Lymphoid enhancer-binding factor 1 explained

Lymphoid enhancer-binding factor 1 (LEF1) is a protein that in humans is encoded by the LEF1 gene.^[1] It is a member of T cell factor/lymphoid enhancer factor (TCF/LEF) family.

Function

Lymphoid enhancer-binding factor-1 (LEF1) is a 48-kD nuclear protein that is expressed in pre-B and T cells. It binds to a functionally important site in the T-cell receptor-alpha (TCRA) enhancer and confers maximal enhancer activity. LEF1 belongs to a family of regulatory proteins that share homology with high mobility group protein-1 (HMG1).^[2]

Clinical significance

LEF1 is highly overexpressed and associated with disease progression and poor prognosis in B-cell chronic lymphocytic leukemia^[3] and other kinds of malignancies like colorectal cancer.^[4] It is also a promising potential drug target.^[5]

Interactions

Lymphoid enhancer-binding factor 1 has been shown to interact with:

• ALX4,^[6]
• AML-1,^[7]
• Catenin beta-1/β-catenin/CTNNB1,^{[8] [9] [10] [11]} including transgenically,^[12]
• EP300,^[13]
• MITF^[14]
• PIAS4,^[15]
• SMAD2,^[11] and
• SMAD3.^[11]

Further reading

• Waterman ML . Lymphoid enhancer factor/T cell factor expression in colorectal cancer . Cancer and Metastasis Reviews . 23 . 1–2 . 41–52 . 2004 . 15000148 . 10.1023/A:1025858928620 . 20996511 .
• Skokowa J, Welte K . LEF-1 is a decisive transcription factor in neutrophil granulopoiesis . Annals of the New York Academy of Sciences . 1106 . 143–151 . June 2007 . 1 . 17360796 . 10.1196/annals.1392.012 . 2007NYASA1106..143S . 30579011 .
• Travis A, Amsterdam A, Belanger C, Grosschedl R . LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected] . Genes & Development . 5 . 5 . 880–894 . May 1991 . 1827423 . 10.1101/gad.5.5.880 . free .
• van de Wetering M, Oosterwegel M, Dooijes D, Clevers H . Identification and cloning of TCF-1, a T lymphocyte-specific transcription factor containing a sequence-specific HMG box . The EMBO Journal . 10 . 1 . 123–132 . January 1991 . 1989880 . 452620 . 10.1002/j.1460-2075.1991.tb07928.x .
• Waterman ML, Fischer WH, Jones KA . A thymus-specific member of the HMG protein family regulates the human T cell receptor C alpha enhancer . Genes & Development . 5 . 4 . 656–669 . April 1991 . 2010090 . 10.1101/gad.5.4.656 . free .
• Zhou P, Byrne C, Jacobs J, Fuchs E . Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate . Genes & Development . 9 . 6 . 700–713 . March 1995 . 7537238 . 10.1101/gad.9.6.700 . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–174 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Prieve MG, Guttridge KL, Munguia JE, Waterman ML . The nuclear localization signal of lymphoid enhancer factor-1 is recognized by two differentially expressed Srp1-nuclear localization sequence receptor proteins . The Journal of Biological Chemistry . 271 . 13 . 7654–7658 . March 1996 . 8631802 . 10.1074/jbc.271.13.7654 . free .
• Behrens J, von Kries JP, Kühl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W . Functional interaction of beta-catenin with the transcription factor LEF-1 . Nature . 382 . 6592 . 638–642 . August 1996 . 8757136 . 10.1038/382638a0 . 1996Natur.382..638B . 4369341 .
• Bagga R, Emerson BM . An HMG I/Y-containing repressor complex and supercoiled DNA topology are critical for long-range enhancer-dependent transcription in vitro . Genes & Development . 11 . 5 . 629–639 . March 1997 . 9119227 . 10.1101/gad.11.5.629 . free .
• Bruhn L, Munnerlyn A, Grosschedl R . ALY, a context-dependent coactivator of LEF-1 and AML-1, is required for TCRalpha enhancer function . Genes & Development . 11 . 5 . 640–653 . March 1997 . 9119228 . 10.1101/gad.11.5.640 . free .
• Brannon M, Gomperts M, Sumoy L, Moon RT, Kimelman D . A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus . Genes & Development . 11 . 18 . 2359–2370 . September 1997 . 9308964 . 316518 . 10.1101/gad.11.18.2359 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–156 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Korinek V, Barker N, Willert K, Molenaar M, Roose J, Wagenaar G, Markman M, Lamers W, Destree O, Clevers H . 6 . Two members of the Tcf family implicated in Wnt/beta-catenin signaling during embryogenesis in the mouse . Molecular and Cellular Biology . 18 . 3 . 1248–1256 . March 1998 . 9488439 . 108837 . 10.1128/MCB.18.3.1248 .
• Prieve MG, Guttridge KL, Munguia J, Waterman ML . 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 . Molecular and Cellular Biology . 18 . 8 . 4819–4832 . August 1998 . 9671491 . 109067 . 10.1128/MCB.18.8.4819 .
• Levanon D, Goldstein RE, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y . 6 . Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors . Proceedings of the National Academy of Sciences of the United States of America . 95 . 20 . 11590–11595 . September 1998 . 9751710 . 21685 . 10.1073/pnas.95.20.11590 . 1998PNAS...9511590L . free .
• Hovanes K, Li TW, Waterman ML . The human LEF-1 gene contains a promoter preferentially active in lymphocytes and encodes multiple isoforms derived from alternative splicing . Nucleic Acids Research . 28 . 9 . 1994–2003 . May 2000 . 10756202 . 103301 . 10.1093/nar/28.9.1994 .
• Labbé E, Letamendia A, Attisano L . 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 . Proceedings of the National Academy of Sciences of the United States of America . 97 . 15 . 8358–8363 . July 2000 . 10890911 . 26952 . 10.1073/pnas.150152697 . 2000PNAS...97.8358L . free .
• Brantjes H, Roose J, van De Wetering M, Clevers H . All Tcf HMG box transcription factors interact with Groucho-related co-repressors . Nucleic Acids Research . 29 . 7 . 1410–1419 . April 2001 . 11266540 . 31284 . 10.1093/nar/29.7.1410 .

Notes and References

1. Milatovich A, Travis A, Grosschedl R, Francke U . Gene for lymphoid enhancer-binding factor 1 (LEF1) mapped to human chromosome 4 (q23-q25) and mouse chromosome 3 near Egf . Genomics . 11 . 4 . 1040–1048 . December 1991 . 1783375 . 10.1016/0888-7543(91)90030-I . free .
2. Web site: Entrez Gene: LEF1 lymphoid enhancer-binding factor 1.
3. Erdfelder F, Hertweck M, Filipovich A, Uhrmacher S, Kreuzer KA . High lymphoid enhancer-binding factor-1 expression is associated with disease progression and poor prognosis in chronic lymphocytic leukemia . Hematology Reports . 2 . 1 . e3 . January 2010 . 22184516 . 3222268 . 10.4081/hr.2010.e3 .
4. Eskandari E, Mahjoubi F, Motalebzadeh J . An integrated study on TFs and miRNAs in colorectal cancer metastasis and evaluation of three co-regulated candidate genes as prognostic markers . Gene . 679 . 150–159 . December 2018 . 30193961 . 10.1016/j.gene.2018.09.003 . 52172531 .
5. Gandhirajan RK, Staib PA, Minke K, Gehrke I, Plickert G, Schlösser A, Schmitt EK, Hallek M, Kreuzer KA . 6 . Small molecule inhibitors of Wnt/beta-catenin/lef-1 signaling induces apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo . Neoplasia . 12 . 4 . 326–335 . April 2010 . 20360943 . 2847740 . 10.1593/neo.91972 .
6. Boras K, Hamel PA . Alx4 binding to LEF-1 regulates N-CAM promoter activity . The Journal of Biological Chemistry . 277 . 2 . 1120–1127 . January 2002 . 11696550 . 10.1074/jbc.M109912200 . free .
7. Lutterbach B, Westendorf JJ, Linggi B, Isaac S, Seto E, Hiebert SW . A mechanism of repression by acute myeloid leukemia-1, the target of multiple chromosomal translocations in acute leukemia . The Journal of Biological Chemistry . 275 . 1 . 651–656 . January 2000 . 10617663 . 10.1074/jbc.275.1.651 . free .
8. Edlund S, Lee SY, Grimsby S, Zhang S, Aspenström P, Heldin CH, Landström M . Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis . Molecular and Cellular Biology . 25 . 4 . 1475–1488 . February 2005 . 15684397 . 548008 . 10.1128/MCB.25.4.1475-1488.2005 .
9. Grueneberg DA, Pablo L, Hu KQ, August P, Weng Z, Papkoff J . A functional screen in human cells identifies UBF2 as an RNA polymerase II transcription factor that enhances the beta-catenin signaling pathway . Molecular and Cellular Biology . 23 . 11 . 3936–3950 . June 2003 . 12748295 . 155208 . 10.1128/MCB.23.11.3936-3950.2003 .
10. Behrens J, von Kries JP, Kühl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W . Functional interaction of beta-catenin with the transcription factor LEF-1 . Nature . 382 . 6592 . 638–642 . August 1996 . 8757136 . 10.1038/382638a0 . 1996Natur.382..638B . 4369341 .
11. Labbé E, Letamendia A, Attisano L . 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 . Proceedings of the National Academy of Sciences of the United States of America . 97 . 15 . 8358–8363 . July 2000 . 10890911 . 26952 . 10.1073/pnas.150152697 . 2000PNAS...97.8358L . free .
12. Barolo S, Posakony JW . Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling . Genes & Development . 16 . 10 . 1167–1181 . May 2002 . 12023297 . 10.1101/gad.976502 . . 1170 . 14376483 . In ... zebrafish, reporter transgenes containing the TOPFLASH promoter are expressed in certain Wnt-responsive cell types (...Dorsky et al. 2002). . free .
13. Hecht A, Stemmler MP . Identification of a promoter-specific transcriptional activation domain at the C terminus of the Wnt effector protein T-cell factor 4 . The Journal of Biological Chemistry . 278 . 6 . 3776–3785 . February 2003 . 12446687 . 10.1074/jbc.M210081200 . free .
14. Yasumoto K, Takeda K, Saito H, Watanabe K, Takahashi K, Shibahara S . Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling . The EMBO Journal . 21 . 11 . 2703–2714 . June 2002 . 12032083 . 126018 . 10.1093/emboj/21.11.2703 .
15. Sachdev S, Bruhn L, Sieber H, Pichler A, Melchior F, Grosschedl R . PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies . Genes & Development . 15 . 23 . 3088–3103 . December 2001 . 11731474 . 312834 . 10.1101/gad.944801 .