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Gene Review

Lef1  -  lymphoid enhancer binding factor 1

Mus musculus

Synonyms: 3000002B05, AI451430, LEF-1, Lef-1, Lymphoid enhancer-binding factor 1, ...
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Disease relevance of Lef1


High impact information on Lef1

  • An effector of intercellular adhesion, beta-catenin also functions in Wnt signaling, associating with Lef-1/Tcf DNA-binding proteins to form a transcription factor [6].
  • As in embryologically initiated hair germs, transgenic follicles induce Lef-1, but follicles are disoriented and defective in sonic hedgehog polarization [6].
  • LEF-1 recognizes a specific nucleotide sequence through a high-mobility-group (HMG) domain [7].
  • In the absence of Wnt signaling, LEF-1/TCF proteins repress transcription in association with Groucho and CBP [8].
  • The LEF-1/TCF transcription factors can also interact with other cofactors and play an architectural role in the assembly of multiprotein enhancer complexes, which may allow for the integration of multiple signaling pathways [8].

Chemical compound and disease context of Lef1

  • LEF1, a downstream component of the Wnt signaling pathway, defines a distinct, her-2/neu negative (non-overexpressing) subset of breast/mammary cancers in both humans and mice, mediates breast cancer cell invasion, and may be regulated in part by estradiol [5].

Biological context of Lef1

  • At the initiation of organ development, formation of the epithelial primordium of the whisker but not tooth is dependent on mesenchymal Lef1 gene expression [9].
  • However, targeted gene inactivations of Lef1, Tcf1, or Tcf4 in the mouse do not produce phenotypes that mimic any known Wnt mutation [10].
  • Subsequent formation of a whisker and tooth mesenchymal papilla and completion of organogenesis require transient expression of Lef1 in the epithelium [9].
  • We further show that Lef1-/- pro-B cells display elevated levels of fas and c-myc transcription, providing a potential mechanism for their increased sensitivity to apoptosis [11].
  • Lef1-mediated canonical Wnt signaling is required for morphogenesis of these skin appendages during embryogenesis [12].

Anatomical context of Lef1

  • In previous tissue recombination experiments with normal and Lef1(-/-) tooth germs, we found that the effect of LEF1 expression in the epithelium is tissue nonautonomous and transferred to the subjacent mesenchyme [13].
  • Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin [14].
  • In fetal thymic organ cultures from Lef1-/- Tcf1-/- mice, alpha/beta T cell differentiation is completely arrested at the immature CD8+ single-positive (CD8+ ISP) stage and is markedly impaired at an earlier stage [15].
  • In transgenic mouse epidermis, overexpression of beta-catenin leads to formation of hair follicle tumors, whereas overexpression of N-terminally truncated Lef1, which blocks beta-catenin signaling, results in spontaneous sebaceous tumors [16].
  • We have investigated the molecular mechanisms of mammary placode development using Lef1 as a marker for the epithelial component of the placode, and mice deficient for Fgf10 or Fgfr2b, both of which fail to develop normal mammary glands [17].

Associations of Lef1 with chemical compounds

  • HIC-5 is a novel repressor of lymphoid enhancer factor/T-cell factor-driven transcription [18].
  • In vitro, the high mobility group domain of LEF-1 interacts with the runt DNA binding and proline-, serine-, threonine-rich activation domains of CBFalpha [19].
  • With the characterization of HIC-5 as a binding partner of the alternatively spliced exon in LEF/TCF transcription factors, we identified a novel molecular mechanism in the dialog of steroid and canonical Wnt signaling that is LEF/TCF subtype-dependent [18].
  • This interaction is mediated through a specific proline-rich domain in the N-terminal region of Alx4 and requires the DNA-binding domain (HMG-box) of LEF-1 [20].
  • This result suggests that tyrosine phosphorylation of beta-catenin has effects on the binding to cadherins in the cytoplasm but not on its LEF-1-dependent transactivating function in the nucleus [21].

Physical interactions of Lef1


Co-localisations of Lef1

  • Furthermore, beta-catenin colocalized with transcription factor LEF-1 in the nucleus, and coprecipitated with LEF-1-related proteins from cell extracts [27].

Regulatory relationships of Lef1

  • Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development [9].
  • Conversely, PS1 specifically represses LEF-dependent transcription in a dose-dependent manner [28].
  • We found that Tbx3 is expressed earlier than Lef1 and that Pyst1 is also expressed early but only transiently [29].
  • Lymphoid enhancer factor 1 makes cells resistant to transforming growth factor beta-induced repression of c-myc [1].
  • Additionally, we show that the movo1 promoter is activated by the lymphoid enhancer factor 1 (LEF1)/beta-catenin complex, a transducer of wnt signaling [30].

Other interactions of Lef1

  • Here we show that null mutations in both Lef1 and Tcf1, which are expressed in an overlapping pattern in the early mouse embryo, cause a severe defect in the differentiation of paraxial mesoderm and lead to the formation of additional neural tubes, phenotypes identical to those reported for Wnt3a-deficient mice [10].
  • FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice [13].
  • Redundant regulation of T cell differentiation and TCRalpha gene expression by the transcription factors LEF-1 and TCF-1 [15].
  • For example, epithelially expressed Bmp4 induces Msx1 and Lef1 as well as itself in the underlying mesenchyme [31].
  • While these potential cis-regulatory elements could be recognized and activated by corresponding transcription factors, such as Lef1 and Smad1, Wnt-Lef-beta-catenin signal failed to induce endogenous Slug expression in quail neural plate tissue prepared from forebrain and midbrain levels [32].

Analytical, diagnostic and therapeutic context of Lef1

  • Our analysis of Pitx2-/- mutant mice showed reduced Lef-1 expression in facial tissues by RT-PCR and quantitative RT-PCR [33].
  • The location of the LEF1 gene on human and mouse chromosomes was determined by Southern blot analysis of DNA from panels of interspecies somatic cell hybrids using a murine cDNA probe [34].
  • We collected mRNA for PCR analysis from individual transforming MEE cells by laser microdissection techniques and demonstrated that TGFbeta3 stimulates lymphoid-enhancing factor 1 (LEF1) mRNA synthesis in MEE cells [22].
  • Using electrophoretic mobility shift assays, we found that NO-releasing agents (E)-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexeneamide and S-nitroso-N-acetylpenicillamine greatly enhanced the formation of beta-catenin/LEF-1 DNA binding complex in a concentration- and time-dependent fashion in YAMC and IMCE cells [35].
  • In the current report, several animal models were utilized to functionally investigate the role of LEF1 in initiating and supporting gland development in the airway [3].


  1. Lymphoid enhancer factor 1 makes cells resistant to transforming growth factor beta-induced repression of c-myc. Sasaki, T., Suzuki, H., Yagi, K., Furuhashi, M., Yao, R., Susa, S., Noda, T., Arai, Y., Miyazono, K., Kato, M. Cancer Res. (2003) [Pubmed]
  2. Wnt/beta-catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy. Armstrong, D.D., Esser, K.A. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  3. Submucosal gland development in the airway is controlled by lymphoid enhancer binding factor 1 (LEF1). Duan, D., Yue, Y., Zhou, W., Labed, B., Ritchie, T.C., Grosschedl, R., Engelhardt, J.F. Development (1999) [Pubmed]
  4. Overexpression of beta-catenin induces apoptosis independent of its transactivation function with LEF-1 or the involvement of major G1 cell cycle regulators. Kim, K., Pang, K.M., Evans, M., Hay, E.D. Mol. Biol. Cell (2000) [Pubmed]
  5. Wnt pathway component LEF1 mediates tumor cell invasion and is expressed in human and murine breast cancers lacking ErbB2 (her-2/neu) overexpression. Nguyen, A., Rosner, A., Milovanovic, T., Hope, C., Planutis, K., Saha, B., Chaiwun, B., Lin, F., Imam, S.A., Marsh, J.L., Holcombe, R.F. Int. J. Oncol. (2005) [Pubmed]
  6. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Gat, U., DasGupta, R., Degenstein, L., Fuchs, E. Cell (1998) [Pubmed]
  7. Structural basis for DNA bending by the architectural transcription factor LEF-1. Love, J.J., Li, X., Case, D.A., Giese, K., Grosschedl, R., Wright, P.E. Nature (1995) [Pubmed]
  8. Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Eastman, Q., Grosschedl, R. Curr. Opin. Cell Biol. (1999) [Pubmed]
  9. Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development. Kratochwil, K., Dull, M., Farinas, I., Galceran, J., Grosschedl, R. Genes Dev. (1996) [Pubmed]
  10. Wnt3a-/--like phenotype and limb deficiency in Lef1(-/-)Tcf1(-/-) mice. Galceran, J., Fariñas, I., Depew, M.J., Clevers, H., Grosschedl, R. Genes Dev. (1999) [Pubmed]
  11. Wnt signaling regulates B lymphocyte proliferation through a LEF-1 dependent mechanism. Reya, T., O'Riordan, M., Okamura, R., Devaney, E., Willert, K., Nusse, R., Grosschedl, R. Immunity (2000) [Pubmed]
  12. Lef1 is required for the transition of Wnt signaling from mesenchymal to epithelial cells in the mouse embryonic mammary gland. Boras-Granic, K., Chang, H., Grosschedl, R., Hamel, P.A. Dev. Biol. (2006) [Pubmed]
  13. FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Kratochwil, K., Galceran, J., Tontsch, S., Roth, W., Grosschedl, R. Genes Dev. (2002) [Pubmed]
  14. Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Merrill, B.J., Gat, U., DasGupta, R., Fuchs, E. Genes Dev. (2001) [Pubmed]
  15. Redundant regulation of T cell differentiation and TCRalpha gene expression by the transcription factors LEF-1 and TCF-1. Okamura, R.M., Sigvardsson, M., Galceran, J., Verbeek, S., Clevers, H., Grosschedl, R. Immunity (1998) [Pubmed]
  16. Indian hedgehog and beta-catenin signaling: role in the sebaceous lineage of normal and neoplastic mammalian epidermis. Niemann, C., Unden, A.B., Lyle, S., Zouboulis, C.h.C., Toftgård, R., Watt, F.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  17. Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Mailleux, A.A., Spencer-Dene, B., Dillon, C., Ndiaye, D., Savona-Baron, C., Itoh, N., Kato, S., Dickson, C., Thiery, J.P., Bellusci, S. Development (2002) [Pubmed]
  18. HIC-5 is a novel repressor of lymphoid enhancer factor/T-cell factor-driven transcription. Ghogomu, S.M., van Venrooy, S., Ritthaler, M., Wedlich, D., Gradl, D. J. Biol. Chem. (2006) [Pubmed]
  19. Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor alpha regulation of ELA2. Li, F.Q., Person, R.E., Takemaru, K., Williams, K., Meade-White, K., Ozsahin, A.H., Güngör, T., Moon, R.T., Horwitz, M. J. Biol. Chem. (2004) [Pubmed]
  20. Alx4 binding to LEF-1 regulates N-CAM promoter activity. Boras, K., Hamel, P.A. J. Biol. Chem. (2002) [Pubmed]
  21. Tyrosine phosphorylation translocates beta-catenin from cell-->cell interface to the cytoplasm, but does not significantly enhance the LEF-1-dependent transactivating function. Kim, K., Lee, K.Y. Cell Biol. Int. (2001) [Pubmed]
  22. TGFbeta3 signaling activates transcription of the LEF1 gene to induce epithelial mesenchymal transformation during mouse palate development. Nawshad, A., Hay, E.D. J. Cell Biol. (2003) [Pubmed]
  23. Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice. Yamada, T., Mori, Y., Hayashi, R., Takada, M., Ino, Y., Naishiro, Y., Kondo, T., Hirohashi, S. Cancer Res. (2003) [Pubmed]
  24. Differential expression of prostaglandin endoperoxide H synthase-2 and formation of activated beta-catenin-LEF-1 transcription complex in mouse colonic epithelial cells contrasting in Apc. Mei, J.M., Hord, N.G., Winterstein, D.F., Donald, S.P., Phang, J.M. Carcinogenesis (1999) [Pubmed]
  25. Differential importin-alpha recognition and nuclear transport by nuclear localization signals within the high-mobility-group DNA binding domains of lymphoid enhancer factor 1 and T-cell factor 1. Prieve, M.G., Guttridge, K.L., Munguia, J., Waterman, M.L. Mol. Cell. Biol. (1998) [Pubmed]
  26. PITX2 and beta-catenin interactions regulate Lef-1 isoform expression. Amen, M., Liu, X., Vadlamudi, U., Elizondo, G., Diamond, E., Engelhardt, J.F., Amendt, B.A. Mol. Cell. Biol. (2007) [Pubmed]
  27. Epithelial mesenchymal transition by c-Fos estrogen receptor activation involves nuclear translocation of beta-catenin and upregulation of beta-catenin/lymphoid enhancer binding factor-1 transcriptional activity. Eger, A., Stockinger, A., Schaffhauser, B., Beug, H., Foisner, R. J. Cell Biol. (2000) [Pubmed]
  28. Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing. Soriano, S., Kang, D.E., Fu, M., Pestell, R., Chevallier, N., Zheng, H., Koo, E.H. J. Cell Biol. (2001) [Pubmed]
  29. Interactions between FGF and Wnt signals and Tbx3 gene expression in mammary gland initiation in mouse embryos. Eblaghie, M.C., Song, S.J., Kim, J.Y., Akita, K., Tickle, C., Jung, H.S. J. Anat. (2004) [Pubmed]
  30. The LEF1/beta -catenin complex activates movo1, a mouse homolog of Drosophila ovo required for epidermal appendage differentiation. Li, B., Mackay, D.R., Dai, Q., Li, T.W., Nair, M., Fallahi, M., Schonbaum, C.P., Fantes, J., Mahowald, A.P., Waterman, M.L., Fuchs, E., Dai, X. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  31. Analysis of epithelial-mesenchymal interactions in the initial morphogenesis of the mammalian tooth. Dassule, H.R., McMahon, A.P. Dev. Biol. (1998) [Pubmed]
  32. Regulation of Slug transcription in embryonic ectoderm by beta-catenin-Lef/Tcf and BMP-Smad signaling. Sakai, D., Tanaka, Y., Endo, Y., Osumi, N., Okamoto, H., Wakamatsu, Y. Dev. Growth Differ. (2005) [Pubmed]
  33. PITX2, beta-catenin and LEF-1 interact to synergistically regulate the LEF-1 promoter. Vadlamudi, U., Espinoza, H.M., Ganga, M., Martin, D.M., Liu, X., Engelhardt, J.F., Amendt, B.A. J. Cell. Sci. (2005) [Pubmed]
  34. Gene for lymphoid enhancer-binding factor 1 (LEF1) mapped to human chromosome 4 (q23-q25) and mouse chromosome 3 near Egf. Milatovich, A., Travis, A., Grosschedl, R., Francke, U. Genomics (1991) [Pubmed]
  35. Differential formation of beta-catenin/lymphoid enhancer factor-1 DNA binding complex induced by nitric oxide in mouse colonic epithelial cells differing in adenomatous polyposis coli (Apc) genotype. Mei, J.M., Hord, N.G., Winterstein, D.F., Donald, S.P., Phang, J.M. Cancer Res. (2000) [Pubmed]
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