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  1. Article ; Online: SOX9 and TCF transcription factors associate to mediate Wnt/β-catenin target gene activation in colorectal cancer.

    Ramakrishnan, Aravinda-Bharathi / Burby, Peter E / Adiga, Kavya / Cadigan, Ken M

    The Journal of biological chemistry

    2022  Volume 299, Issue 1, Page(s) 102735

    Abstract: Activation of the Wnt/β-catenin pathway regulates gene expression by promoting the formation of a β-catenin-T-cell factor (TCF) complex on target enhancers. In addition to TCFs, other transcription factors interact with the Wnt/β-catenin pathway at ... ...

    Abstract Activation of the Wnt/β-catenin pathway regulates gene expression by promoting the formation of a β-catenin-T-cell factor (TCF) complex on target enhancers. In addition to TCFs, other transcription factors interact with the Wnt/β-catenin pathway at different levels to produce tissue-specific patterns of Wnt target gene expression. The transcription factor SOX9 potently represses many Wnt target genes by downregulating β-catenin protein levels. Here, we find using colony formation and cell growth assays that SOX9 surprisingly promotes the proliferation of Wnt-driven colorectal cancer (CRC) cells. In contrast to how it indirectly represses Wnt targets, SOX9 directly co-occupies and activates multiple Wnt-responsive enhancers in CRC cells. Our examination of the binding site grammar of these enhancers shows the presence of TCF and SOX9 binding sites that are necessary for transcriptional activation. In addition, we identify a physical interaction between the DNA-binding domains of TCFs and SOX9 and show that TCF-SOX9 interactions are important for target gene regulation and CRC cell growth. Our work demonstrates a highly context-dependent effect of SOX9 on Wnt targets, with the presence or absence of SOX9-binding sites on Wnt-regulated enhancers determining whether they are directly activated or indirectly repressed by SOX9.
    MeSH term(s) Humans ; beta Catenin/genetics ; beta Catenin/metabolism ; Colorectal Neoplasms/genetics ; SOX9 Transcription Factor/genetics ; SOX9 Transcription Factor/metabolism ; TCF Transcription Factors/metabolism ; Transcriptional Activation ; Wnt Signaling Pathway
    Chemical Substances beta Catenin ; SOX9 protein, human ; SOX9 Transcription Factor ; TCF Transcription Factors
    Language English
    Publishing date 2022-11-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.102735
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Diffusion and function of Wnt ligands.

    Stewart, Richard A / Ramakrishnan, Aravinda-Bharathi / Cadigan, Ken M

    PLoS genetics

    2019  Volume 15, Issue 6, Page(s) e1008154

    MeSH term(s) Intestines ; Ligands ; Wnt Proteins
    Chemical Substances Ligands ; Wnt Proteins
    Language English
    Publishing date 2019-06-13
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1008154
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif.

    Ramakrishnan, Aravinda-Bharathi / Chen, Lisheng / Burby, Peter E / Cadigan, Ken M

    Nucleic acids research

    2021  Volume 49, Issue 15, Page(s) 8625–8641

    Abstract: Transcriptional regulation by Wnt signalling is primarily thought to be accomplished by a complex of β-catenin and TCF family transcription factors (TFs). Although numerous studies have suggested that additional TFs play roles in regulating Wnt target ... ...

    Abstract Transcriptional regulation by Wnt signalling is primarily thought to be accomplished by a complex of β-catenin and TCF family transcription factors (TFs). Although numerous studies have suggested that additional TFs play roles in regulating Wnt target genes, their mechanisms of action have not been investigated in detail. We characterised a Wnt-responsive element (WRE) downstream of the Wnt target gene Axin2 and found that TCFs and Caudal type homeobox (CDX) proteins were required for its activation. Using a new separation-of-function TCF mutant, we found that WRE activity requires the formation of a TCF/CDX complex. Our systematic mutagenesis of this enhancer identified other sequences essential for activation by Wnt signalling, including several copies of a novel CAG DNA motif. Computational and experimental evidence indicates that the TCF/CDX/CAG mode of regulation is prevalent in multiple WREs. Put together, our results demonstrate the complex nature of cis- and trans- interactions required for signal-dependent enhancer activity.
    MeSH term(s) Axin Protein/genetics ; Binding Sites ; DNA/chemistry ; Enhancer Elements, Genetic ; Gene Expression Regulation ; HEK293 Cells ; HeLa Cells ; Homeodomain Proteins/metabolism ; Humans ; Nucleotide Motifs ; Proto-Oncogene Proteins c-myc/genetics ; TCF Transcription Factors/metabolism ; Transcription Factor 7-Like 2 Protein/metabolism ; Wnt Signaling Pathway
    Chemical Substances AXIN2 protein, human ; Axin Protein ; Homeodomain Proteins ; Proto-Oncogene Proteins c-myc ; TCF Transcription Factors ; Transcription Factor 7-Like 2 Protein ; DNA (9007-49-2)
    Language English
    Publishing date 2021-08-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkab657
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
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  4. Article ; Online: The matrix protein Tiggrin regulates plasmatocyte maturation in

    Zhang, Chen U / Cadigan, Ken M

    Development (Cambridge, England)

    2017  Volume 144, Issue 13, Page(s) 2415–2427

    Abstract: The lymph gland (LG) is a major source of hematopoiesis ... ...

    Abstract The lymph gland (LG) is a major source of hematopoiesis during
    MeSH term(s) Animals ; Cell Differentiation ; Cell Lineage ; Clone Cells ; Drosophila Proteins/chemistry ; Drosophila Proteins/metabolism ; Drosophila melanogaster/cytology ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Extracellular Matrix/metabolism ; Extracellular Matrix Proteins/chemistry ; Extracellular Matrix Proteins/metabolism ; Gene Expression Regulation, Developmental ; Genes, Reporter ; Larva/cytology ; Larva/metabolism ; Lymphoid Tissue/cytology ; Lymphoid Tissue/metabolism ; Models, Biological ; Mutation/genetics ; Protein Binding ; Protein Domains ; Stem Cells/cytology ; Stem Cells/metabolism ; Transcription, Genetic
    Chemical Substances Drosophila Proteins ; Extracellular Matrix Proteins ; Tig protein, Drosophila
    Language English
    Publishing date 2017--01
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 90607-4
    ISSN 1477-9129 ; 0950-1991
    ISSN (online) 1477-9129
    ISSN 0950-1991
    DOI 10.1242/dev.149641
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Wnt target genes and where to find them.

    Ramakrishnan, Aravinda-Bharathi / Cadigan, Ken M

    F1000Research

    2017  Volume 6, Page(s) 746

    Abstract: Wnt/β-catenin signaling is highly conserved throughout metazoans, is required for numerous essential events in development, and serves as a stem cell niche signal in many contexts. Misregulation of the pathway is linked to several human pathologies, most ...

    Abstract Wnt/β-catenin signaling is highly conserved throughout metazoans, is required for numerous essential events in development, and serves as a stem cell niche signal in many contexts. Misregulation of the pathway is linked to several human pathologies, most notably cancer. Wnt stimulation results in stabilization and nuclear import of β-catenin, which then acts as a transcriptional co-activator. Transcription factors of the T-cell family (TCF) are the best-characterized nuclear binding partners of β-catenin and mediators of Wnt gene regulation. This review provides an update on what is known about the transcriptional activation of Wnt target genes, highlighting recent work that modifies the conventional model. Wnt/β-catenin signaling regulates genes in a highly context-dependent manner, and the role of other signaling pathways and TCF co-factors in this process will be discussed. Understanding Wnt gene regulation has served to elucidate many biological roles of the pathway, and we will use examples from stem cell biology, metabolism, and evolution to illustrate some of the rich Wnt biology that has been uncovered.
    Language English
    Publishing date 2017
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2699932-8
    ISSN 2046-1402
    ISSN 2046-1402
    DOI 10.12688/f1000research.11034.1
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  6. Article ; Online: TCFs and Wnt/β-catenin signaling: more than one way to throw the switch.

    Cadigan, Ken M

    Current topics in developmental biology

    2012  Volume 98, Page(s) 1–34

    Abstract: Wnts are conserved, secreted signaling proteins that can influence cell behavior by stabilizing β-catenin. Accumulated β-catenin enters the nucleus, where it physically associates with T-cell factor (TCF) family members to regulate target gene expression ...

    Abstract Wnts are conserved, secreted signaling proteins that can influence cell behavior by stabilizing β-catenin. Accumulated β-catenin enters the nucleus, where it physically associates with T-cell factor (TCF) family members to regulate target gene expression in many developmental and adult tissues. Recruitment of β-catenin to Wnt response element (WRE) chromatin converts TCFs from transcriptional repressors to activators. This review will outline the complex interplay between factors contributing to TCF repression and coactivators working with β-catenin to regulate Wnt targets. In addition, three variations of the standard transcriptional switch model will be discussed. One is the Wnt/β-catenin symmetry pathway in Caenorhabditis elegans, where Wnt-mediated nuclear efflux of TCF is crucial for activation of targets. Another occurs in vertebrates, where distinct TCF family members are associated with repression and activation, and recent evidence suggests that Wnt signaling facilitates a "TCF exchange" on WRE chromatin. Finally, a "reverse switch" mechanism for target genes that are directly repressed by Wnt/β-catenin signaling occurs in Drosophila cells. The diversity of TCF regulatory mechanisms may help to explain how a small group of transcription factors can function in so many different contexts to regulate target gene expression.
    MeSH term(s) Animals ; Gene Expression Regulation, Developmental ; Humans ; Signal Transduction ; TCF Transcription Factors/metabolism ; Transcriptional Activation ; Wnt Proteins/metabolism ; beta Catenin/metabolism
    Chemical Substances TCF Transcription Factors ; Wnt Proteins ; beta Catenin
    Language English
    Publishing date 2012
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ISSN 1557-8933 ; 0070-2153
    ISSN (online) 1557-8933
    ISSN 0070-2153
    DOI 10.1016/B978-0-12-386499-4.00001-X
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  7. Article: The Role of the C-Clamp in Wnt-Related Colorectal Cancers.

    Ravindranath, Aditi J / Cadigan, Ken M

    Cancers

    2016  Volume 8, Issue 8

    Abstract: T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) transcription factors are major regulators of Wnt targets, and the products of the TCF7 and TCF7L2 genes have both been implicated in the progression of colorectal cancer in animal models and humans. TCFs ... ...

    Abstract T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) transcription factors are major regulators of Wnt targets, and the products of the TCF7 and TCF7L2 genes have both been implicated in the progression of colorectal cancer in animal models and humans. TCFs recognize specific DNA sequences through their high mobility group (HMG) domains, but invertebrate TCFs and some isoforms of vertebrate TCF7 and TCF7L2 contain a second DNA binding domain known as the C-clamp. This review will cover the basic properties of C-clamps and their importance in Wnt signaling, using data from Drosophila, C. elegans, and mammalian cell culture. The connection between C-clamp containing TCFs and colorectal cancer will also be discussed.
    Language English
    Publishing date 2016-08-03
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers8080074
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  8. Article ; Online: Repression of Wnt/β-catenin signaling by SOX9 and Mastermind-like transcriptional coactivator 2.

    Sinha, Abhishek / Fan, Vinson B / Ramakrishnan, Aravinda-Bharathi / Engelhardt, Nicole / Kennell, Jennifer / Cadigan, Ken M

    Science advances

    2021  Volume 7, Issue 8

    Abstract: Wnt/β-catenin signaling requires inhibition of a multiprotein destruction complex that targets β-catenin for proteasomal degradation. SOX9 is a potent antagonist of the Wnt pathway and has been proposed to act through direct binding to β-catenin or the β- ...

    Abstract Wnt/β-catenin signaling requires inhibition of a multiprotein destruction complex that targets β-catenin for proteasomal degradation. SOX9 is a potent antagonist of the Wnt pathway and has been proposed to act through direct binding to β-catenin or the β-catenin destruction complex. Here, we demonstrate that SOX9 promotes turnover of β-catenin in mammalian cell culture, but this occurs independently of the destruction complex and the proteasome. This activity requires SOX9's ability to activate transcription. Transcriptome analysis revealed that SOX9 induces the expression of the Notch coactivator Mastermind-like transcriptional activator 2 (MAML2), which is required for SOX9-dependent Wnt/β-catenin antagonism. MAML2 promotes β-catenin turnover independently of Notch signaling, and MAML2 appears to associate directly with β-catenin in an in vitro binding assay. This work defines a previously unidentified pathway that promotes β-catenin degradation, acting in parallel to established mechanisms. SOX9 uses this pathway to restrict Wnt/β-catenin signaling.
    MeSH term(s) Animals ; Mammals/metabolism ; Proteasome Endopeptidase Complex/metabolism ; SOX9 Transcription Factor/genetics ; Wnt Signaling Pathway ; beta Catenin/genetics ; beta Catenin/metabolism
    Chemical Substances SOX9 Transcription Factor ; beta Catenin ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2021-02-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abe0849
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  9. Article ; Online: Receptor endocytosis: Frizzled joins the ubiquitin club.

    Cadigan, Ken M

    The EMBO journal

    2010  Volume 29, Issue 13, Page(s) 2099–2100

    MeSH term(s) Animals ; Frizzled Receptors/metabolism ; Ubiquitin Thiolesterase/metabolism ; Ubiquitination ; Wnt Proteins/metabolism
    Chemical Substances Frizzled Receptors ; Wnt Proteins ; Ubiquitin Thiolesterase (EC 3.4.19.12)
    Language English
    Publishing date 2010-07-07
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.1038/emboj.2010.132
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  10. Article: Wnt-beta-catenin signaling.

    Cadigan, Ken M

    Current biology : CB

    2008  Volume 18, Issue 20, Page(s) R943–7

    MeSH term(s) Active Transport, Cell Nucleus ; Animals ; Cell Communication ; Cell Nucleus/metabolism ; Gene Expression Regulation ; Protein Sorting Signals ; Signal Transduction ; Transcription, Genetic ; Wnt Proteins/genetics ; Wnt Proteins/metabolism ; Wnt Proteins/secretion ; beta Catenin/genetics ; beta Catenin/metabolism
    Chemical Substances Protein Sorting Signals ; Wnt Proteins ; beta Catenin
    Language English
    Publishing date 2008-10-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 1071731-6
    ISSN 1879-0445 ; 0960-9822
    ISSN (online) 1879-0445
    ISSN 0960-9822
    DOI 10.1016/j.cub.2008.08.017
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