increased rates of DNA replication but also of apoptosis, resulting in severe pancreatic atrophy. The expression of genes involved in DNA replication and cell cycle control was upregulated in the E2F1/E2F2 compound mutant pancreas. Iglesias et al. (2004) suggested that E2F1/E2F2 activity negatively controls growth of mature pancreatic cells and is necessary for the maintenance of differentiated pancreatic phenotypes in the adult.
Fajas et al. (2004) generated E2f1 -/- mice to evaluate the effects of E2F1 on glucose homeostasis. The E2f1-null mice demonstrated impaired insulin secretion in response to a glucose challenge due to a defect in postnatal pancreatic growth and islet cell dysfunction. The E2f1-null mice did not develop overt diabetes mellitus, however, because they were insulin hypersensitive as a consequence of reduced adipose tissue mass.
Qin et al. (2006) found that E2f1 -/- mice exhibited enhanced angiogenesis due to overproduction of Vegf (192240). Under hypoxic conditions, E2f1 associated with p53 and specifically downregulated expression of Vegf, but not other hypoxia-inducible genes. Qin et al. (2006) determined that the minimum Vegf promoter mediating E2f1-induced repression contains an E2f1-binding site with 4 Sp1 (189906) sites in close proximity.
To begin to evaluate the genetic complexity of the E2F factors, Tsai et al. (2008) targeted the inactivation of the entire subset of activators (E2F1; E2F2, 600426; E2F3A and E2F3B, see 600427) singly or in combination in mice. They demonstrated that E2f3a is sufficient to support mouse embryonic and postnatal development. Remarkably, expression of E2f3b or E2f1 from the E2f3a locus suppressed all the postnatal phenotypes associated with the inactivation of E2f3a. Tsai et al. (2008) concluded that there is significant functional redundancy among activators and that the specific requirement for E2f3a during postnatal development is dictated by regulatory sequences governing its selective spatiotemporal expression and not by its intrinsic protein functions. They also concluded that their findings provided a molecular basis for the observed specificity among E2F activators during development.
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