e2f3 transcription factor


Summary: An E2F transcription factor that interacts directly with RETINOBLASTOMA PROTEIN and CYCLIN A. E2F3 regulates GENETIC TRANSCRIPTION required for CELL CYCLE entry and DNA synthesis.

Top Publications

  1. Gill R, Hamel P. Subcellular compartmentalization of E2F family members is required for maintenance of the postmitotic state in terminally differentiated muscle. J Cell Biol. 2000;148:1187-201 pubmed
    ..These data demonstrate that regulation of the subcellular compartmentalization of E2F-family members is required to maintain nuclei in a quiescent state in terminally differentiated cells. ..
  2. Opavsky R, Tsai S, Guimond M, Arora A, Opavska J, Becknell B, et al. Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis. Proc Natl Acad Sci U S A. 2007;104:15400-5 pubmed
    ..These results identify the E2f2 locus as a tumor suppressor through its ability to modulate apoptosis. ..
  3. DeGregori J. The genetics of the E2F family of transcription factors: shared functions and unique roles. Biochim Biophys Acta. 2002;1602:131-50 pubmed
  4. Saavedra H, Wu L, de Bruin A, Timmers C, Rosol T, Weinstein M, et al. Specificity of E2F1, E2F2, and E2F3 in mediating phenotypes induced by loss of Rb. Cell Growth Differ. 2002;13:215-25 pubmed
    ..These results provide clear evidence for functional specificity among E2Fs in the control of Rb-dependent proliferation and apoptosis in a tissue-specific manner. ..
  5. Ouseph M, Li J, Chen H, Pécot T, Wenzel P, Thompson J, et al. Atypical E2F repressors and activators coordinate placental development. Dev Cell. 2012;22:849-62 pubmed publisher
  6. Grasemann C, Gratias S, Stephan H, Schuler A, Schramm A, Klein Hitpass L, et al. Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma. Oncogene. 2005;24:6441-9 pubmed
    ..In summary, our results suggest that DEK and E2F3 are potential targets of 6p gains in retinoblastoma. ..
  7. Wenzel P, Chong J, Sáenz Robles M, Ferrey A, Hagan J, Gomez Y, et al. Cell proliferation in the absence of E2F1-3. Dev Biol. 2011;351:35-45 pubmed publisher
    ..Together, these data implicate E2F1-3 in mediating transcriptional repression by Rb during cell cycle exit and point to a critical role for their repressive functions in cell survival. ..
  8. Moberg K, Starz M, Lees J. E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry. Mol Cell Biol. 1996;16:1436-49 pubmed
    ..Despite this, a considerable amount of E2F-4 exists as free E2F. In G1 cells, this accounts for almost all of the free activity. Once the cells enter S phase, free E2F is composed of an equal mixture of E2F-4 and E2F-1. ..
  9. Lukas J, Petersen B, Holm K, Bartek J, Helin K. Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression. Mol Cell Biol. 1996;16:1047-57 pubmed
    ..Since E2F-4 and E2F-5 cannot promote S-phase entry by themselves, our results may provide an explanation for the apparent lack of aberrations in p107 or p130 in human cancer. ..

More Information


  1. Olsson A, Feber A, Edwards S, te Poele R, Giddings I, Merson S, et al. Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells. Oncogene. 2007;26:1028-37 pubmed
    ..When taken together, these observations indicate that E2F3 levels have a critical role in modifying cellular proliferation rate in human bladder and prostate cancer. ..
  2. Takahashi Y, Rayman J, Dynlacht B. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 2000;14:804-16 pubmed
    ..These findings suggest that repression and activation of E2F-responsive genes may occur through distinct E2F heterodimers that direct the sequential recruitment of enzymes able to deacetylate and then acetylate core histones. ..
  3. Araki K, Nakajima Y, Eto K, Ikeda M. Distinct recruitment of E2F family members to specific E2F-binding sites mediates activation and repression of the E2F1 promoter. Oncogene. 2003;22:7632-41 pubmed
    ..Taken together, these findings indicate that the two E2F-binding sites play distinct roles in the regulation of E2F1 transcription by interacting with different sets of E2F members and cooperating with the contiguous repressor element. ..
  4. Welch C, Chen Y, Stallings R. MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene. 2007;26:5017-22 pubmed
    ..Thus, adding to the increasing role of miRNAs in cancer, miR-34a may act as a suppressor of NB tumorgenesis. ..
  5. Orlic M, Spencer C, Wang L, Gallie B. Expression analysis of 6p22 genomic gain in retinoblastoma. Genes Chromosomes Cancer. 2006;45:72-82 pubmed
  6. Kong L, Chang J, Bild A, Nevins J. Compensation and specificity of function within the E2F family. Oncogene. 2007;26:321-7 pubmed
    ..We conclude that the long-term loss of E2F activity does lead to compensation by other family members and that the analysis of acute loss of function reveals specific and distinct roles for these proteins. ..
  7. Aslanian A, Iaquinta P, Verona R, Lees J. Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. Genes Dev. 2004;18:1413-22 pubmed
    ..We propose that monitoring of E2F levels and/or activity is a key component of Arf's ability to respond to inappropriate, but not normal cellular proliferation. ..
  8. McClellan K, Vanderluit J, Julian L, Andrusiak M, Dugal Tessier D, Park D, et al. The p107/E2F pathway regulates fibroblast growth factor 2 responsiveness in neural precursor cells. Mol Cell Biol. 2009;29:4701-13 pubmed publisher
    ..By identifying novel roles for p107/E2F in regulating genes outside of the classical cell cycle machinery targets, we uncover a new mechanism whereby Rb/E2F mediates proliferation through regulating growth factor responsiveness. ..
  9. Strom D, Cleveland J, Chellappan S, Nip J, Hiebert S. E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation. Cell Growth Differ. 1998;9:59-69 pubmed
    ..Therefore, E2F-1, but not E2F-3, can temporally replace the requirement for growth factors to promote cell cycle progression, and in terminally differentiating cells, this leads to a block in differentiation and induction of apoptosis. ..
  10. Leone G, Nuckolls F, Ishida S, Adams M, Sears R, Jakoi L, et al. Identification of a novel E2F3 product suggests a mechanism for determining specificity of repression by Rb proteins. Mol Cell Biol. 2000;20:3626-32 pubmed
    ..Thus, the previously described specificity of Rb function as a transcriptional repressor in quiescent cells coincides with the association of Rb with this novel E2F product. ..
  11. Chen L, Chen D, Kurtyka C, Rawal B, Fulp W, Haura E, et al. Tripartite motif containing 28 (Trim28) can regulate cell proliferation by bridging HDAC1/E2F interactions. J Biol Chem. 2012;287:40106-18 pubmed publisher
    ..Taken together, these results suggest that Trim28 has anti-proliferative activity in lung cancers via repression of members of the E2F family that are critical for cell proliferation. ..
  12. Oeggerli M, Tomovska S, Schraml P, Calvano Forte D, Schafroth S, Simon R, et al. E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer. Oncogene. 2004;23:5616-23 pubmed
    ..E2F3 expression appears to provide a growth advantage to tumor cells by activating cell proliferation in a subset of bladder tumors. ..
  13. Akao Y, Noguchi S, Iio A, Kojima K, Takagi T, Naoe T. Dysregulation of microRNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells. Cancer Lett. 2011;300:197-204 pubmed publisher
    ..These findings suggest that miR-34a targeting the Sirt1 and E2F3 genes could negatively regulate, at least in part, the resistance to 5-FU in human colorectal cancer DLD-1 cells. ..
  14. Ziebold U, Lee E, Bronson R, Lees J. E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas. Mol Cell Biol. 2003;23:6542-52 pubmed
    ..We show that, instead, E2F3 loss leads to an increase in the rate of tumor initiation. Finally, analysis of Rb(+/-); E2f3(+/-) mice shows that this tumor-suppressive function of E2F3 is dose dependent. ..
  15. 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. ..
  16. Wu L, Timmers C, Maiti B, Saavedra H, Sang L, Chong G, et al. The E2F1-3 transcription factors are essential for cellular proliferation. Nature. 2001;414:457-62 pubmed
    ..By targeting the entire subclass of E2F transcriptional activators we provide direct genetic evidence for their essential role in cell cycle progression, proliferation and development. ..
  17. Fajas L, Landsberg R, Huss Garcia Y, Sardet C, Lees J, Auwerx J. E2Fs regulate adipocyte differentiation. Dev Cell. 2002;3:39-49 pubmed
    ..This underscores the complex role of the E2F protein family in the control of both cell proliferation and differentiation. ..
  18. Ziebold U, Reza T, Caron A, Lees J. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev. 2001;15:386-91 pubmed
    ..Thus, contrary to the prevailing view of E2F action, E2F3 makes a major contribution to the apoptosis resulting from pRB loss. ..
  19. He Y, Cress W. E2F-3B is a physiological target of cyclin A. J Biol Chem. 2002;277:23493-9 pubmed
    ..Finally, in synchronized cells, we observe down-regulation of E2F-3B protein expression coincident with the up-regulation of cyclin A. We conclude that E2F-3B is a physiological target of cyclin A. ..
  20. Humbert P, Verona R, Trimarchi J, Rogers C, Dandapani S, Lees J. E2f3 is critical for normal cellular proliferation. Genes Dev. 2000;14:690-703 pubmed
    ..We conclude that E2F3 is critical for the transcriptional activation of genes that control the rate of proliferation of both primary and tumor cells. ..
  21. Ginsberg D, Vairo G, Chittenden T, Xiao Z, Xu G, Wydner K, et al. E2F-4, a new member of the E2F transcription factor family, interacts with p107. Genes Dev. 1994;8:2665-79 pubmed
    ..p107 binding not only can be linked to the regulation of E2F-4 transcriptional activity, but also to suppression of the ability of E2F-4 to transform an immortalized rodent cell line. ..
  22. Timmers C, Sharma N, Opavsky R, Maiti B, Wu L, Wu J, et al. E2f1, E2f2, and E2f3 control E2F target expression and cellular proliferation via a p53-dependent negative feedback loop. Mol Cell Biol. 2007;27:65-78 pubmed
    ..These findings suggest that a critical function of the E2F1, E2F2, and E2F3 activators is in the control of a p53-dependent axis that indirectly regulates E2F-mediated transcriptional repression and cellular proliferation. ..
  23. Hurst C, Tomlinson D, Williams S, Platt F, Knowles M. Inactivation of the Rb pathway and overexpression of both isoforms of E2F3 are obligate events in bladder tumours with 6p22 amplification. Oncogene. 2008;27:2716-27 pubmed
    ..Indeed, a phospho-specific Rb antibody showed much Rb protein in a hyperphosphorylated (inactive) form. We conclude that inactivation of the Rb pathway is required in addition to E2F3 overexpression in this subset of bladder tumours. ..
  24. Martinez L, Goluszko E, Chen H, Leone G, Post S, Lozano G, et al. E2F3 is a mediator of DNA damage-induced apoptosis. Mol Cell Biol. 2010;30:524-36 pubmed publisher
    ..Finally, using both in vitro and in vivo approaches, we establish that E2f3 is required for DNA damage-induced apoptosis. Thus, our data reveal the novel ability of E2f3 to function as a master regulator of the DNA damage response. ..
  25. Tordai A, Wang J, Andre F, Liedtke C, Yan K, Sotiriou C, et al. Evaluation of biological pathways involved in chemotherapy response in breast cancer. Breast Cancer Res. 2008;10:R37 pubmed publisher
    ..The mutant p53 signature and expression of ER-related genes were associated with lower sensitivity to chemotherapy in ER+ breast tumors only. ..
  26. Dagnino L, Fry C, Bartley S, Farnham P, Gallie B, Phillips R. Expression patterns of the E2F family of transcription factors during mouse nervous system development. Mech Dev. 1997;66:13-25 pubmed
    ..We conclude that individual E2F forms are differentially regulated during the development of distinct tissues, and especially during neuronal development. ..
  27. Feber A, Clark J, Goodwin G, Dodson A, Smith P, Fletcher A, et al. Amplification and overexpression of E2F3 in human bladder cancer. Oncogene. 2004;23:1627-30 pubmed
    ..When considered together with the established role of E2F3 in cell cycle progression, these results suggest that the E2F3 gene represents a candidate bladder cancer oncogene that is activated by DNA amplification and overexpression. ..
  28. Giangrande P, Hallstrom T, Tunyaplin C, Calame K, Nevins J. Identification of E-box factor TFE3 as a functional partner for the E2F3 transcription factor. Mol Cell Biol. 2003;23:3707-20 pubmed
    ..We propose that the physical interaction of TFE3 and E2F3 facilitates transcriptional activation of the p68 gene and provides strong evidence for the specificity of E2F function. ..
  29. Leone G, DeGregori J, Yan Z, Jakoi L, Ishida S, Williams R, et al. E2F3 activity is regulated during the cell cycle and is required for the induction of S phase. Genes Dev. 1998;12:2120-30 pubmed
  30. DeGregori J, Leone G, Miron A, Jakoi L, Nevins J. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci U S A. 1997;94:7245-50 pubmed
    ..We conclude that E2F family members play distinct roles in cell cycle control and that E2F1 may function as a specific signal for the initiation of an apoptosis pathway that must normally be blocked for a productive proliferation event. ..
  31. Karlseder J, Rotheneder H, Wintersberger E. Interaction of Sp1 with the growth- and cell cycle-regulated transcription factor E2F. Mol Cell Biol. 1996;16:1659-67 pubmed
    ..Our data are in line with the hypothesis that E2F functions as a growth- and cell cycle regulated tethering factor between Sp1 and the basic transcription machinery. ..
  32. Cooper C, Nicholson A, Foster C, Dodson A, Edwards S, Fletcher A, et al. Nuclear overexpression of the E2F3 transcription factor in human lung cancer. Lung Cancer. 2006;54:155-62 pubmed
    The E2F3 transcription factor has an established role in controlling cell cycle progression...
  33. Chen Q, Liang D, Yang T, Leone G, Overbeek P. Distinct capacities of individual E2Fs to induce cell cycle re-entry in postmitotic lens fiber cells of transgenic mice. Dev Neurosci. 2004;26:435-45 pubmed
    ..E2F3a and E2F4, but not E2F5, function to induce cell cycle entry, although E2F4 has more modest activity. E2F3a may induce cell death primarily through activation of p73alpha. ..
  34. Sharma N, Timmers C, Trikha P, Saavedra H, Obery A, Leone G. Control of the p53-p21CIP1 Axis by E2f1, E2f2, and E2f3 is essential for G1/S progression and cellular transformation. J Biol Chem. 2006;281:36124-31 pubmed
    ..These results suggest that the negative regulation of the p53-p21(CIP1) axis by the E2F1-3 factors is critical for cell cycle progression and cellular transformation. ..
  35. Lees J, Saito M, Vidal M, Valentine M, Look T, Harlow E, et al. The retinoblastoma protein binds to a family of E2F transcription factors. Mol Cell Biol. 1993;13:7813-25 pubmed
    ..These observations suggest that the E2F activities described previously result from the combined action of a family of proteins. ..
  36. He Y, Armanious M, Thomas M, Cress W. Identification of E2F-3B, an alternative form of E2F-3 lacking a conserved N-terminal region. Oncogene. 2000;19:3422-33 pubmed
    ..These observations make E2F-3B the first example of an E2F gene giving rise to two different protein species and also suggest that E2F-3 and E2F-3B may have opposing roles in cell cycle control. ..
  37. Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park C, et al. Myc requires distinct E2F activities to induce S phase and apoptosis. Mol Cell. 2001;8:105-13 pubmed
    ..From this data, we propose that the induction of specific E2F activities is an essential component in the Myc pathways that control cell proliferation and cell fate decisions. ..
  38. Tsai S, Opavsky R, Sharma N, Wu L, Naidu S, Nolan E, et al. Mouse development with a single E2F activator. Nature. 2008;454:1137-41 pubmed publisher
    ..These findings provide a molecular basis for the observed specificity among E2F activators during development. ..
  39. Cloud J, Rogers C, Reza T, Ziebold U, Stone J, Picard M, et al. Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo. Mol Cell Biol. 2002;22:2663-72 pubmed
    ..These data strongly suggest that tumor suppression is a specific property of E2F1 and not E2F3. ..
  40. Lazzerini Denchi E, Helin K. E2F1 is crucial for E2F-dependent apoptosis. EMBO Rep. 2005;6:661-8 pubmed
    ..These results are consistent with previous findings that E2F1, but not other E2Fs, can have tumour-suppressing activities. ..
  41. Chong J, Tsai S, Sharma N, Opavsky R, Price R, Wu L, et al. E2f3a and E2f3b contribute to the control of cell proliferation and mouse development. Mol Cell Biol. 2009;29:414-24 pubmed publisher
    ..Together, we conclude that the contributions of E2F3a and E2F3b in cell proliferation and development are context dependent. ..
  42. Fogal V, Kartasheva N, Trigiante G, Llanos S, Yap D, Vousden K, et al. ASPP1 and ASPP2 are new transcriptional targets of E2F. Cell Death Differ. 2005;12:369-76 pubmed
    ..The identification of ASPP1 and ASPP2 genes as transcriptional targets of E2F provides another mechanism by which E2F cooperates with p53 to induce apoptosis. ..
  43. Trikha P, Sharma N, Opavsky R, Reyes A, Pena C, Ostrowski M, et al. E2f1-3 are critical for myeloid development. J Biol Chem. 2011;286:4783-95 pubmed publisher
    ..In summary, this work places E2f1-3 in a specific signaling cascade that is critical for myeloid development in vivo. ..
  44. Wang H, Tan G, Dong L, Cheng L, Li K, Wang Z, et al. Circulating MiR-125b as a marker predicting chemoresistance in breast cancer. PLoS ONE. 2012;7:e34210 pubmed publisher
    ..This finding has important implications in the development of targeted therapeutics for overcoming chemotherapeutic resistance in novel anti-cancer strategies. ..
  45. King J, Moskowitz I, Burgon P, Ahmad F, Stone J, Seidman J, et al. E2F3 plays an essential role in cardiac development and function. Cell Cycle. 2008;7:3775-80 pubmed
    ..These data demonstrate a clear role for E2F3 in myocardial and cardiac function during both development and adulthood. ..
  46. Pipinikas C, Nair S, Kirby R, Carter N, Fenske C. Measurement of blood E2F3 mRNA in prostate cancer by quantitative RT-PCR: a preliminary study. Biomarkers. 2007;12:541-57 pubmed
    ..This study demonstrates the strength of E2F3 as a potential marker for discriminating benign and malignant disease, addressing the current limitations of serum PSA measurements. ..
  47. Parisi T, Yuan T, Faust A, Caron A, Bronson R, Lees J. Selective requirements for E2f3 in the development and tumorigenicity of Rb-deficient chimeric tissues. Mol Cell Biol. 2007;27:2283-93 pubmed
    ..This hyperproliferative state is thought to represent the preneoplastic lesion of small-cell lung carcinoma. Therefore, our observation highlights a potential role for E2F3 in the early stages of this tumor type. ..
  48. Parisi T, Pollice A, Di Cristofano A, Calabrò V, La Mantia G. Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors. Biochem Biophys Res Commun. 2002;291:1138-45 pubmed
    ..Moreover, our data suggest that the ARF promoter is regulated by E2F through both direct binding to the promoter sequences and indirectly, probably by being tethered to the ARF promoter by Sp1-like factors. ..
  49. Dynlacht B, Brook A, Dembski M, Yenush L, Dyson N. DNA-binding and trans-activation properties of Drosophila E2F and DP proteins. Proc Natl Acad Sci U S A. 1994;91:6359-63 pubmed
    ..The isolation of these genes will provide important reagents for the genetic analysis of the E2F pathway. ..
  50. Zhang Y, Chao T, Li R, Chen Y, Yan X, Gong Y, et al. MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J Mol Med (Berl). 2009;87:43-51 pubmed publisher
    ..Taken together, our study demonstrates that miR-128 can inhibit proliferation of glioma cells through one of its targets, E2F3a. ..
  51. Sampieri K, Mencarelli M, Epistolato M, Toti P, Lazzi S, Bruttini M, et al. Genomic differences between retinoma and retinoblastoma. Acta Oncol. 2008;47:1483-92 pubmed publisher
    ..These results also confirm the pre-malignant nature of retinoma. ..
  52. Paulson Q, McArthur M, Johnson D. E2F3a stimulates proliferation, p53-independent apoptosis and carcinogenesis in a transgenic mouse model. Cell Cycle. 2006;5:184-90 pubmed
    ..The phenotype of K5 E2F3a transgenic mice is distinct from similar transgenic mice expressing E2F1 or E2F4. In particular, E2F3a has a unique apoptotic activity and lacks the tumor suppressive property of E2F1 in this model system. ..
  53. Hallstrom T, Nevins J. Specificity in the activation and control of transcription factor E2F-dependent apoptosis. Proc Natl Acad Sci U S A. 2003;100:10848-53 pubmed
    ..We conclude that the unique capacity of E2F1 to trigger apoptosis reflects a specificity of transcriptional activation potential, and that this role for E2F1 is regulated through the action of the Akt protein kinase. ..