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Gene Review

LEF1  -  lymphoid enhancer-binding factor 1

Homo sapiens

Synonyms: LEF-1, Lymphoid enhancer-binding factor 1, T cell-specific transcription factor 1-alpha, TCF1-alpha, TCF10, ...
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Disease relevance of LEF1

  • We report here that LEF1 is a new type of target gene ectopically activated in colon cancer [1].
  • Expression of enamel proteins and LEF1 in adamantinomatous craniopharyngioma: evidence for its odontogenic epithelial differentiation [2].
  • Previously, precursor T lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LyL) was found to express TCF-1, and we find that 9 of 10 cases of T-ALL/LyL express LEF-1 as well as TCF-1, exhibiting uniform nuclear immunostaining for both transcription factors [3].
  • In addition, a significant subset of cases of peripheral T cell lymphoma (PTCL), 39 of 81 cases (48%), are immunoreactive for LEF-1 and/or TCF-1, with 36 of 38 cases immunoreactive for both, indicating that these transcription factors are coordinately expressed in PTCL [3].
  • Of the Th1-like PTCL studied, 33 of 42 (79%) were immunoreactive for LEF-1 and 32 of 42 (76%) were immunoreactive for TCF-1, including most cases of angioimmunoblastic lymphoma and all cases of lymphoepithelioid lymphoma [3].

High impact information on LEF1


Biological context of LEF1

  • Coexpression of mammalian beta-cat with TCF4 or LEF1 results in nuclear accumulation of these proteins and a functional complex that activates reporter gene transcription from constructs containing leukocyte enhancer factor (LEF)/T cell factor (TCF) response elements [7].
  • Herein, we show that Smad3 physically interacts with the HMG box domain of LEF1 and that TGFbeta and Wnt pathways synergize to activate transcription of the Xenopus homeobox gene twin (Xtwn) [8].
  • Consistent with this hypothesis, under repression conditions the promoter region of a LEF1 target gene is hypoacetylated [9].
  • The lymphoid enhancer factor-1 LEF1 locus produces multiple mRNAs via alternative promoters [10].
  • Using a dicistronic vector in transient DNA transfections, we show that the LEF1 5'-UTR mediates cap-independent translation [10].

Anatomical context of LEF1

  • In this study, we show that LEF1 and TCF7 (TCF-1) are not only expressed in thymocytes, but also in mature T cells [11].
  • In this study we tested the hypothesis that the long, GC-rich 5'-UTR within the full-length LEF1 mRNA contains an internal ribosome entry site (IRES) [10].
  • This isoform might either act in a dominant-negative manner by interfering with native LEF-1, or might bind beta-catenin in the cytosol, which would result in attenuation of the signals transmitted by the LEF-beta-catenin pathway [12].
  • Among others, LEF-1 regulates expression of cytokeratin genes involved in formation of hair follicles and the gene encoding the cell-adhesion molecule E-cadherin [12].
  • The detection of this protein selectively in extracts of lymphoid cells correlates with the presence of the E box-binding activity LEF1/BCF1 in these cells; this binding activity was previously shown to be efficiently recognized by antiserum directed against E2A gene products [13].

Associations of LEF1 with chemical compounds


Physical interactions of LEF1


Enzymatic interactions of LEF1

  • Here, we identify CK1 and CK2 as major kinases that directly bind to and phosphorylate LEF-1 inducing distinct, kinase-specific changes in the LEF-1/DNA complex [19].

Regulatory relationships of LEF1

  • Mutant LEF1 not only inhibited expression of beta-catenin target genes but also stimulated expression of sebocyte markers, suggesting that it may determine the differentiated characteristics of sebaceous tumors [5].
  • Beta-catenin-histone deacetylase interactions regulate the transition of LEF1 from a transcriptional repressor to an activator [9].
  • Surprisingly we found that the LEF1 promoter is selectively activated by specific isoforms of the LEF/TCF transcription factor family that contain an alternative C-terminal "E" tail [20].
  • CONCLUSIONS: TGF-beta and Wnt signaling pathways can independently or cooperatively regulate LEF1/TCF target genes [21].
  • We showed that the expression of c-myc binding protein (MYCBP) in colon carcinoma cells was consistently upregulated by overexpressed LEF-1, which is confirmed by microarray data, RT-PCR and luciferase assay [22].

Other interactions of LEF1


Analytical, diagnostic and therapeutic context of LEF1


  1. Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Hovanes, K., Li, T.W., Munguia, J.E., Truong, T., Milovanovic, T., Lawrence Marsh, J., Holcombe, R.F., Waterman, M.L. Nat. Genet. (2001) [Pubmed]
  2. Expression of enamel proteins and LEF1 in adamantinomatous craniopharyngioma: evidence for its odontogenic epithelial differentiation. Sekine, S., Takata, T., Shibata, T., Mori, M., Morishita, Y., Noguchi, M., Uchida, T., Kanai, Y., Hirohashi, S. Histopathology (2004) [Pubmed]
  3. Loss of expression of the WNT/beta-catenin-signaling pathway transcription factors lymphoid enhancer factor-1 (LEF-1) and T cell factor-1 (TCF-1) in a subset of peripheral T cell lymphomas. Dorfman, D.M., Greisman, H.A., Shahsafaei, A. Am. J. Pathol. (2003) [Pubmed]
  4. The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Giese, K., Cox, J., Grosschedl, R. Cell (1992) [Pubmed]
  5. Human sebaceous tumors harbor inactivating mutations in LEF1. Takeda, H., Lyle, S., Lazar, A.J., Zouboulis, C.C., Smyth, I., Watt, F.M. Nat. Med. (2006) [Pubmed]
  6. LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Skokowa, J., Cario, G., Uenalan, M., Schambach, A., Germeshausen, M., Battmer, K., Zeidler, C., Lehmann, U., Eder, M., Baum, C., Grosschedl, R., Stanulla, M., Scherr, M., Welte, K. Nat. Med. (2006) [Pubmed]
  7. A yeast model system for functional analysis of beta-catenin signaling. Lee, M.S., D'Amour, K.A., Papkoff, J. J. Cell Biol. (2002) [Pubmed]
  8. Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways. Labbé, E., Letamendia, A., Attisano, L. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  9. Beta-catenin-histone deacetylase interactions regulate the transition of LEF1 from a transcriptional repressor to an activator. Billin, A.N., Thirlwell, H., Ayer, D.E. Mol. Cell. Biol. (2000) [Pubmed]
  10. An internal ribosome entry site mediates translation of lymphoid enhancer factor-1. Jimenez, J., Jang, G.M., Semler, B.L., Waterman, M.L. RNA (2005) [Pubmed]
  11. Human naive CD8 T cells down-regulate expression of the WNT pathway transcription factors lymphoid enhancer binding factor 1 and transcription factor 7 (T cell factor-1) following antigen encounter in vitro and in vivo. Willinger, T., Freeman, T., Herbert, M., Hasegawa, H., McMichael, A.J., Callan, M.F. J. Immunol. (2006) [Pubmed]
  12. A novel isoform of human lymphoid enhancer-binding factor-1 (LEF-1) gene transcript encodes a protein devoid of HMG domain and nuclear localization signal. Kobielak, A., Kobielak, K., Trzeciak, W.H. Acta Biochim. Pol. (2001) [Pubmed]
  13. Cell-specific expression of helix-loop-helix transcription factors encoded by the E2A gene. Aronheim, A., Shiran, R., Rosen, A., Walker, M.D. Nucleic Acids Res. (1993) [Pubmed]
  14. Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling. Ishitani, T., Ninomiya-Tsuji, J., Matsumoto, K. Mol. Cell. Biol. (2003) [Pubmed]
  15. Overexpressed LEF-1 proteins display different nuclear localization patterns of beta-catenin in normal versus tumor cells. Ki, H., Jung, H.C., Park, J.H., Kim, J.S., Lee, K.Y., Kim, T.S., Kim, K. Cell Biol. Int. (2006) [Pubmed]
  16. {beta}-catenin relieves I-mfa-mediated suppression of LEF-1 in mammalian cells. Pan, W., Jia, Y., Huang, T., Wang, J., Tao, D., Gan, X., Li, L. J. Cell. Sci. (2006) [Pubmed]
  17. Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling. Yasumoto, K., Takeda, K., Saito, H., Watanabe, K., Takahashi, K., Shibahara, S. EMBO J. (2002) [Pubmed]
  18. A thymus-specific member of the HMG protein family regulates the human T cell receptor C alpha enhancer. Waterman, M.L., Fischer, W.H., Jones, K.A. Genes Dev. (1991) [Pubmed]
  19. A second protein kinase CK1-mediated step negatively regulates Wnt signalling by disrupting the lymphocyte enhancer factor-1/beta-catenin complex. Hämmerlein, A., Weiske, J., Huber, O. Cell. Mol. Life Sci. (2005) [Pubmed]
  20. A new beta-catenin-dependent activation domain in T cell factor. Atcha, F.A., Munguia, J.E., Li, T.W., Hovanes, K., Waterman, M.L. J. Biol. Chem. (2003) [Pubmed]
  21. Transcriptional regulation by Smads: crosstalk between the TGF-beta and Wnt pathways. Letamendia, A., Labbé, E., Attisano, L. The Journal of bone and joint surgery. American volume. (2001) [Pubmed]
  22. Identification of MYCBP as a beta-catenin/LEF-1 target using DNA microarray analysis. Jung, H.C., Kim, K. Life Sci. (2005) [Pubmed]
  23. Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling. Salins, P., Shawesh, S., He, Y., Dibrov, A., Kashour, T., Arthur, G., Amara, F. Neurosci. Lett. (2007) [Pubmed]
  24. Smad4 cooperates with lymphoid enhancer-binding factor 1/T cell-specific factor to increase c-myc expression in the absence of TGF-beta signaling. Lim, S.K., Hoffmann, F.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  25. Isolation of a novel human gene, MARKL1, homologous to MARK3 and its involvement in hepatocellular carcinogenesis. Kato, T., Satoh, S., Okabe, H., Kitahara, O., Ono, K., Kihara, C., Tanaka, T., Tsunoda, T., Yamaoka, Y., Nakamura, Y., Furukawa, Y. Neoplasia (2001) [Pubmed]
  26. Developmental expression of catenins and associated proteins during submucosal gland morphogenesis in the airway. Ritchie, T.C., Zhou, W., McKinstry, E., Hosch, M., Zhang, Y., Nathke, I., Engelhardt, J.F. Exp. Lung Res. (2001) [Pubmed]
  27. Lymphocyte enhancer-binding factor 1 (Lef1) inhibits terminal differentiation of osteoblasts. Kahler, R.A., Galindo, M., Lian, J., Stein, G.S., van Wijnen, A.J., Westendorf, J.J. J. Cell. Biochem. (2006) [Pubmed]
  28. Alterations of lymphoid enhancer factor-1 isoform expression in solid tumors and acute leukemias. Wang, W., Ji, P., Steffen, B., Metzger, R., Schneider, P.M., Halfter, H., Schrader, M., Berdel, W.E., Serve, H., Müller-Tidow, C. Acta Biochim. Biophys. Sin. (Shanghai) (2005) [Pubmed]
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