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Gene Review

E2f1  -  E2F transcription factor 1

Mus musculus

Synonyms: E2F-1, Transcription factor E2F1, mKIAA4009
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Disease relevance of E2f1


Psychiatry related information on E2f1

  • Levels of E2F1 protein were greater in the nucleus of neurons in brains of HIV-infected patients exhibiting dementia when compared to HIV-negative subjects or HIV-positive neurologically normal patients [6].

High impact information on E2f1

  • To determine whether E2F-1 deregulation--as a result of loss of pRB--promotes proliferation in vivo, we have tested whether loss of E2f1 interferes with the pituitary and thyroid tumorigenesis that occurs in Rb1(+/-) mice [7].
  • As pRB is known to repress E2F transcriptional activity and overexpression of E2F is sufficient for cell cycle progression, it is thought that pRB suppresses growth in part by repressing E2F-mediated transcription [7].
  • Although overexpression of E2F-1 in tissue culture cells can stimulate cell proliferation and be oncogenic, loss of E2F-1 in mice results in tumorigenesis, demonstrating that E2F-1 also functions as a tumor suppressor [8].
  • Mice lacking E2F-1 are viable and fertile, yet experience testicular atrophy and exocrine gland dysplasia [8].
  • Disruption of this linkage resulted in S phase delay/arrest followed by regrowth or apoptosis, depending upon whether the DNA-bound E2F-1 could transactivate [9].

Chemical compound and disease context of E2f1


Biological context of E2f1

  • Myc-mediated proliferation and lymphomagenesis, but not apoptosis, are compromised by E2f1 loss [1].
  • To test this model, we examined the phenotypes of E2f1 E2f3 compound mutant mice [14].
  • Overexpression of E2f1 was associated with a strong alteration in lipid metabolism, and Srebp1was identified as a candidate transcription factor responsible for lipogenic enzyme induction [2].
  • Chromosomal positioning of the locus for p107 (designated Rbl1) as well as E2f1 to the distal end of mouse Chromosome (Chr) 2 also suggests a close but unlinked genetic relationship between these cell cycle regulatory transcription factors [15].
  • The retinoblastoma tumour suppressor (Rb) pathway is believed to have a critical role in the control of cellular proliferation by regulating E2F activities [16].

Anatomical context of E2f1


Associations of E2f1 with chemical compounds


Physical interactions of E2f1

  • Various assays have demonstrated a tight correlation between the functional capacity of Rb as a growth suppressor and its ability to bind to E2F [28].
  • Thus, distinct E2F complexes directly contribute to the normal repression and oncogenic activation of Arf [29].
  • The addition of bacterially expressed, purified His-C/EBPalpha to the E2F binding reaction resulted in the disruption of E2F complexes containing p107 in nuclear extracts from C/EBPalpha knockout mouse livers [20].
  • Activation depends on the E2F binding site in the DHFR promoter, known to mediate its activation at the G1/S transition in vivo [30].
  • Aberrant proliferation in the CNS correlates with increased free E2F DNA binding activity and increased expression of cyclin E, an E2F target gene and critical cell cycle regulator [31].

Enzymatic interactions of E2f1

  • As a consequence of this enforced expression, retinoblastoma protein is phosphorylated and E2F-1 transcription factor is activated as well [32].

Regulatory relationships of E2f1

  • Cyclin D1 can also activate the adenovirus E2 promoter via E2F [30].
  • Here, we show that E2F directly participates in the transcriptional control of Arf in both normal and transformed cells [29].
  • Moreover, like the Rb protein, p107 inhibits E2F-dependent transcription in a co-transfection assay [28].
  • We now show that additional E2F target genes share a common promoter architecture and are also regulated by the combined action of TFE3 and E2F3 [33].
  • E2F1 induces phosphorylation of p53 that is coincident with p53 accumulation and apoptosis [21].
  • The temporal induction in cerebral ischemia-induced E2F1 binding to the NRP-1 promoter correlated with the temporal-induction profile of NRP-1 mRNA, confirming that E2F1 positively regulates NRP-1 during cerebral ischemia [34].
  • Because p202 inhibits the E2F1-mediated transcriptional activation of genes, we compared the expression of E2F1 and its target genes in splenic cells from lupus-prone B6.Nba2 congenic mice, which express increased levels of p202, with age-matched C57BL/6 mice [35].

Other interactions of E2f1

  • Thus, contrary to the prevailing view of E2F action, E2F3 makes a major contribution to the apoptosis resulting from pRB loss [36].
  • Thus, cyclin E possesses an E2F-independent function required to enter S-phase [37].
  • In cultured primary cells, the Dmp1 promoter was efficiently activated by oncogenic Ha-Ras(V12), but not by overexpressed c-Myc or E2F-1 [38].
  • As a transcriptional target of E2F-1, a regulator of p53, and an important mediator of apoptosis, ARF was a strong candidate for such a role, especially since it can be upregulated in the absence of Rb [39].
  • Increased E2F1 modulated neuronal apoptosis, since E2F1-/- CGNs were significantly less susceptible to Fas-mediated apoptosis in comparison with the wild-type CGNs [40].
  • The demonstration of a functional link between C/EBPbeta and CBP/p300 for E2F target gene activation provides a potential mechanism for how coactivators such as CBP/p300 can be selectively recruited to E2F target genes in response to tissue-specific growth stimuli [41].

Analytical, diagnostic and therapeutic context of E2f1


  1. Myc-mediated proliferation and lymphomagenesis, but not apoptosis, are compromised by E2f1 loss. Baudino, T.A., Maclean, K.H., Brennan, J., Parganas, E., Yang, C., Aslanian, A., Lees, J.A., Sherr, C.J., Roussel, M.F., Cleveland, J.L. Mol. Cell (2003) [Pubmed]
  2. Oncogene-specific gene expression signatures at preneoplastic stage in mice define distinct mechanisms of hepatocarcinogenesis. Coulouarn, C., Gomez-Quiroz, L.E., Lee, J.S., Kaposi-Novak, P., Conner, E.A., Goldina, T.A., Onishchenko, G.E., Factor, V.M., Thorgeirsson, S.S. Hepatology (2006) [Pubmed]
  3. Visualizing dynamic E2F-mediated repression in vivo. Agromayor, M., Wloga, E., Naglieri, B., Abrashkin, J., Verma, K., Yamasaki, L. Mol. Cell. Biol. (2006) [Pubmed]
  4. Regulation of E2F4 mitogenic activity during terminal differentiation by its heterodimerization partners for nuclear translocation. Puri, P.L., Cimino, L., Fulco, M., Zimmerman, C., La Thangue, N.B., Giordano, A., Graessmann, A., Levrero, M. Cancer Res. (1998) [Pubmed]
  5. Induction of p53 and melanoma cell death is reciprocal with down-regulation of E2F, cyclin D1 and pRB. Rieber, M., Strasberg-Rieber, M. Int. J. Cancer (1998) [Pubmed]
  6. Role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology. Shimizu, S., Khan, M.Z., Hippensteel, R.L., Parkar, A., Raghupathi, R., Meucci, O. Neurobiol. Dis. (2007) [Pubmed]
  7. Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/-)mice. Yamasaki, L., Bronson, R., Williams, B.O., Dyson, N.J., Harlow, E., Jacks, T. Nat. Genet. (1998) [Pubmed]
  8. Tumor induction and tissue atrophy in mice lacking E2F-1. Yamasaki, L., Jacks, T., Bronson, R., Goillot, E., Harlow, E., Dyson, N.J. Cell (1996) [Pubmed]
  9. Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint. Krek, W., Xu, G., Livingston, D.M. Cell (1995) [Pubmed]
  10. Impaired pancreatic growth, beta cell mass, and beta cell function in E2F1 (-/- )mice. Fajas, L., Annicotte, J.S., Miard, S., Sarruf, D., Watanabe, M., Auwerx, J. J. Clin. Invest. (2004) [Pubmed]
  11. Adenovirus-mediated E2F-1 gene transfer sensitizes melanoma cells to apoptosis induced by topoisomerase II inhibitors. Dong, Y.B., Yang, H.L., Elliott, M.J., McMasters, K.M. Cancer Res. (2002) [Pubmed]
  12. Cyclin-dependent kinase 2 and cyclin A interaction with E2F are targets for tyrosine induction of B16 melanoma terminal differentiation. Rieber, M., Rieber, M.S. Cell Growth Differ. (1994) [Pubmed]
  13. Inhibition of E2F abrogates the development of cardiac myocyte hypertrophy. Vara, D., Bicknell, K.A., Coxon, C.H., Brooks, G. J. Biol. Chem. (2003) [Pubmed]
  14. Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo. Cloud, J.E., Rogers, C., Reza, T.L., Ziebold, U., Stone, J.R., Picard, M.H., Caron, A.M., Bronson, R.T., Lees, J.A. Mol. Cell. Biol. (2002) [Pubmed]
  15. Molecular cloning, chromosomal mapping, and expression of the mouse p107 gene. Huppi, K., Siwarski, D., Mock, B.A., Dosik, J., Hamel, P.A. Mamm. Genome (1996) [Pubmed]
  16. The E2F1-3 transcription factors are essential for cellular proliferation. Wu, L., Timmers, C., Maiti, B., Saavedra, H.I., Sang, L., Chong, G.T., Nuckolls, F., Giangrande, P., Wright, F.A., Field, S.J., Greenberg, M.E., Orkin, S., Nevins, J.R., Robinson, M.L., Leone, G. Nature (2001) [Pubmed]
  17. The development of diabetes in E2f1/E2f2 mutant mice reveals important roles for bone marrow-derived cells in preventing islet cell loss. Li, F.X., Zhu, J.W., Tessem, J.S., Beilke, J., Varella-Garcia, M., Jensen, J., Hogan, C.J., DeGregori, J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  18. Control of the p53-p21CIP1 Axis by E2f1, E2f2, and E2f3 Is Essential for G1/S Progression and Cellular Transformation. Sharma, N., Timmers, C., Trikha, P., Saavedra, H.I., Obery, A., Leone, G. J. Biol. Chem. (2006) [Pubmed]
  19. Multiple members of the E2F transcription factor family are the products of oncogenes. Xu, G., Livingston, D.M., Krek, W. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  20. C/EBPalpha regulates formation of S-phase-specific E2F-p107 complexes in livers of newborn mice. Timchenko, N.A., Wilde, M., Darlington, G.J. Mol. Cell. Biol. (1999) [Pubmed]
  21. E2F1 induces phosphorylation of p53 that is coincident with p53 accumulation and apoptosis. Rogoff, H.A., Pickering, M.T., Debatis, M.E., Jones, S., Kowalik, T.F. Mol. Cell. Biol. (2002) [Pubmed]
  22. Induction and modulation of cerebellar granule neuron death by E2F-1. O'Hare, M.J., Hou, S.T., Morris, E.J., Cregan, S.P., Xu, Q., Slack, R.S., Park, D.S. J. Biol. Chem. (2000) [Pubmed]
  23. Involvement of the transcription factor E2F1/Rb in kainic acid-induced death of murine cerebellar granule cells. Smith, R.A., Walker, T., Xie, X., Hou, S.T. Brain Res. Mol. Brain Res. (2003) [Pubmed]
  24. Vanadate activated Akt and promoted S phase entry. Zhang, Z., Gao, N., He, H., Huang, C., Luo, J., Shi, X. Mol. Cell. Biochem. (2004) [Pubmed]
  25. Differential effect of silibinin on E2F transcription factors and associated biological events in chronically UVB-exposed skin versus tumors in SKH-1 hairless mice. Gu, M., Singh, R.P., Dhanalakshmi, S., Mohan, S., Agarwal, R. Mol. Cancer Ther. (2006) [Pubmed]
  26. E2F1 regulates the base excision repair gene XRCC1 and promotes DNA repair. Chen, D., Yu, Z., Zhu, Z., Lopez, C.D. J. Biol. Chem. (2008) [Pubmed]
  27. Regulation of the PDK4 isozyme by the Rb-E2F1 complex. Hsieh, M.C., Das, D., Sambandam, N., Zhang, M.Q., Nahlé, Z. J. Biol. Chem. (2008) [Pubmed]
  28. Interactions of the p107 and Rb proteins with E2F during the cell proliferation response. Schwarz, J.K., Devoto, S.H., Smith, E.J., Chellappan, S.P., Jakoi, L., Nevins, J.R. EMBO J. (1993) [Pubmed]
  29. Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. Aslanian, A., Iaquinta, P.J., Verona, R., Lees, J.A. Genes Dev. (2004) [Pubmed]
  30. Activation of the E2F transcription factor by cyclin D1 is blocked by p16INK4, the product of the putative tumor suppressor gene MTS1. Schulze, A., Zerfass, K., Spitkovsky, D., Henglein, B., Jansen-Dürr, P. Oncogene (1994) [Pubmed]
  31. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. Macleod, K.F., Hu, Y., Jacks, T. EMBO J. (1996) [Pubmed]
  32. A role for nuclear phospholipase Cbeta 1 in cell cycle control. Faenza, I., Matteucci, A., Manzoli, L., Billi, A.M., Aluigi, M., Peruzzi, D., Vitale, M., Castorina, S., Suh, P.G., Cocco, L. J. Biol. Chem. (2000) [Pubmed]
  33. Combinatorial gene control involving E2F and E Box family members. Giangrande, P.H., Zhu, W., Rempel, R.E., Laakso, N., Nevins, J.R. EMBO J. (2004) [Pubmed]
  34. Neuropilin-1 is a direct target of the transcription factor E2F1 during cerebral ischemia-induced neuronal death in vivo. Jiang, S.X., Sheldrick, M., Desbois, A., Slinn, J., Hou, S.T. Mol. Cell. Biol. (2007) [Pubmed]
  35. Disruption of mutually negative regulatory feedback loop between interferon-inducible p202 protein and the E2F family of transcription factors in lupus-prone mice. Panchanathan, R., Xin, H., Choubey, D. J. Immunol. (2008) [Pubmed]
  36. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Ziebold, U., Reza, T., Caron, A., Lees, J.A. Genes Dev. (2001) [Pubmed]
  37. Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. Alevizopoulos, K., Vlach, J., Hennecke, S., Amati, B. EMBO J. (1997) [Pubmed]
  38. Ras-Raf-Arf signaling critically depends on the Dmp1 transcription factor. Sreeramaneni, R., Chaudhry, A., McMahon, M., Sherr, C.J., Inoue, K. Mol. Cell. Biol. (2005) [Pubmed]
  39. ARF is not required for apoptosis in Rb mutant mouse embryos. Tsai, K.Y., MacPherson, D., Rubinson, D.A., Crowley, D., Jacks, T. Curr. Biol. (2002) [Pubmed]
  40. Activation of the Rb/E2F1 pathway by the nonproliferative p38 MAPK during Fas (APO1/CD95)-mediated neuronal apoptosis. Hou, S.T., Xie, X., Baggley, A., Park, D.S., Chen, G., Walker, T. J. Biol. Chem. (2002) [Pubmed]
  41. C/EBPbeta activates E2F-regulated genes in vivo via recruitment of the coactivator CREB-binding protein/P300. Wang, H., Larris, B., Peiris, T.H., Zhang, L., Le Lay, J., Gao, Y., Greenbaum, L.E. J. Biol. Chem. (2007) [Pubmed]
  42. C/EBPbeta cooperates with RB:E2F to implement Ras(V12)-induced cellular senescence. Sebastian, T., Malik, R., Thomas, S., Sage, J., Johnson, P.F. EMBO J. (2005) [Pubmed]
  43. Unique roles for E2F1 in the mouse lens in the absence of functional pRB proteins. Hyde, R.K., Griep, A.E. Invest. Ophthalmol. Vis. Sci. (2002) [Pubmed]
  44. The paradox of E2F1: oncogene and tumor suppressor gene. Johnson, D.G. Mol. Carcinog. (2000) [Pubmed]
  45. Differential expression of members of the E2F family of transcription factors in rodent testes. El-Darwish, K.S., Parvinen, M., Toppari, J. Reprod. Biol. Endocrinol. (2006) [Pubmed]
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