Cancer and Metastasis Reviews

, Volume 18, Issue 2, pp 231–246 | Cite as

The Control of β-catenin and TCF During Embryonic Development and Cancer

  • Lucas Waltzer
  • Mariann Bienz


The Wnt signaling pathway functions reiteratively during animal development to control cell fate decisions. Inappropriate deregulation of this pathway leads to cancer in a number of tissues. The components that transduce the Wnt signal from the cell membrane to the cell nucleus are well conserved between vertebrates and Drosophila. A pivotal Wnt effector is the protein β-catenin/Armadillo whose stability in the cytoplasm is low in unstimulated cells. β-catenin/Armadillo is targetted for proteasome-mediated degradation by a protein complex to which it binds. This complex consists of Axin, a putative scaffold protein which also binds to the tumor suppressor Adenomatous polyposis coli (APC) and glycogen synthase kinase 3 (GSK3)/Shaggy. Wnt signaling somehow inhibits the kinase activity of the quaternary complex. As a consequence, β-catenin/Armadillo accumulates in the cytoplasm, translocates to the nucleus and becomes a transcriptional co-activator of T cell factor (TCF), the ultimate nuclear target of Wnt signaling. TCF is an architectural protein, mediating the assembly of multi-protein enhancer complexes. It cooperates with other enhancer-binding proteins and, together with β-catenin/Armadillo, stimulates the transcription of Wnt target genes. Recently, repressors have been identified that prevent TCF from being active in the absence of Wnt signaling.

Wnt signaling Wingless Armadillo T cell factor Axin Adenomatous polyposis coli 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nusse R, Varmus H: Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31: 99–109, 1982Google Scholar
  2. 2.
    Nusse R, Varmus H: Wnt genes. Cell 69: 1073–1087, 1992Google Scholar
  3. 3.
    Rijsewijk F, Schuermann M, Wagenaar E, Parren P, Weigel D, Nusse R: The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell 50: 649–657, 1987Google Scholar
  4. 4.
    Peifer M, Rauskolb C, Williams M, Riggleman B, Wieschaus E: The segment polarity gene armadillo interacts with the wingless signaling pathway in both embryonic and adult pattern formation. Development 111: 1029–1043, 1991Google Scholar
  5. 5.
    Klingensmith J, Nusse R, Perrimon N: The Drosophila segment polarity gene dishevelled encodes a novel protein required for response to the wingless signal. Genes Dev 8: 118–130, 1994Google Scholar
  6. 6.
    Theisen H, Purcell J, Bennett M, Kansagara D, Syed A, Marsh JL: dishevelled is required during wingless signaling to establish both cell polarity and cell identity. Development 120: 347–360, 1994Google Scholar
  7. 7.
    Siegfried E, Chou TB, Perrimon N: wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate. Cell 71: 1167–1179, 1992Google Scholar
  8. 8.
    Noordermeer J, Klingensmith J, Perrimon N, Nusse R: dishevelled and armadillo act in the Wingless signaling pathway in Drosophila. Nature 367: 80–82, 1994Google Scholar
  9. 9.
    Peifer M, Sweeton D, Casey M, Wieschaus E: Wingless signal and Zeste-white 3 kinase trigger opposing changes in the intracellular distribution of Armadillo. Development 120: 369–380, 1994Google Scholar
  10. 10.
    Siegfried E, Wilder EL, Perrimon N: Components of wingless signaling in Drosophila. Nature 367: 76–80, 1994Google Scholar
  11. 11.
    Perrimon N: The genetic basis of patterned boldness in Drosophila. Cell 781–784, 1994Google Scholar
  12. 12.
    Heasman J, Crawford A, Goldstone K, Garner-Hamrick P, Gumbiner B, McCrea P, Kintner C, Noro CY, Wylie C: Overexpression of cadherins and underexpression of β-catenin inhibit dorsal mesoderm induction in early Xenopus embryos. Cell 79: 791–803, 1994Google Scholar
  13. 13.
    He X, Saint-Jeannet J-P, Woodgett J, Varmus H, Dawid I: Glycogen synthase kinase-3 and dorsalventral patterning in Xenopus embryos. Nature 374: 617–622, 1995Google Scholar
  14. 14.
    Yost C, Torres M, Miller JR, Huang E, Kimelman D, Moon RT: The axis-inducing activity, stability, and subcellular distribution of β-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev 10: 1443–1454, 1996Google Scholar
  15. 15.
    Korinek V, Barker N, Morin P, van Wichen D, de Weger R, Kinzler K, Vogelstein B, Clevers H: Constitutive transcriptional activation by a β-catenin-Tcf complex in APC-/-colon carcinoma. Science 275: 1784–1787, 1997Google Scholar
  16. 16.
    Morin P, Sparks A, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler K: Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275: 1787–1790, 1997Google Scholar
  17. 17.
    Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P: Stabilization of β-catenin by genetic defects in melanoma cell lines. Science 275: 1790–1792, 1997Google Scholar
  18. 18.
    Polakis P: The oncogenic activation of β-catenin. Curr Op Genet Dev 9: 15–21, 1999Google Scholar
  19. 19.
    Eastman Q, Grosschedl R: Regulation of LEF1/TCF transcription factors by Wnt and other signals. Curr Op Cell Biol 11: 233–240, 1999Google Scholar
  20. 20.
    Gumbiner B: Propagation and localization of Wnt signaling. Curr Op Genet Dev 8: 430–435, 1999Google Scholar
  21. 21.
    Dierick H, Bejsovec A: Cellular mechanisms of Wingless/Wnt signal transduction. Curr Top Dev Biol 43: 153–190, 1999Google Scholar
  22. 22.
    Ben-Ze'ev A, Geiger B: Differential molecular interactions of β-catenin and plakoglobin in adhesion, signaling and cancer. Curr Op Cell Biol 10: 629–639, 1998Google Scholar
  23. 23.
    Tepass U: Epithelial differentiation in Drosophila. Bioessays 19: 673–682, 1997Google Scholar
  24. 24.
    Haegel H, Larue L, Ohsugi M, Fedorov L, Herrenknecht K, Kemler R: Lack of β-catenin affects mouse development at gastrulation. Development 121: 3529–3537, 1995Google Scholar
  25. 25.
    Müller H-A, Wieschaus E: armadillo, bazooka, and stardust are critical for early stages in formation of the zonula adherens and maintenance of the polarized blastoderm epithelium in Drosophila. J Cell Biol 134: 149–163, 1996Google Scholar
  26. 26.
    Cox R, Kirkpatrick C, Peifer M: Armadillo is required for adherens junction assembly, cell polarity and morphogenesis during Drosophila embryogenesis. J Cell Biol 134: 133–148, 1996Google Scholar
  27. 27.
    Yu X, Hoppler S, Eresh S, Bienz M: decapentaplegic, a target gene of the wingless signaling pathway in the Drosophila midgut. Development 122: 849–858, 1996Google Scholar
  28. 28.
    Fagotto F, Funayama N, Glück U, Gumbiner B: Binding to cadherins antagonizes the signaling activity of β-catenin during axis formation in Xenopus. J Cell Biol 132: 1105–1114, 1996Google Scholar
  29. 29.
    Funayama N, Fagotto F, McCrea P, Gumbiner B: Embryonic axis induction by the armadillo repeat domain of β-catenin: evidence for intracellular signaling. J Cell Biol 128: 959–968, 1995Google Scholar
  30. 30.
    Hülsken J, Birchmeier W, Behrens J: E-cadherin and APC compete for the interaction with β-catenin and the cytoskeleton. J Cell Biol 127: 2061–2069, 1994Google Scholar
  31. 31.
    Rubinfeld B, Souza B, Albert I, Munemitsu S, Polakis P: The APC protein and E-cadherin form similar but independent complexes with α-catenin, β-catenin, and plakoglobin. J Biol Chem 3270: 5549–5555, 1995Google Scholar
  32. 32.
    Behrens J, von Kries J, Kühl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W: Functional interaction of β-catenin with the transcription factor LEF-1. Nature 382: 638–642, 1996Google Scholar
  33. 33.
    Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H: XTcf-3 transcription factor mediates β-catenin-induced axis formation in Xenopus embryos. Cell 86: 391–399, 1996Google Scholar
  34. 34.
    Orsulic S, Peifer M: An in vivo structure-function study of Armadillo, the β-catenin homolog, reveals both separate and overlapping regions of the protein required for cell adhesion and for Wingless signaling. J Cell Biol 134: 1283–1301, 1996Google Scholar
  35. 35.
    van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M, Clevers H: Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88: 789–799, 1997Google Scholar
  36. 36.
    Pai LM, Kirkpatrick C, Blanton J, Oda H, Takeichi M, Peifer M: Drosophila α-catenin and E-cadherin bind to distinct regions of Drosophila Armadillo. J Biol Chem 271: 32411–32420, 1997Google Scholar
  37. 37.
    Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A: Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3β and β-catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J 17: 1371–1384, 1998Google Scholar
  38. 38.
    Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T: Axin, an inhibitor of the Wnt signaling pathway, interacts with β-catenin, GSK-3β and APC and reduces the β-catenin level. Genes Cells 3: 395–403, 1998Google Scholar
  39. 39.
    Orsulic S, Huber O, Aberle H, Arnold S, Kemler R: E-cadherin binding prevents β-catenin nuclear localization and β-catenin/LEF-1-mediated transactivation. J Cell Sci 112: 1237–1245, 1999Google Scholar
  40. 40.
    Huber A, Nelson W, Weis W: Three-dimensional structure of the armadillo repeat region of β-catenin. Cell 90: 871–882, 1997Google Scholar
  41. 41.
    Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemistu S, Polakis P: Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly. Science 272: 1023–1026, 1996Google Scholar
  42. 42.
    Brunner E, Peter O, Schweizer L, Basler K: pangolin encodes a Lef-1 homolog that acts downstream of Armadillo to transduce the Wingless signal. Nature 385: 829–833, 1997Google Scholar
  43. 43.
    Sanson B, White P, Vincent J-P: Uncoupling cadherinbased adhesion from wingless signaling in Drosophila. Nature 383: 627–630, 1996Google Scholar
  44. 44.
    Yanagawa S, Lee JS, Haruna T, Oda H, Uemura T, Takeichi M, Ishimoto A: Accumulation of Armadillo induced by Wingless, Dishevelled, and dominant-negative Zeste-White 3 leads to elevated DE-cadherin in Drosophila clone 8 wing disc cells. J Biol Chem 272: 25243–25251, 1997Google Scholar
  45. 45.
    Riggleman B, Schedl P, Wieschaus E: Spatial expression of the Drosophila segment polarity gene armadillo is post-transcriptionally regulated by wingless. Cell 63: 549–560, 1990Google Scholar
  46. 46.
    Van Leeuwen F, Samos CF, Nusse R: Biological activity of soluble Wingless protein in cultured Drosophila imaginal disc cells. Nature 368: 342–344, 1994Google Scholar
  47. 47.
    Cook D, Fry MJ, Hughes K, Sumathipala R, Woodgett J, Dale T: Wingless inactivates glycogen synthase kinase-3 via an intracellular signaling path way which involves a protein kinase C. EMBO J 15: 4526–4536, 1996Google Scholar
  48. 48.
    Pai L, Orsulic S, Besjovec A, Peifer M: Negative regulation of Armadillo, a Wingless effector in Drosophila. Development 124: 2255–2266, 1997Google Scholar
  49. 49.
    Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F: The mouse fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90: 181–192, 1997Google Scholar
  50. 50.
    Behrens J, Jerchow B, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D, Birchmeier W: Functional interaction of an axin homolog, conductin, with β-catenin, APC, and GSK3β. Science 280: 596–599, 1998Google Scholar
  51. 51.
    Itoh K, Krupnik V, Sokol S: Axis determination in Xenopus involves biochemical interactions of axin, glycogen synthase kinase 3 and β-catenin. Curr Biol 8: 591–594, 1998Google Scholar
  52. 52.
    Hamada F, Tomoyasu Y, Takatsu Y, Nakamura M, Nagai S, Suzuki A, Fujita F, Shibuya H, Toyoshima K, Ueno N, Akiyama T: Negative regulation of Wingless signaling by D-Axin, a Drosophila homolog of Axin. Science 283: 1739–1742, 1999Google Scholar
  53. 53.
    Sakanaka C, Weiss JB, Williams LT: Bridging of β-catenin and glycogen synthase kinase-3β by axin and inhibition of β-catenin-mediated transcription. Proc Natl Acad Sci USA 95: 3020–3023, 1998.Google Scholar
  54. 54.
    Hart M, de los Santos R, Albert I, Rubinfeld B, Polakis P: Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK3β. Curr Biol 8: 573–581, 1998Google Scholar
  55. 55.
    Kishida S, Yamamoto H, Ikeda S, Kishida M, Sakamoto I, Koyama S, Kikuchi A: Axin, a negative regulator of the Wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of β-catenin. J Biol Chem 273: 10823–10826, 1998Google Scholar
  56. 56.
    Kishida M, Koyama S, Kishida S, Matsubara K, Nakashima S, Higano K, Takada R, Takada S, Kikuchi A: Axin prevents Wnt-3a-induced accumulation of β-catenin. Oncogene 18: 979–985, 1999Google Scholar
  57. 57.
    Polakis P: The adenomatous polyposis coli (APC) tumor suppressor. Biochim Biophys Acta 1332: F127-F147, 1997Google Scholar
  58. 58.
    Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P: Association of the APC gene product with β-catenin. Science 262: 1731–1734, 1993Google Scholar
  59. 59.
    Su L-K, Volgelstein B, Kinzler KW: Association of the APC tumor suppressor protein with catenins. Science 262: 1734–1737, 1993Google Scholar
  60. 60.
    Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P: Regulation of intracellular β-catenin levels by the adenomatous polyposis coli (APC) tumour-suppressor protein. Proc Natl Acad Sci USA 92: 3046–3050, 1995Google Scholar
  61. 61.
    Vleminckx K, Wong E, Guger K, Rubinfeld B, Polakis P, Gumbiner BM: Adenomatous polyposis coli tumor suppressor protein has signaling activity in Xenopus laevis embryos resulting in the induction of an ectopic dorsoanterior axis. J Cell Biol 136: 411–420, 1997Google Scholar
  62. 62.
    Miller J, Moon R: Analysis of the signaling activities of localization mutants of β-catenin during axis specification in Xenopus. J Cell Biol 139: 229–243, 1997Google Scholar
  63. 63.
    Rocheleau CE, Downs WD, Lin R, Wittmann C, Bei Y, Cha YH, Ali M, Priess JR, Mello CC: Wnt signaling and an APC-related gene specify endoderm in early C. elegans embryos. Cell 90: 707–716, 1997Google Scholar
  64. 64.
    Nakagawa H, Murata Y, Koyama K, Fujiyama A, Miyoshi Y, Monden M, Akiyama T, Nakamura Y: Identification of a brain-specific APC homologue, APCL, and its interaction with β-catenin. Cancer Res 58: 5176–5181, 1998Google Scholar
  65. 65.
    van Es JH, Kirkpatrick C, van de Wetering M, Molenaar M, Miles A, Kuipers J, Destree O, Peifer M, Clevers H: Identification of APC2, a homologue of the adenomatous polyposis coli tumour suppressor. Curr Biol 9: 105–108, 1999Google Scholar
  66. 66.
    Hayashi S, Rubinfeld B, Souza B, Polakis P, Wieschaus E, Levine A: A Drosophila homology of the tumor suppressor gene adenomatous polyposis coli down-regulates β-catenin, but its zygotic expression is not essential for the regulation of Armadillo. Proc Natl Acad Sci USA 94: 242–247, 1997Google Scholar
  67. 67.
    Yu X, Bienz M: Ubiquitous expression of a Drosophila adenomatous polyposis coli homolog and its localization in cortical actin caps. Mech Dev 84: 69–73, 1999Google Scholar
  68. 68.
    Ahmed Y, Hayashi S, Levine A, Wieschaus E: Regulation of armadillo by a Drosophila APC inhibits neuronal apoptosis during retinal development Cell 93: 1171–1182, 1998Google Scholar
  69. 69.
    Yu X, Waltzer L, Bienz M: A new Drosophila APC homolog associated with adhesive zones of epithelial cells. Nature Cell Biol 1: 144–151, 1999Google Scholar
  70. 70.
    Sakanaka C, Williams LT: Functional domains of axin. Importance of the C terminus as an oligomerization domain. J Biol Chem 274: 14090–14093, 1999Google Scholar
  71. 71.
    Hsu W, Zeng L, Costantini F: Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain. J Biol Chem 274: 3439–3445, 1999Google Scholar
  72. 72.
    Seeling JM, Miller JR, Gil R, Moon RT, White R, Virshup DM: Regulation of β-catenin signaling by the B56 subunit of protein phosphatase 2A. Science 283: 2089–2091, 1999Google Scholar
  73. 73.
    Yost C, Farr GH, Pierce SB, Ferkey DM, Chen MM, Kimelman D: GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis. Cell 93: 1031–1041, 1998Google Scholar
  74. 74.
    Aberle H, Bauer A, Stappert J, Kispert A, Kemler R: β-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 16: 3797–3804, 1997Google Scholar
  75. 75.
    Orford K, Crockett C, Jensen J, Weissman A, Byers S: Serine phosphorylation-regulated ubiquitination and degradation of β-catenin. J Biol Chem 272: 24735–24738, 1997Google Scholar
  76. 76.
    Jiang J, Struhl G: Regulation of the Hedgehog and Wingless signaling pathways by the F-box/WD40-repeat protein Slimb. Nature 391: 493–496, 1998Google Scholar
  77. 77.
    Margottin F, Bour S, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R: A novel human WD protein, h-βTrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol Cell 1: 565–574, 1998Google Scholar
  78. 78.
    Marikawa Y, Elinson R: β-TrCP is a negative regulator of the Wnt/β-catenin signaling pathway and dorsal axis formation in Xenopus embryos. Mech Dev 77: 75–80, 1998Google Scholar
  79. 79.
    Hart M, Concordet J, Lassot I, Albert I, del los Santos R, Durand H, Perret C, Rubinfeld B, Margottin F, Benarous R, Polakis P: The F-box protein β-TrCP associates with phosphorylated β-catenin and regulates its activity in the cell. Curr Biol 9: 207–210, 1999Google Scholar
  80. 80.
    Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, Nakamichi I, Kikuchi A, Nakayama K, Nakayama K: An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of β-catenin. EMBO J 18: 2401–2410, 1999Google Scholar
  81. 81.
    Winston JT, Struck P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW: The SCF β-TrCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in Iκ Bα and β-catenin and stimulates IκBα ubiquitination in vitro. Genes Dev 13: 270–283, 1999Google Scholar
  82. 82.
    Maniatis T: A ubiquitin ligase complex essential for the NFκB, Wnt/Wingless and Hedgehog signaling pathways. Genes Dev 13: 505–510, 1999Google Scholar
  83. 83.
    Smalley MJ, Sara E, Patterson H, Naylor S, Cook D, Jayatilake H, Fryer LG, Hutchinson L, Fry MJ, Dale TC: Interaction of Axin and Dvl-2 proteins regulates Dvl-2-stimulated TCF-dependent transcription. EMBO J 18: 2823–2835, 1999Google Scholar
  84. 84.
    Schneider S, Steinbeisser H, Warga RM, Hausen P: β-catenin translocation into nuclei demarcates the dorsalizing centers in frog and fish embryos. Mech Dev 57: 191–198, 1996Google Scholar
  85. 85.
    Cox R, Pai L, Miller J, Orsulic S, Stein J, McCormick C, Audeh Y, Wang W, Moon R, Peifer M: Membrane-tethered Drosophila Armadillo cannot transduce Wingless signal on its own. Development 126: 1327–1335, 1999Google Scholar
  86. 86.
    Huber O, Korn R, McLaughlin J, Ohsugi M, Herrmann B, Kemler R: Nuclear localization of β-catenin by interaction with transcription factor LEF-1. Mech Dev 59: 3–10, 1996Google Scholar
  87. 87.
    Fagotto F, Gluck U, Gumbiner B: Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of β-catenm. Curr Biol 12: 181–190, 1998Google Scholar
  88. 88.
    Yokoya F, Imamoto N, Tachibana T, Yoneda Y: β-catenin can be transported into the nucleus in a ran-unassisted manner. Mol Biol Cell 10: 1119–1131, 1999Google Scholar
  89. 89.
    Görlich D, Mattaj I: Nucleocytoplasmic transport. Science 271: 1513–1518, 1996Google Scholar
  90. 90.
    Clevers H, van de Wetering M: TCF/LEF factors earn their wings. Trends Genet 13: 485–489, 1997Google Scholar
  91. 91.
    Pelegri F, Maischein H-M: Function of zebrafish β-catenin and TCF-3 in dorsoventral patterning. Mech Dev 77: 63–74, 1998Google Scholar
  92. 92.
    Kengaku M, Capdevila J, Rodriguez-Esteban C, De La Pena J, Johnson R, Belmonte J, Tabin C: Distinct WNT pathways regulating AER formation and dorsoventral polarity in the chick limb bud. Science 180: 1274–1277, 1998Google Scholar
  93. 93.
    Riese J, Yu X, Munnerlyn A, Eresh S, Shu-Chi H, Grosschedl R, Bienz M: LEF-1, a nuclear factor coordinating wingless and decapentaplegic signaling. Cell 88: 777–787, 1997Google Scholar
  94. 94.
    Brannon M, Gomperts M, Sumoy L, Moon R, Kimelman D: A β-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. Genes Dev 11: 2359–2370, 1997Google Scholar
  95. 95.
    McKendry R, Hsu S, Harland R, Grosschedl R: LEF-1/TCF proteins mediate Wnt-inducible transcription from the Xenopus nodal-related 3 promoter. Dev Biol 192: 420–431, 1997Google Scholar
  96. 96.
    Laurent M, Blitz I, Hashimoto C, Rothbacher U, Cho K: The Xenopus homeobox gene twin mediates Wnt induction of goosecoid in establishment of Spemann's organizer. Development 124: 4905–4916, 1997Google Scholar
  97. 97.
    Verbeek S, Izon D, Hofhuis F, Robanus-Maandag E, te Riele H, van de Wetering M, Oosterwegel M, Wilson A, MacDonald HR, Clevers H: An HMG-box-containing T-cell factor required for thymocyte differentiation. Nature 374: 70–74, 1995Google Scholar
  98. 98.
    van Genderen C, Okamura RM, Farinas I, Quo RG, Parslow TG, Bruhn L, Grosschedl R: Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev 8: 2691–2703, 1994Google Scholar
  99. 99.
    Gat U, DasGupta R, Degenstein L, Fuchs E: De novo hair follicle morphogenesis and hair tumors in mice expressing a truncated β-catenin in skin. Cell 95: 605–614, 1998Google Scholar
  100. 100.
    Galceran J, Farinas I, Depew M, Clevers H, Grosschedl R: Wnt3a-/-like phenotype and limb deficiency in Lef1-/-Tcf1-/-mice. Genes Dev 13: 709–717, 1999Google Scholar
  101. 101.
    Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters P, Clevers H: Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genet 19: 379–383, 1998Google Scholar
  102. 102.
    Grosschedl R, Giese K, Pagel J: HMG domain proteins: architectural elements in the assembly of nucleoprotein structures. Trends Genet 10: 94–100, 1994Google Scholar
  103. 103.
    Van de Wetering M, Castrop J, Korinek V, Clevers H: Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties. Mol Cell Biol 16: 742–752, 1996Google Scholar
  104. 104.
    Hsu S, Galceran J, Grosschedl R: Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with β-catenin. Mol Cell Biol 18: 4807–4818, 1998Google Scholar
  105. 105.
    Giese K, Grosschedl R: LEF-1 contains an activation domain that stimulates transcription only in a specific context of factor-binding sites. EMBO J 12: 4667–4676, 1993Google Scholar
  106. 106.
    Carlsson P, Waterman M, Jones K: The hLEF/TCF-1α HMG protein contains a context-dependent transcriptional activation domain that induces the TCRα enhancer in T cells. Genes Dev 7: 2418–2430, 1993Google Scholar
  107. 107.
    Mayall T, Sheridan P, Montminy M, Jones K: Distinct roles for P-CREB and LEF-1 in TCRα enhancer assembly and activation on chromatin templates in vitro. Genes Dev 11: 887–899, 1997Google Scholar
  108. 108.
    Giese K, Cox J, Grosschedl R: The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell 69: 185–195, 1992Google Scholar
  109. 109.
    Love J, Li X, Case D, Giese K, Grosschedl R, Wright P: Structural basis for DNA bending by the architectural transcription factor LEF-1. Nature 376: 791–795, 1995Google Scholar
  110. 110.
    Giese K, Kinsley C, Kirshner J, Grosschedl R: Assembly and function of a TCRα enhancer complex is dependent on LEF-1-induced DNA bending and multipleprotein-protein interactions. Genes Dev 9: 995–1008, 1995Google Scholar
  111. 111.
    Bruhn L, Munnerlyn A, Grosschedl R: ALY, a context-dependent coactivator of LEF-1 and AML-1, is required for TCRα enhancer function. Genes Dev 11: 640–653, 1997Google Scholar
  112. 112.
    Eresh S, Riese J, Jackson D, Bohmann D, Bienz M: A CREB binding site as target for decapentaplegic signaling during Drosophila endoderm induction. EMBO J 16: 2014–2022, 1997Google Scholar
  113. 113.
    Szüts D, Eresh S, Bienz M: Functional intertwining of Dpp and EGFR signaling during Drosophila endoderm induction. Genes Dev 12: 2022–2035, 1998Google Scholar
  114. 114.
    Bienz M: Endoderm induction in Drosophila: the nuclear targets of the inducing signals. Curr Op Genet Dev 7: 683–688, 1997Google Scholar
  115. 115.
    Tetsu O, McCormick F: β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398: 422–426, 1999Google Scholar
  116. 116.
    Vleminckx K, Kemler R, Hecht A: The C-terminal transactivation domain of β-catenin is necessary and sufficient for signaling by the Lef-l/β-catenin complex in Xenopus laevis. Mech Dev 81: 65–74, 1999Google Scholar
  117. 117.
    Waltzer L, Bienz M: A function of CBP as a transcriptional co-activator during Dpp signaling. EMBO J 18: 1630–1641, 1999Google Scholar
  118. 118.
    Bienz M: TCF: transcriptional activator or repressor? Curr Op Cell Biol 10: 366–372, 1998Google Scholar
  119. 119.
    Crawford H, Fingleton B, Rudolph-Owen L, Goss K, Rubinfeld B, Polakis P, Matrisian L: The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors. Oncogene 18: 2883–2891, 1999Google Scholar
  120. 120.
    Cavallo R, Cox R, Moline M, Roose J, Polevoy G, Clevers H, Peifer M, Bejsovec A: Drosophila Tcf and Groucho interact to repress Wingless signaling activity. Nature 395: 604–608, 1998Google Scholar
  121. 121.
    Fisher A, Caudy M: Groucho proteins: transcriptional corepressors for specific subsets of DNA-binding transcription factors in vertebrates and invertebrates. Genes Dev 12: 1931–1940, 1998Google Scholar
  122. 122.
    Roose J, Molenaar M, Peterson J, Hurenkamp J, Brantjes H, Moerer P, van de Wetering M, Destree O, Clevers H: The Xenopus Wnt effector XTcf-3 interacts with Grouchorelated transcriptional repressors. Nature 395: 608–612, 1998Google Scholar
  123. 123.
    Levanon D, Goldstein R, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y: Transcriptional repression by AML-1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc Natl Acad Sci USA 95: 11590–11595, 1998Google Scholar
  124. 124.
    Palaparti A, Baratz A, Stifani S: The Groucho/transducin-like enhancer of split transcriptional repressors interact with the genetically defined amino-terminal silencing domain of histone H3. J Biol Chem 272: 26604–26610, 1997Google Scholar
  125. 125.
    Waltzer L, Bienz M: Drosophila CBP represses the transcription factor TCF to antagonize Wingless signaling. Nature 395: 521–525, 1998Google Scholar
  126. 126.
    Chrivia J, Kwok R, Lamb N, Hagiwara M, Montminy M, Goodman R: Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365: 855–859, 1993Google Scholar
  127. 127.
    Feng XH, Zhang Y, Wu RY, Derynck R: The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for Smad3 in TGF-β-induced transcriptional activation. Genes Dev 12: 2153–2163, 1998Google Scholar
  128. 128.
    Janknecht R, Wells NJ, Hunter T: TGF-β-stimulated cooperation of Smad proteins with the coactivators CBP/p300. Genes Dev 12: 2114–2119, 1998Google Scholar
  129. 129.
    Pouponnot C, Jayaraman L, Massague J: Physical and functional interaction of SMADs and p300/CBP. J Biol Chem 273: 22865–22868, 1998Google Scholar
  130. 130.
    Jacobson S, Pillus L: Modifying chromatin and concepts of cancer. Curr Op Genet Dev 9: 175–184, 1999Google Scholar
  131. 131.
    Munshi N, Merika M, Yie J, Senger K, Chen G, Thanos D: Acetylation of HMG I(Y) by CBP turns off IFN β expression by disrupting the enhanceosome. Mol Cell 2:457–467, 1998Google Scholar
  132. 132.
    Lin R, Thompson S, Priess J: pop-1 encodes an HMG box protein required for the specification of a mesoderm precursor in early C. elegans embryos. Cell 83: 599–609, 1995Google Scholar
  133. 133.
    Thorpe CJ, Schlesinger A, Carter JC, Bowerman B: Wnt signaling polarizes an early C. elegans blastomere to distinguish endoderm from mesoderm. Cell 90: 695–705, 1997Google Scholar
  134. 134.
    Axelrod J, Miller J, Shulman J, Moon R, Perrimon N: Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev 12: 2610–2622, 1998Google Scholar
  135. 135.
    Boutros M, Paricio N, Strutt D, Mlodzik M: Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling. Cell 94: 109–118, 1998Google Scholar
  136. 136.
    Gallet A, Erkner A, Charroux B, Fasano L, Kerridge S: Trunk-specific modulation of wingless signaling in Drosophila by Teashirt binding to Armadillo. Curr Biol 8: 893–902, 1998Google Scholar
  137. 137.
    Gallet A, Angelats C, Erkner A, Charroux B, Fasano L, Kerridge S: The C-terminal domain of Armadillo binds to hypophosphorylated Teashirt to modulate Wingless signaling in Drosophila. EMBO J 18: 2208–2217, 1999Google Scholar
  138. 138.
    Hoppler S, Bienz M: Two different thresholds of wingless signaling with distinct developmental consequences in the Drosophila midgut. EMBO J 14: 5016–5026, 1995Google Scholar
  139. 139.
    Yu X, Riese J, Eresh S, Bienz M: Transcriptional repression due to high levels of Wingless signaling. EMBO J 17: 7021–7032, 1998Google Scholar
  140. 140.
    Kinzler K, Vogelstein B: Lessons from hereditary colorectal cancer. Cell 87: 159–170, 1996Google Scholar
  141. 141.
    Muraoka M, Konishi M, Kikuchi-Yanoshita R, Tanaka K, Shitara N, Chong J, Iwama T, Miyaki M: p300 gene alterations in colorectal and gastric carcinomas. Oncogene 12: 1565–1569, 1996Google Scholar
  142. 142.
    Korinek V, Barker N, Willert K, Molenaar M, Roose J, Wagenaar G, Markman M, Lamers W, Destree O, Clevers H: Two members of the Tcf family implicated in Wnt/β-catenin signaling during embryogenesis in the mouse. Mol Cell Biol 18: 1248–1256, 1998Google Scholar
  143. 143.
    Sparks AB, Morin PJ, Vogelstein B, Kinzler KW: Mutational analysis of the APC/β-catenin/Tcf pathway in colorectal cancer. Cancer Res 58: 1130–1134, 1998Google Scholar
  144. 144.
    Aoki M, Hecht A, Kruse U, Kemler R, Vogt P: Nuclear endpoint of Wnt signaling: neoplastic transformation induced by transactivating lymphoid-enhancing factor 1. Proc Natl Acad Sci USA 96: 139–144, 1999Google Scholar
  145. 145.
    Whitehead I, Kirk H, Kay R: Expression cloning of oncogenes by retroviral transfer of cDNA libraries. Mol Cell Biol 15: 704–710, 1995Google Scholar
  146. 146.
    He T, Sparks A, Rago C, Hermeking H, Zawel L, da Costa L, Morin P, Vogelstein B, Kinzler K: Identification of c-MYC as a target of the APC pathway. Science 281: 1509–1512, 1998Google Scholar
  147. 147.
    Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A: The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 96: 5522–5527, 1999Google Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Lucas Waltzer
    • 1
  • Mariann Bienz
    • 1
  1. 1.MRC Laboratory of Molecular BiologyCambridgeUK

Personalised recommendations