CoChat
Sign Up
Cited by 124Wnt/β-catenin signaling in development and cancerSignaling Pathways in DiseaseDevelopmental Biology and Gene Regulation

Regulation of Tcf7l1 DNA Binding and Protein Stability as Principal Mechanisms of Wnt/β-Catenin Signaling

Open access
Shy, Brian R., Wu, Chun-I., Khramtsova, Galina F., Zhang, Jenny Y., Olopade, Olufunmilayo I., Goss, Kathleen H., Merrill, Bradley J.·2013·Cell Reports
DOI 10.1016/j.celrep.2013.06.001PMC PMC3759994
Open this paper in CoChat — free accountOpen PDF

Abstract

Wnt/β-catenin signal transduction requires direct binding of β-catenin to Tcf/Lef proteins, an event that is classically associated with stimulating transcription by recruiting coactivators. This molecular cascade plays critical roles throughout embryonic development and normal postnatal life by affecting stem cell characteristics and tumor formation. Here, we show that this pathway utilizes a fundamentally different mechanism to regulate Tcf7l1 (formerly named Tcf3) activity. β-catenin inactivates Tcf7l1 without a switch to a coactivator complex by removing it from DNA, which leads to Tcf7l1 protein degradation. Mouse genetic experiments demonstrate that Tcf7l1 inactivation is the only required effect of the Tcf7l1-β-catenin interaction. Given the expression of Tcf7l1 in pluripotent embryonic and adult stem cells, as well as in poorly differentiated breast cancer, these findings provide mechanistic insights into the regulation of pluripotency and the role of Wnt/β-catenin in breast cancer.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2013.06.001

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • TCF7L1 and TCF7L2 may bind to the same motif-TCF7L2 pericentrally for activation and TCF7L1 periportally for repression.

    “this may suggest that TCF7L1 and TCF7L2 bind to the same motif—TCF7L2 pericentrally for activation and TCF7L1 periportally for repression14.”

    From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [14]

    The Introduction and Results report Tcf7l1 acting as a transcriptional repressor, including in DNA-binding-dependent reporter experiments. They do not establish that TCF7L1 and TCF7L2 bind the same motif or assign them periportal and pericentral roles; the reported experiments concern embryonic stem cells and breast cancer cells, not liver zonation. Page numbers are unavailable in our copy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Tcf7l1 and Tcf7l2 may bind to the same motif, with Tcf7l2 acting pericentrally for activation and Tcf7l1 periportally for repression.

    “this may suggest that Tcf7l1 and Tcf7l2 bind to the same motif: Tcf7l2 pericentrally for activation, and Tcf7l1 periportally for repression36.”

    From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [36]

    The Introduction and Results report that Tcf7l1 acts as a transcriptional repressor. The paper does not establish that Tcf7l1 and Tcf7l2 bind the same motif or assign them periportal and pericentral roles, respectively (searched: shared DNA-binding motif, pericentral, periportal). (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 42

  1. Aberle H Bauer A Stappert J Kispert A Kemler R beta-catenin is a target for the ubiquitin-proteasome pathway EMBO J 1997 16 3797 3804 9233789 PMC1170003
  2. Alexander CM Goel S Fakhraldeen SA Kim S Wnt signaling in mammary glands: plastic cell fates and combinatorial signaling Cold Spring Harb. Perspect. Biol 2012 4 PMC3475175 22661590
  3. Ben-Porath I Thomson MW Carey VJ Ge R Bell GW Regev A Weinberg RA An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors Nat. Genet 2008 40 499 507 18443585 PMC2912221
  4. 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 Dev 1997 11 2359 2370 9308964 PMC316518
  5. Cadigan KM Waterman ML TCF/LEFs and Wnt signaling in the nucleus Cold Spring Harb. Perspect. Biol 2012 4 4 PMC3536346 23024173
  6. Cavallo RA Cox RT Moline MM Roose J Polevoy GA Clevers H Peifer M Bejsovec A Drosophila Tcf and Groucho interact to repress Wingless signalling activity Nature 1998 395 604 608 9783586
  7. Daniels DL Weis WI Beta-catenin directly displaces Groucho/ TLE repressors from Tcf/Lef in Wnt-mediated transcription activation Nat. Struct. Mol. Biol 2005 12 364 371 15768032
  8. Filali M Cheng N Abbott D Leontiev V Engelhardt JF Wnt-3A/beta-catenin signaling induces transcription from the LEF-1 promoter J. Biol. Chem 2002 277 33398 33410 12052822
  9. Geyer FC Lacroix-Triki M Savage K Arnedos M Lambros MB MacKay A Natrajan R Reis-Filho JS β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation Mod. Pathol 2011 24 209 231 21076461
  10. Hart M Concordet JP Lassot I Albert I del los Santos R Durand H Perret C Rubinfeld B Margottin F Benarous R Polakis P The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell Curr. Biol 1999 9 207 210 10074433
  11. Hikasa H Sokol SY Phosphorylation of TCF proteins by homeodomain-interacting protein kinase 2 J. Biol. Chem 2011 286 12093 12100 21285352 PMC3069413
  12. Hikasa H Ezan J Itoh K Li X Klymkowsky MW Sokol SY Regulation of TCF3 by Wnt-dependent phosphorylation during vertebrate axis specification Dev. Cell 2010 19 521 532 20951344 PMC2963175
  13. Hoffman JA Wu CI Merrill BJ Tcf7l1 prepares epiblast cells in the gastrulating mouse embryo for lineage specification Development 2013 140 1665 1675 23487311 PMC3621485
  14. 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 Res 2000 28 1994 2003 10756202 PMC103301
  15. Ivanova NB Dimos JT Schaniel C Hackney JA Moore KA Lemischka IR A stem cell molecular signature Science 2002 298 601 604 12228721
  16. Kelly KF Ng DY Jayakumaran G Wood GA Koide H Doble BW β-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF-independent mechanism Cell Stem Cell 2011 8 214 227 21295277 PMC3465368
  17. Khramtsov AI Khramtsova GF Tretiakova M Huo D Olopade OI Goss KH Wnt/beta-catenin pathway activation is enriched in basallike breast cancers and predicts poor outcome Am. J. Pathol 2010 176 2911 2920 20395444 PMC2877852
  18. Lόpez-Knowles E Zardawi SJ McNeil CM Millar EK Crea P Musgrove EA Sutherland RL O’Toole SA Cytoplasmic localization of beta-catenin is a marker of poor outcome in breast cancer patients Cancer Epidemiol. Biomarkers Prev 2010 19 301 309 20056651
  19. Lyashenko N Winter M Migliorini D Biechele T Moon RT Hart-mann C Differential requirement for the dual functions of β-catenin in embryonic stem cell self-renewal and germ layer formation Nat. Cell Biol 2011 13 753 761 21685890 PMC3130149
  20. Merrill BJ Gat U DasGupta R Fuchs E Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin Genes Dev 2001 15 1688 1705 11445543 PMC312726
  21. Merrill BJ Pasolli HA Polak L Rendl M Garcίa-Garcίa MJ Anderson KV Fuchs E Tcf3: a transcriptional regulator of axis induction in the early embryo Development 2004 131 263 274 14668413
  22. Mizuno H Spike BT Wahl GM Levine AJ Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures Proc. Natl. Acad. Sci. USA 2010 107 22745 22750 21149740 PMC3012457
  23. Molenaar M van de Wetering M Oosterwegel M Peterson-Maduro J Godsave S Korinek V Roose J Destrée O Clevers H XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos Cell 1996 86 391 399 8756721
  24. Nusse R Wnt signaling. Cold Spring Harb Perspect. Biol 2012 4 4 PMC3331700 22550232
  25. Nusse R van Ooyen A Cox D Fung YK Varmus H Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15 Nature 1984 307 131 136 6318122
  26. Reiner A Neumeister B Spona J Reiner G Schemper M Jakesz R Immunocytochemical localization of estrogen and progesterone receptor and prognosis in human primary breast cancer Cancer Res 1990 50 7057 7061 2208173
  27. Roose J Molenaar M Peterson J Hurenkamp J Brantjes H Moerer P van de Wetering M Destre´e O Clevers H The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors Nature 1998 395 608 612 9783587
  28. Roose J Huls G van Beest M Moerer P van der Horn K Goldschmeding R Logtenberg T Clevers H Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1 Science 1999 285 1923 1926 10489374
  29. Salomonis N Schlieve CR Pereira L Wahlquist C Colas A Zambon AC Vranizan K Spindler MJ Pico AR Cline MS Alternative splicing regulates mouse embryonic stem cell pluripotency and differentiation Proc. Natl. Acad. Sci. USA 2010 107 10514 10519 20498046 PMC2890851
  30. Slyper M Shahar A Bar-Ziv A Granit RZ Hamburger T Maly B Peretz T Ben-Porath I Control of breast cancer growth and initiation by the stem cell-associated transcription factor TCF3 Cancer Res 2012 72 5613 5624 23090119
  31. Spike BT Engle DD Lin JC Cheung SK La J Wahl GM A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer Cell Stem Cell 2012 10 183 197 22305568 PMC3277444
  32. Staal FJ Burgering BM van de Wetering M Clevers HC Tcf-1-mediated transcription in T lymphocytes: differential role for glycogen synthase kinase-3 in fibroblasts and T cells Int. Immunol 1999 11 317 323 10221643
  33. Stamos JL Weis WI The β-catenin destruction complex Cold Spring Harb. Perspect. Biol 2013 5 a007898 23169527 PMC3579403
  34. Tumbar T Guasch G Greco V Blanpain C Lowry WE Rendl M Fuchs E Defining the epithelial stem cell niche in skin Science 2004 303 359 363 14671312 PMC2405920
  35. Tutter AV Fryer CJ Jones KA Chromatin-specific regulation of LEF-1-beta-catenin transcription activation and inhibition in vitro Genes Dev 2001 15 3342 3354 11751639 PMC312851
  36. van de Wetering M Cavallo R Dooijes D van Beest M van Es J Loureiro J Ypma A Hursh D Jones T Bejsovec A Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF Cell 1997 88 789 799 9118222
  37. Wang Y Medvid R Melton C Jaenisch R Blelloch R DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal Nat. Genet 2007 39 380 385 17259983 PMC3008549
  38. Waterman ML Lymphoid enhancer factor/T cell factor expression in colorectal cancer Cancer Metastasis Rev 2004 23 41 52 15000148
  39. Wray J Kalkan T Gomez-Lopez S Eckardt D Cook A Kemler R Smith A Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation Nat. Cell Biol 2011 13 838 845 21685889 PMC3160487
  40. Wu CI Hoffman JA Shy BR Ford EM Fuchs E Nguyen H Merrill BJ Function of Wnt/β-catenin in counteracting Tcf3 repression through the Tcf3-β-catenin interaction Development 2012a 139 2118 2129 22573616 PMC3357906
  41. Wu ZQ Li XY Hu CY Ford M Kleer CG Weiss SJ Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression Proc. Natl. Acad. Sci. USA 2012b 109 16654 16659 23011797 PMC3478591
  42. Yost C Torres M Miller JR Huang E Kimelman D Moon RT The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3 Genes Dev 1996 10 1443 1454 8666229

Cited by

Sorted by citations

Authors
Shy, B. R., Wu, C.-I., Khramtsova, G. F., Zhang, J. Y., Olopade, O. I., Goss, K. H., & Merrill, B. J.
Affiliations
  • University of Illinois Chicago (US)
  • University of Chicago (US)
Corresponding author
Merrill, Bradley J.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2013-07
Volume
4
Issue
1
Pages
1-9
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2013.06.001
PMC
PMC3759994
OpenAlex
W2001896691
Cited by
124
References
4
Citations by year
2026: 2 · 2025: 6 · 2024: 10 · 2023: 8 · 2022: 4 · 2021: 7 · 2020: 10 · 2019: 12 · 2018: 16 · 2017: 13 · 2016: 8 · 2015: 12 · 2014: 10 · 2013: 6
FWCI
5.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by-nc-nd)
Funders
  • American Cancer Society
  • National Institutes of Health (UL1TR000050)
  • Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston
  • National Cancer Institute (R01CA128571, P50CA125183)
  • National Institute of General Medical Sciences (T32GM079086)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
Wnt/β-catenin signaling, TCF7L1, TCF3, β-catenin, DNA binding, protein stability, protein degradation, transcriptional repression, pluripotency, embryonic stem cells, adult stem cells, breast cancer, stem cell differentiation
MeSH terms
Animals, Chromatin, Humans, Protein Binding, Stem Cells, beta Catenin, Mice, Protein Stability, Transcription Factor 7-Like 1 Protein, Wnt Signaling Pathway, MCF-7 Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review