Genomes and Genes
e2f transcription factors
Summary: A family of basic helix-loop-helix transcription factors that control expression of a variety of GENES involved in CELL CYCLE regulation. E2F transcription factors typically form heterodimeric complexes with TRANSCRIPTION FACTOR DP1 or transcription factor DP2, and they have N-terminal DNA binding and dimerization domains. E2F transcription factors can act as mediators of transcriptional repression or transcriptional activation.
- Burkhart D, Ngai L, Roake C, Viatour P, Thangavel C, Ho V, et al. Regulation of RB transcription in vivo by RB family members. Mol Cell Biol. 2010;30:1729-45 pubmed publisher..These experiments identify novel regulatory feedback mechanisms within the RB pathway in mammalian cells. ..
- Usskilat C, Skerka C, Saluz H, Hänel F. The transcription factor Egr-1 is a regulator of the human TopBP1 gene. Gene. 2006;380:144-50 pubmed..These data indicate a cooperative regulation of the TopBP1 promoter by Egr-1 and E2F. ..
- Berckmans B, Lammens T, Van Den Daele H, Magyar Z, Bogre L, De Veylder L. Light-dependent regulation of DEL1 is determined by the antagonistic action of E2Fb and E2Fc. Plant Physiol. 2011;157:1440-51 pubmed publisher..Strikingly, modified DEL1 expression levels uncoupled the link between light and endoreduplication in hypocotyls, implying that DEL1 acts as a regulatory connection between endocycle control and the photomorphogenic response. ..
- Bester A, Roniger M, Oren Y, Im M, Sarni D, Chaoat M, et al. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell. 2011;145:435-46 pubmed publisher..Our results suggest a model for early oncogenesis in which uncoordinated activation of factors regulating cell proliferation leads to insufficient nucleotides that fail to support normal replication and genome stability. ..
- Datta A, Sen J, Hagen J, Korgaonkar C, Caffrey M, Quelle D, et al. ARF directly binds DP1: interaction with DP1 coincides with the G1 arrest function of ARF. Mol Cell Biol. 2005;25:8024-36 pubmed..Also, the interaction between ARF and DP1 is enhanced during oncogenic stress and "culture shock." Taken together, our results show that DP1 is a critical direct target of ARF. ..
- Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci U S A. 2007;104:15472-7 pubmed..Abrogation of miR-34a function could contribute to aberrant cell proliferation, leading to colon cancer development. ..
- Chong J, Wenzel P, Sáenz Robles M, Nair V, Ferrey A, Hagan J, et al. E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature. 2009;462:930-4 pubmed publisher..This 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. ..
- Milton A, Luoto K, Ingram L, Munro S, Logan N, Graham A, et al. A functionally distinct member of the DP family of E2F subunits. Oncogene. 2006;25:3212-8 pubmedb>E2F transcription factors regulate genes involved in cell-cycle progression. In mammalian cells, physiological E2F exists as an E2F/DP heterodimer. Currently, eight E2F and two DP subunits have been characterized...
- Rubin S, Gall A, Zheng N, Pavletich N. Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release. Cell. 2005;123:1093-106 pubmedThe retinoblastoma (Rb) protein negatively regulates the G1-S transition by binding to the E2F transcription factors, until cyclin-dependent kinases phosphorylate Rb, causing E2F release...
- Viatour P, Ehmer U, Saddic L, Dorrell C, Andersen J, Lin C, et al. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med. 2011;208:1963-76 pubmed publisher..In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth...
- Sdek P, Zhao P, Wang Y, Huang C, Ko C, Butler P, et al. Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes. J Cell Biol. 2011;194:407-23 pubmed publisher..proliferation are targeted to heterochromatin by retinoblastoma (Rb) family members interacting with E2F transcription factors and recruiting heterochromatin protein 1 (HP1) proteins...
- Iaquinta P, Aslanian A, Lees J. Regulation of the Arf/p53 tumor surveillance network by E2F. Cold Spring Harb Symp Quant Biol. 2005;70:309-16 pubmed..suppressive activity is at least partially dependent on its ability to regulate the activity of the E2F transcription factors. E2F controls the expression of genes that encode the cellular proliferation machinery...
- Korenjak M, Brehm A. E2F-Rb complexes regulating transcription of genes important for differentiation and development. Curr Opin Genet Dev. 2005;15:520-7 pubmed
- Biswas S, Liu D, Greene L. Bim is a direct target of a neuronal E2F-dependent apoptotic pathway. J Neurosci. 2005;25:8349-58 pubmed..These findings support a model in which apoptotic stimuli lead to cdk4 activation, consequent de-repression of E2F-regulated mybs, and induction of pro-apoptotic Bim. ..
- Johnson D, DeGregori J. Putting the Oncogenic and Tumor Suppressive Activities of E2F into Context. Curr Mol Med. 2006;6:731-8 pubmed..Thus, the ability of some E2F family members to behave as both oncogene and tumor suppressor gene can be reconciled by putting E2F into context. ..
- McLaughlin Drubin M, Munger K. The human papillomavirus E7 oncoprotein. Virology. 2009;384:335-44 pubmed publisher..This function is directly reflected in the transforming activities of E7, including tumor initiation and induction of genomic instability. ..
- Wan Z, Zhi N, Wong S, Keyvanfar K, Liu D, Raghavachari N, et al. Human parvovirus B19 causes cell cycle arrest of human erythroid progenitors via deregulation of the E2F family of transcription factors. J Clin Invest. 2010;120:3530-44 pubmed publisher..These findings provide new insight into the molecular pathogenesis of B19V in highly permissive erythroid progenitors...
- Bueno M, Gómez de Cedrón M, Laresgoiti U, Fernandez Piqueras J, Zubiaga A, Malumbres M. Multiple E2F-induced microRNAs prevent replicative stress in response to mitogenic signaling. Mol Cell Biol. 2010;30:2983-95 pubmed publisher..Given the known function of E2F of inducing other oncogenic miRNAs, control of miRNAs by E2F is likely to play multiple roles in cell proliferation and in proliferative diseases such as cancer. ..
- Knudsen E, Knudsen K. Tailoring to RB: tumour suppressor status and therapeutic response. Nat Rev Cancer. 2008;8:714-24 pubmed publisher..Particularly, loss of RB function is associated with differential response to wide-ranging therapeutic agents. Thus, the status of this tumour suppressor may be particularly informative in directing treatment regimens. ..
- Aguda B, Kim Y, Piper Hunter M, Friedman A, Marsh C. MicroRNA regulation of a cancer network: consequences of the feedback loops involving miR-17-92, E2F, and Myc. Proc Natl Acad Sci U S A. 2008;105:19678-83 pubmed publisher..Using the concept and model prediction of a "cancer zone," the oncogenic and tumor suppressor properties of miR-17-92 is demonstrated to parallel the same properties of E2F and Myc. ..
- Leung J, Ehmann G, Giangrande P, Nevins J. A role for Myc in facilitating transcription activation by E2F1. Oncogene. 2008;27:4172-9 pubmed publisher..As such, Myc thus provides a link between the development of a growth-competent state during the initial stage of G(1) and the activation of genes essential for DNA replication at G(1)/S. ..
- Wang H, Larris B, Peiris T, Zhang L, Le Lay J, Gao Y, et al. C/EBPbeta activates E2F-regulated genes in vivo via recruitment of the coactivator CREB-binding protein/P300. J Biol Chem. 2007;282:24679-88 pubmedThe E2F transcription factors play an essential role in regulating the G(1)- to S-phase transition of the cell cycle...
- Rastogi S, Joshi B, Dasgupta P, Morris M, Wright K, Chellappan S. Prohibitin facilitates cellular senescence by recruiting specific corepressors to inhibit E2F target genes. Mol Cell Biol. 2006;26:4161-71 pubmed..These studies show that prohibitin plays a vital role in inducing cellular senescence. ..
- Chi W, Reinke V. Promotion of oogenesis and embryogenesis in the C. elegans gonad by EFL-1/DPL-1 (E2F) does not require LIN-35 (pRB). Development. 2006;133:3147-57 pubmed..Thus, in vivo, C. elegans E2F directly promotes oogenesis and embryogenesis through the activation of a tissue-specific transcriptional program that does not require LIN-35. ..
- Macaluso M, Montanari M, Giordano A. Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzymes. Oncogene. 2006;25:5263-7 pubmed..In fact, each of Rb family proteins binds to distinct members of the E2F transcription factors, which regulate the expression of genes whose protein products are necessary for cell proliferation and ..
- Araki K, Kawauchi K, Tanaka N. IKK/NF-kappaB signaling pathway inhibits cell-cycle progression by a novel Rb-independent suppression system for E2F transcription factors. Oncogene. 2008;27:5696-705 pubmed publisher..Our study describes a novel growth inhibitory system that functions by Rb-independent suppression of E2Fs by the IKK/NF-kappaB signaling pathway. ..
- Swiss V, CASACCIA P. Cell-context specific role of the E2F/Rb pathway in development and disease. Glia. 2010;58:377-90 pubmed publisher..Overall, the available data suggest a time-dependent and cell-context specific role of E2F and Rb family members in the developing and adult CNS. ..
- Munakata T, Nakamura M, Liang Y, Li K, Lemon S. Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. Proc Natl Acad Sci U S A. 2005;102:18159-64 pubmed..protein (Rb) plays a critical role in controlling cellular proliferation and apoptosis by regulating E2F transcription factors. Rb is a key target of oncoproteins expressed by DNA tumor viruses, but RNA viruses are not known to ..
- Burkhart D, Wirt S, Zmoos A, Kareta M, Sage J. Tandem E2F binding sites in the promoter of the p107 cell cycle regulator control p107 expression and its cellular functions. PLoS Genet. 2010;6:e1001003 pubmed publisher..These experiments also suggest novel therapeutic strategies to increase the p107 levels in tumor cells. ..
- Rivadeneira D, Mayhew C, Thangavel C, Sotillo E, Reed C, Grana X, et al. Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology. 2010;138:1920-30 pubmed publisher..These data show that CDK4/6 inhibition is a potent mediator of cytostasis and that RB loss can be readily compensated for in the context of both hepatoma cell lines and liver tissue. ..
- Tyagi S, Chabes A, Wysocka J, Herr W. E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases. Mol Cell. 2007;27:107-19 pubmed..These results suggest that HCF-1 induces cell-cycle-specific transcriptional activation by E2F proteins to promote cell proliferation. ..
- Kherrouche Z, Blais A, Ferreira E, De Launoit Y, Monte D. ASK-1 (apoptosis signal-regulating kinase 1) is a direct E2F target gene. Biochem J. 2006;396:547-56 pubmed..the expression of ASK-1 and suggest that some of the cellular functions of ASK-1 may be under the control of E2F transcription factors. Moreover, the up-regulation of ASK-1 may also favour the p53-independent E2F1 apoptotic activity.
- Yao G, Tan C, West M, Nevins J, You L. Origin of bistability underlying mammalian cell cycle entry. Mol Syst Biol. 2011;7:485 pubmed publisher..Our findings suggested basic design principles for the robust control of the bistable cell cycle entry at the R-point. ..
- DeGregori J, Johnson D. Distinct and Overlapping Roles for E2F Family Members in Transcription, Proliferation and Apoptosis. Curr Mol Med. 2006;6:739-48 pubmedSince the discovery almost fifteen years ago that E2F transcription factors are key targets of the retinoblastoma protein (RB), studies of the E2F family have uncovered critical roles in the control of transcription, cell cycle and ..
- de Jager S, Scofield S, Huntley R, Robinson A, den Boer B, Murray J. Dissecting regulatory pathways of G1/S control in Arabidopsis: common and distinct targets of CYCD3;1, E2Fa and E2Fc. Plant Mol Biol. 2009;71:345-65 pubmed publisherActivation of E2F transcription factors at the G1-to-S phase boundary, with the resultant expression of genes needed for DNA synthesis and S-phase, is due to phosphorylation of the retinoblastoma-related (RBR) protein by cyclin D-..
- Caldon C, Sergio C, Schütte J, Boersma M, Sutherland R, Carroll J, et al. Estrogen regulation of cyclin E2 requires cyclin D1 but not c-Myc. Mol Cell Biol. 2009;29:4623-39 pubmed publisher..This contrasts with the predominant regulation of cyclin E1-Cdk2 activity via CDK inhibitor association downstream of both c-Myc and cyclin D1 and indicates that cyclins E1 and E2 are not always coordinately regulated. ..
- Schmit F, Korenjak M, Mannefeld M, Schmitt K, Franke C, von Eyss B, et al. LINC, a human complex that is related to pRB-containing complexes in invertebrates regulates the expression of G2/M genes. Cell Cycle. 2007;6:1903-13 pubmed..In S-phase, LINC selectively binds to the promoters of G2/M genes whose products are required for mitosis and plays an important role in their cell cycle dependent activation. ..
- Black E, Hallstrom T, Dressman H, West M, Nevins J. Distinctions in the specificity of E2F function revealed by gene expression signatures. Proc Natl Acad Sci U S A. 2005;102:15948-53 pubmed
- Vandromme M, Chailleux C, Escaffit F, Trouche D. Binding of the retinoblastoma protein is not the determinant for stable repression of some E2F-regulated promoters in muscle cells. Mol Cancer Res. 2008;6:418-25 pubmed publisher..Thus, our data indicate that during muscle differentiation, permanent silencing and H3K9 trimethylation of some E2F-dependent genes are not directly specified by Rb binding, in contrast to what is proposed for senescence. ..
- Lacerte A, Korah J, Roy M, Yang X, Lemay S, Lebrun J. Transforming growth factor-beta inhibits telomerase through SMAD3 and E2F transcription factors. Cell Signal. 2008;20:50-9 pubmed..These findings highlight the prominent role of TGFbeta in regulating telomerase expression and identify Smad3 and E2F-1 as critical mediators of TGFbeta effects in both normal and cancer cells. ..
- Tsantoulis P, Gorgoulis V. Involvement of E2F transcription factor family in cancer. Eur J Cancer. 2005;41:2403-14 pubmed..In this review we provide a brief but concise overview of E2F function and its putative role in the most common human tumour types. ..
- Zhang Y, Akinmade D, Hamburger A. The ErbB3 binding protein Ebp1 interacts with Sin3A to repress E2F1 and AR-mediated transcription. Nucleic Acids Res. 2005;33:6024-33 pubmed..These results demonstrate that Ebp1 participates in transcriptional regulation via its interaction with the Sin3-HDAC. ..
- Lee T, Yao G, Bennett D, Nevins J, You L. Stochastic E2F activation and reconciliation of phenomenological cell-cycle models. PLoS Biol. 2010;8: pubmed publisher..It also suggests a potential utility of the TP or GC models in defining concise, quantitative phenotypes of cell physiology. This may have implications in classifying cell types or states. ..
- Naouar N, Vandepoele K, Lammens T, Casneuf T, Zeller G, Van Hummelen P, et al. Quantitative RNA expression analysis with Affymetrix Tiling 1.0R arrays identifies new E2F target genes. Plant J. 2009;57:184-94 pubmed publisher..The latter groups increase the number of excellent candidates for new, direct E2F targets by almost twofold, from 181 to 334. ..
- Nagl N, Wang X, Patsialou A, Van Scoy M, Moran E. Distinct mammalian SWI/SNF chromatin remodeling complexes with opposing roles in cell-cycle control. EMBO J. 2007;26:752-63 pubmed..The specific complexes control access of factors such as E2F1, Tip60, and HDAC1/2/3 to the promoters of various cell-cycle-specific genes, with c-Myc emerging as a particularly critical target. ..
- Gu M, Singh R, Dhanalakshmi S, Mohan S, Agarwal R. Differential effect of silibinin on E2F transcription factors and associated biological events in chronically UVB-exposed skin versus tumors in SKH-1 hairless mice. Mol Cancer Ther. 2006;5:2121-9 pubmed..These differential effects of silibinin on E2F1 versus E2F2 and E2F3 and their associated molecular alterations and biological effects in chronic UVB-exposed skin suggest their role in silibinin interference with photocarcinogenesis. ..
- Chen H, Tsai S, Leone G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer. 2009;9:785-97 pubmed publisher..The E2F transcription factors function in cell cycle control and are intimately regulated by RB...
- Ianari A, Natale T, Calo E, Ferretti E, Alesse E, Screpanti I, et al. Proapoptotic function of the retinoblastoma tumor suppressor protein. Cancer Cell. 2009;15:184-94 pubmed publisherThe retinoblastoma protein (pRB) tumor suppressor blocks cell proliferation by repressing the E2F transcription factors. This inhibition is relieved through mitogen-induced phosphorylation of pRB, triggering E2F release and activation of ..
- Tavner F, Frampton J, Watson R. Targeting an E2F site in the mouse genome prevents promoter silencing in quiescent and post-mitotic cells. Oncogene. 2007;26:2727-35 pubmed..This mouse system is the first description of an E2F site mutation in situ and will facilitate the study of E2F function in vivo. ..
- Rowland B, Bernards R. Re-evaluating cell-cycle regulation by E2Fs. Cell. 2006;127:871-4 pubmedActivation of E2F transcription factors is thought to drive the expression of genes essential for the transition of cells from G1 to S phase and for the initiation of DNA replication...
- Chen H, Gu X, Liu Y, Wang J, Wirt S, Bottino R, et al. PDGF signalling controls age-dependent proliferation in pancreatic ?-cells. Nature. 2011;478:349-55 pubmed publisher..The discovery of a conserved pathway controlling age-dependent ?-cell proliferation indicates new strategies for ?-cell expansion. ..
- Buttitta L, Katzaroff A, Edgar B. A robust cell cycle control mechanism limits E2F-induced proliferation of terminally differentiated cells in vivo. J Cell Biol. 2010;189:981-96 pubmed publisher..These mechanisms are essential for proper development, as evading them leads to tissue outgrowths composed of dividing but terminally differentiated cells. ..
- Henriques R, Magyar Z, Monardes A, Khan S, Zalejski C, Orellana J, et al. Arabidopsis S6 kinase mutants display chromosome instability and altered RBR1-E2F pathway activity. EMBO J. 2010;29:2979-93 pubmed publisher..The data suggest a new function for plant S6K as a repressor of cell proliferation and required for maintenance of chromosome stability and ploidy levels. ..
- Lammens T, Li J, Leone G, De Veylder L. Atypical E2Fs: new players in the E2F transcription factor family. Trends Cell Biol. 2009;19:111-8 pubmed publisherAs major regulators of the cell cycle, apoptosis and differentiation, E2F transcription factors have been studied extensively in a broad range of organisms...
- Stanelle J, Pützer B. E2F1-induced apoptosis: turning killers into therapeutics. Trends Mol Med. 2006;12:177-85 pubmed
- Zielke N, Kim K, Tran V, Shibutani S, Bravo M, Nagarajan S, et al. Control of Drosophila endocycles by E2F and CRL4(CDT2). Nature. 2011;480:123-7 pubmed publisher..Many of the regulatory interactions essential to this novel cell cycle oscillator are conserved in animals and plants, indicating that elements of this mechanism act in most growth-dependent cell cycles. ..
- Truscott M, Harada R, Vadnais C, Robert F, Nepveu A. p110 CUX1 cooperates with E2F transcription factors in the transcriptional activation of cell cycle-regulated genes. Mol Cell Biol. 2008;28:3127-38 pubmed publisher..Reporter assays on a subset of common targets confirmed that p110 CUX1 and E2F1 cooperate in their transcriptional activation. Overall, our results show that p110 CUX1 and E2F1 cooperate in the regulation of many cell cycle genes. ..