Abstract
Initially, the E2F transcription factor was discovered as a factor able to bind the adenovirus E2 promoter and activate viral genes. Afterwards it was shown that E2F also binds to promoters of nonviral genes such as C-MYC and DHFR, which were already known at that time to be important for cell growth and DNA metabolism, respectively. These findings provided the first clues that the E2F transcription factor might be an important regulator of the cell cycle. Since this initial discovery in 1987, several additional E2F family members have been identified, and more than 100 targets genes have been shown to be directly regulated by E2Fs, the majority of these are important for controlling the cell cycle.
The progression of a cell through the cell cycle is accompanied with the increased expression of a specific set of genes during one phase of the cell cycle and the decrease of the same set of genes during a later phase of the cell cycle. This roller coaster ride, or oscillation, of gene expression is essential for the proper progression through the cell cycle to allow accurate DNA replication and cell division. The E2F transcription factors have been shown to be critical for the temporal expression of the oscillating cell cycle genes.
This review will focus on how the oscillation of E2Fs and their targets is regulated by transcriptional, post-transcriptional and post-translational mechanism in mammals, yeast, flies, and worms. Furthermore, we will discuss the functional impact of E2Fs on the cell cycle progression and outline the consequences when E2F expression is disturbed.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Wong JV, Dong P, Nevins JR et al (2011) Network calisthenics: control of E2F dynamics in cell cycle entry. Cell Cycle 10:3086–3094
DeGregori J, Leone G, Miron A et al (1997) Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci U S A 94:7245–7250
Weinberg R (2013) The biology of cancer, 2nd edn. Garland Science, New York, NY
Sun A, Bagella L, Tutton S et al (2007) From G0 to S phase: a view of the roles played by the retinoblastoma (Rb) family members in the Rb-E2F pathway. J Cell Biochem 102:1400–1404. doi:10.1002/jcb.21609
Di Stefano L, Jensen MR, Helin K (2003) E2F7, a novel E2F featuring DP-independent repression of a subset of E2F-regulated genes. EMBO J 22:6289–6298. doi:10.1093/emboj/cdg613
de Bruin A, Maiti B, Jakoi L et al (2003) Identification and characterization of E2F7, a novel mammalian E2F family member capable of blocking cellular proliferation. J Biol Chem 278:42041–42049. doi:10.1074/jbc.M308105200
Logan N, Delavaine L, Graham A et al (2004) E2F-7: a distinctive E2F family member with an unusual organization of DNA-binding domains. Oncogene 23:5138–5150. doi:10.1038/sj.onc.1207649
Christensen J, Cloos P, Toftegaard U et al (2005) Characterization of E2F8, a novel E2F-like cell-cycle regulated repressor of E2F-activated transcription. Nucleic Acids Res 33:5458–5470. doi:10.1093/nar/gki855
Maiti B, Li J, de Bruin A et al (2005) Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation. J Biol Chem 280:18211–18220. doi:10.1074/jbc.M501410200
Li J, Ran C, Li E et al (2008) Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development. Dev Cell 14:62–75. doi:10.1016/j.devcel.2007.10.017
Westendorp B, Mokry M, Groot Koerkamp MJA et al (2012) E2F7 represses a network of oscillating cell cycle genes to control S-phase progression. Nucleic Acids Res 40:3511–3523. doi:10.1093/nar/gkr1203
Nakayama KI, Nakayama K (2006) Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6:369–381. doi:10.1038/nrc1881
Peart MJ, Poyurovsky MV, Kass EM et al (2010) APC/C(Cdc20) targets E2F1 for degradation in prometaphase. Cell Cycle 9:3956–3964
Geley S, Kramer E, Gieffers C et al (2001) Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint. J Cell Biol 153:137–148
Trimarchi JM, Lees JA (2002) Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 3:11–20. doi:10.1038/nrm714
Lammens T, Li J, Leone G, De Veylder L (2009) Atypical E2Fs: new players in the E2F transcription factor family. Trends Cell Biol 19:111–118. doi:10.1016/j.tcb.2009.01.002
Leone G, DeGregori J, Yan Z et al (1998) E2F3 activity is regulated during the cell cycle and is required for the induction of S phase. Genes Dev 12:2120–2130
Wenzel PL, Chong J-L, Sáenz-Robles MT et al (2011) Cell proliferation in the absence of E2F1-3. Dev Biol 351:35–45. doi:10.1016/j.ydbio.2010.12.025
Frolov MV, Huen DS, Stevaux O et al (2001) Functional antagonism between E2F family members. Genes Dev 15:2146–2160. doi:10.1101/gad.903901
Logan TJ, Evans DL, Mercer WE et al (1995) Expression of a deletion mutant of the E2F1 transcription factor in fibroblasts lengthens S phase and increases sensitivity to S phase-specific toxins. Cancer Res 55:2883–2891
Humbert PO, Verona R, Trimarchi JM et al (2000) E2f3 is critical for normal cellular proliferation. Genes Dev 14:690–703
Dos Reis Vasques L, Pujiz RS, Strauss BE, Krieger JE (2010) Knockdown of E2f1 by RNA interference impairs proliferation of rat cells in vitro. Genet Mol Biol 33:17–22. doi:10.1590/S1415-47572009005000104
Degregori J, Johnson DG (2006) Distinct and overlapping roles for E2F family members in transcription, proliferation and apoptosis. Curr Mol Med 6:739–748
Zhu JW, Field SJ, Gore L et al (2001) E2F1 and E2F2 determine thresholds for antigen-induced T-cell proliferation and suppress tumorigenesis. Mol Cell Biol 21:8547–8564. doi:10.1128/MCB.21.24.8547-8564.2001
Laresgoiti U, Apraiz A, Olea M et al (2013) E2F2 and CREB cooperatively regulate transcriptional activity of cell cycle genes. Nucleic Acids Res 41:10185–10198. doi:10.1093/nar/gkt821
Chong J-L, Tsai S-Y, Sharma N et al (2009) E2f3a and E2f3b contribute to the control of cell proliferation and mouse development. Mol Cell Biol 29:414–424. doi:10.1128/MCB.01161-08
Wu L, Timmers C, Maiti B et al (2001) The E2F1-3 transcription factors are essential for cellular proliferation. Nature 414:457–462. doi:10.1038/35106593
Tsai S-Y, Opavsky R, Sharma N et al (2008) Mouse development with a single E2F activator. Nature 454:1137–1141. doi:10.1038/nature07066
Stevens C, Smith L, La Thangue NB (2003) Chk2 activates E2F-1 in response to DNA damage. Nat Cell Biol 5:401–409. doi:10.1038/ncb974
Carnevale J, Palander O, Seifried LA, Dick FA (2012) DNA damage signals through differentially modified E2F1 molecules to induce apoptosis. Mol Cell Biol 32:900–912. doi:10.1128/MCB.06286-11
Müller H, Moroni MC, Vigo E et al (1997) Induction of S-phase entry by E2F transcription factors depends on their nuclear localization. Mol Cell Biol 17:5508–5520
Verona R, Moberg K, Estes S et al (1997) E2F activity is regulated by cell cycle-dependent changes in subcellular localization. Mol Cell Biol 17:7268–7282
Attwooll C, Lazzerini Denchi E, Helin K (2004) The E2F family: specific functions and overlapping interests. EMBO J 23:4709–4716. doi:10.1038/sj.emboj.7600481
Lee B-K, Bhinge AA, Iyer VR (2011) Wide-ranging functions of E2F4 in transcriptional activation and repression revealed by genome-wide analysis. Nucleic Acids Res 39:3558–3573. doi:10.1093/nar/gkq1313
Bertoli C, Klier S, McGowan C et al (2013) Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription. Curr Biol 23:1629–1637. doi:10.1016/j.cub.2013.06.063
Lyons TE, Salih M, Tuana BS (2006) Activating E2Fs mediate transcriptional regulation of human E2F6 repressor. Am J Physiol Cell Physiol 290:C189–C199. doi:10.1152/ajpcell.00630.2004
Giangrande PH, Zhu W, Schlisio S et al (2004) A role for E2F6 in distinguishing G1/S- and G2/M-specific transcription. Genes Dev 18:2941–2951. doi:10.1101/gad.1239304
Cross FR, Buchler NE, Skotheim JM (2011) Evolution of networks and sequences in eukaryotic cell cycle control. Philos Trans R Soc Lond B Biol Sci 366:3532–3544. doi:10.1098/rstb.2011.0078
Charvin G, Oikonomou C, Siggia ED, Cross FR (2010) Origin of irreversibility of cell cycle start in budding yeast. PLoS Biol 8, e1000284. doi:10.1371/journal.pbio.1000284
Amon A, Tyers M, Futcher B, Nasmyth K (1993) Mechanisms that help the yeast cell cycle clock tick: G2 cyclins transcriptionally activate G2 cyclins and repress G1 cyclins. Cell 74:993–1007
Bähler J (2005) Cell-cycle control of gene expression in budding and fission yeast. Annu Rev Genet 39:69–94. doi:10.1146/annurev.genet.39.110304.095808
de Bruin RAM, Kalashnikova TI, Chahwan C et al (2006) Constraining G1-specific transcription to late G1 phase: the MBF-associated corepressor Nrm1 acts via negative feedback. Mol Cell 23:483–496. doi:10.1016/j.molcel.2006.06.025
Igual JC, Johnson AL, Johnston LH (1996) Coordinated regulation of gene expression by the cell cycle transcription factor Swi4 and the protein kinase C MAP kinase pathway for yeast cell integrity. EMBO J 15:5001–5013
Verma R, Smiley J, Andrews B, Campbell JL (1992) Regulation of the yeast DNA replication genes through the Mlu I cell cycle box is dependent on SWI6. Proc Natl Acad Sci U S A 89:9479–9483
Koch C, Moll T, Neuberg M et al (1993) A role for the transcription factors Mbp1 and Swi4 in progression from G1 to S phase. Science 261:1551–1557
Sopko R, Huang D, Preston N et al (2006) Mapping pathways and phenotypes by systematic gene overexpression. Mol Cell 21:319–330. doi:10.1016/j.molcel.2005.12.011
Ohtani K, Nevins JR (1994) Functional properties of a Drosophila homolog of the E2F1 gene. Mol Cell Biol 14:1603–1612
Sawado T, Yamaguchi M, Nishimoto Y et al (1998) dE2F2, a novel E2F-family transcription factor in Drosophila melanogaster. Biochem Biophys Res Commun 251:409–415. doi:10.1006/bbrc.1998.9407
Dimova DK, Stevaux O, Frolov MV, Dyson NJ (2003) Cell cycle-dependent and cell cycle-independent control of transcription by the Drosophila E2F/RB pathway. Genes Dev 17:2308–2320. doi:10.1101/gad.1116703
Lee H, Ragusano L, Martinez A et al (2012) A dual role for the dREAM/MMB complex in the regulation of differentiation-specific E2F/RB target genes. Mol Cell Biol 32:2110–2120. doi:10.1128/MCB.06314-11
Ji J-Y, Miles WO, Korenjak M et al (2012) In vivo regulation of E2F1 by Polycomb group genes in Drosophila. G3 (Bethesda) 2:1651–1660. doi:10.1534/g3.112.004333
Shibutani ST, la Cruz de AFA, Tran V et al (2008) Intrinsic negative cell cycle regulation provided by PIP box- and Cul4Cdt2-mediated destruction of E2f1 during S phase. Dev Cell 15:890–900. doi:10.1016/j.devcel.2008.10.003
Duronio RJ, O’Farrell PH (1994) Developmental control of a G1-S transcriptional program in Drosophila. Development 120:1503–1515
Asano M, Nevins JR, Wharton RP (1996) Ectopic E2F expression induces S phase and apoptosis in Drosophila imaginal discs. Genes Dev 10:1422–1432
Frolov MV, Moon N-S, Dyson NJ (2005) dDP is needed for normal cell proliferation. Mol Cell Biol 25:3027–3039. doi:10.1128/MCB.25.8.3027-3039.2005
Ambrus AM, Nicolay BN, Rasheva VI et al (2007) dE2F2-independent rescue of proliferation in cells lacking an activator dE2F1. Mol Cell Biol 27:8561–8570. doi:10.1128/MCB.01068-07
Koreth J, van den Heuvel S (2005) Cell-cycle control in Caenorhabditis elegans: how the worm moves from G1 to S. Oncogene 24:2756–2764. doi:10.1038/sj.onc.1208607
Ceol CJ, Horvitz HR (2001) dpl-1 DP and efl-1 E2F act with lin-35 Rb to antagonize Ras signaling in C. elegans vulval development. Mol Cell 7:461–473
Boxem M, van den Heuvel S (2002) C. elegans class B synthetic multivulva genes act in G(1) regulation. Curr Biol 12:906–911
Roy SH, Tobin DV, Memar N et al (2014) A complex regulatory network coordinating cell cycles during C. elegans development is revealed by a genome-wide RNAi screen. G3 (Bethesda) 4:795–804. doi:10.1534/g3.114.010546
Schertel C, Conradt B (2007) C. elegans orthologs of components of the RB tumor suppressor complex have distinct pro-apoptotic functions. Development 134:3691–3701. doi:10.1242/dev.004606
van den Heuvel S, Dyson NJ (2008) Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol 9:713–724. doi:10.1038/nrm2469
Winn J, Carter M, Avery L, Cameron S (2011) Hox and a newly identified E2F co-repress cell death in Caenorhabditis elegans. Genetics 188:897–905. doi:10.1534/genetics.111.128421
Ouseph MM, Li J, Chen H-Z et al (2012) Atypical E2F repressors and activators coordinate placental development. Dev Cell 22:849–862. doi:10.1016/j.devcel.2012.01.013
Pandit SK, Westendorp B, Nantasanti S et al (2012) E2F8 is essential for polyploidization in mammalian cells. Nat Cell Biol 14:1181–1191. doi:10.1038/ncb2585
Chen H-Z, Ouseph MM, Li J et al (2012) Canonical and atypical E2Fs regulate the mammalian endocycle. Nat Cell Biol 14:1192–1202. doi:10.1038/ncb2595
Hölzel M, Kohlhuber F, Schlosser I et al (2001) Myc/Max/Mad regulate the frequency but not the duration of productive cell cycles. EMBO Rep 2:1125–1132. doi:10.1093/embo-reports/kve251
Dong P, Maddali MV, Srimani JK et al (2014) Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control. Nat Commun 5:4750. doi:10.1038/ncomms5750
Leung JY, Ehmann GL, Giangrande PH, Nevins JR (2008) A role for Myc in facilitating transcription activation by E2F1. Oncogene 27:4172–4179. doi:10.1038/onc.2008.55
O’Donnell KA, Wentzel EA, Zeller KI et al (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435:839–843. doi:10.1038/nature03677
Salvatori B, Iosue I, Mangiavacchi A et al (2012) The microRNA-26a target E2F7 sustains cell proliferation and inhibits monocytic differentiation of acute myeloid leukemia cells. Cell Death Dis 3, e413. doi:10.1038/cddis.2012.151
Fung TK, Poon RYC (2005) A roller coaster ride with the mitotic cyclins. Semin Cell Dev Biol 16:335–342. doi:10.1016/j.semcdb.2005.02.014
Ping Z, Lim R, Bashir T et al (2012) APC/C (Cdh1) controls the proteasome-mediated degradation of E2F3 during cell cycle exit. Cell Cycle 11:1999–2005. doi:10.4161/cc.20402
Xu X, Bieda M, Jin VX et al (2007) A comprehensive ChIP-chip analysis of E2F1, E2F4, and E2F6 in normal and tumor cells reveals interchangeable roles of E2F family members. Genome Res 17:1550–1561. doi:10.1101/gr.6783507
Grant GD, Brooks L, Zhang X et al (2013) Identification of cell cycle-regulated genes periodically expressed in U2OS cells and their regulation by FOXM1 and E2F transcription factors. Mol Biol Cell 24:3634–3650. doi:10.1091/mbc.E13-05-0264
Goda N, Ryan HE, Khadivi B et al (2003) Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia. Mol Cell Biol 23:359–369
Ortmann B, Druker J, Rocha S (2014) Cell cycle progression in response to oxygen levels. Cell Mol Life Sci 71:3569–3582. doi:10.1007/s00018-014-1645-9
Weijts BGMW, Bakker WJ, Cornelissen PWA et al (2012) E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1. EMBO J 31:3871–3884. doi:10.1038/emboj.2012.231
Zhu W, Giangrande PH, Nevins JR (2004) E2Fs link the control of G1/S and G2/M transcription. EMBO J 23:4615–4626. doi:10.1038/sj.emboj.7600459
Liu B, Shats I, Angus SP et al (2013) Interaction of E2F7 transcription factor with E2F1 and C-terminal-binding protein (CtBP) provides a mechanism for E2F7-dependent transcription repression. J Biol Chem 288:24581–24589. doi:10.1074/jbc.M113.467506
Chen H-Z, Tsai S-Y, Leone G (2009) Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer 9:785–797. doi:10.1038/nrc2696
Okami K, Reed AL, Cairns P et al (1999) Cyclin D1 amplification is independent of p16 inactivation in head and neck squamous cell carcinoma. Oncogene 18:3541–3545. doi:10.1038/sj.onc.1202837
Wu L, de Bruin A, Wang H et al (2015) Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis. Oncogene 34:119–128. doi:10.1038/onc.2013.511
Russell JL, Weaks RL, Berton TR, Johnson DG (2006) E2F1 suppresses skin carcinogenesis via the ARF-p53 pathway. Oncogene 25:867–876. doi:10.1038/sj.onc.1209120
Biswas AK, Mitchell DL, Johnson DG (2014) E2F1 responds to ultraviolet radiation by directly stimulating DNA repair and suppressing carcinogenesis. Cancer Res 74:3369–3377. doi:10.1158/0008-5472.CAN-13-3216
Aksoy O, Chicas A, Zeng T et al (2012) The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence. Genes Dev 26:1546–1557. doi:10.1101/gad.196238.112
Carvajal LA, Hamard P-J, Tonnessen C, Manfredi JJ (2012) E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression. Genes Dev 26:1533–1545. doi:10.1101/gad.184911.111
Zalmas LP, Zhao X, Graham AL et al (2008) DNA-damage response control of E2F7 and E2F8. EMBO Rep 9:252–259. doi:10.1038/sj.embor.7401158
Zalmas L-P, Coutts AS, Helleday T, La Thangue NB (2013) E2F-7 couples DNA damage-dependent transcription with the DNA repair process. Cell Cycle 12:3037–3051. doi:10.4161/cc.26078
Pandit SK, Westendorp B, de Bruin A (2013) Physiological significance of polyploidization in mammalian cells. Trends Cell Biol 23:556–566. doi:10.1016/j.tcb.2013.06.002
Reichel R, Kovesdi I, Nevins JR (1987) Developmental control of a promoter-specific factor that is also regulated by the E1A gene product. Cell 48:501–506
Avital G, Hashimshony T, Yanai I (2014) Seeing is believing: new methods for in situ single-cell transcriptomics. Genome Biol 15:110. doi:10.1186/gb4169
Grindberg RV, Yee-Greenbaum JL, McConnell MJ et al (2013) RNA-sequencing from single nuclei. Proc Natl Acad Sci U S A 110:19802–19807. doi:10.1073/pnas.1319700110
Sakaue-Sawano A, Kurokawa H, Morimura T et al (2008) Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell 132:487–498. doi:10.1016/j.cell.2007.12.033
Joyce NC, Harris DL, Mc Alister JC et al (2004) Effect of overexpressing the transcription factor E2F2 on cell cycle progression in rabbit corneal endothelial cells. Invest Ophthalmol Vis Sci 45:1340–1348
Rady B, Chen Y, Vaca P et al (2013) Overexpression of E2F3 promotes proliferation of functional human β cells without induction of apoptosis. Cell Cycle 12:2691–2702. doi:10.4161/cc.25834
Cartwright P, Müller H, Wagener C et al (1998) E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription. Oncogene 17:611–623. doi:10.1038/sj.onc.1201975
Logan N, Graham A, Zhao X et al (2005) E2F-8: an E2F family member with a similar organization of DNA-binding domains to E2F-7. Oncogene 24:5000–5004. doi:10.1038/sj.onc.1208703
Reddien PW, Andersen EC, Huang MC, Horvitz HR (2007) DPL-1 DP, LIN-35 Rb and EFL-1 E2F act with the MCD-1 zinc-finger protein to promote programmed cell death in Caenorhabditis elegans. Genetics 175:1719–1733. doi:10.1534/genetics.106.068148
Acknowledgements
We thank B. Westendorp and W.J. Bakker for critically reviewing the manuscript.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Science+Business Media New York
About this protocol
Cite this protocol
Thurlings, I., de Bruin, A. (2016). E2F Transcription Factors Control the Roller Coaster Ride of Cell Cycle Gene Expression. In: Coutts, A., Weston, L. (eds) Cell Cycle Oscillators. Methods in Molecular Biology, vol 1342. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2957-3_4
Download citation
DOI: https://doi.org/10.1007/978-1-4939-2957-3_4
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-2956-6
Online ISBN: 978-1-4939-2957-3
eBook Packages: Springer Protocols