DOCSLIB.ORG

Elucidating the Roles of Wnt-Secretion and Β-Catenin's

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Elucidating the Roles of Wnt-Secretion and Β-Catenin's Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Elucidating the roles of Wnt-secretion and ฀-catenin’s interaction partners in development and disease Zimmerli, Dario Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-165192 Dissertation Published Version Originally published at: Zimmerli, Dario. Elucidating the roles of Wnt-secretion and ฀-catenin’s interaction partners in develop- ment and disease. 2018, University of Zurich, Faculty of Science. Elucidating the Roles of Wnt-Secretion and b-Catenin’s Interaction Partners in Development and Disease Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Dario Zimmerli von Oftringen, Aargau Promotionskommission Prof. Dr. Konrad Basler (Vorsitz und Leitung der Dissertation) Prof. Dr. Maries van den BroeK Prof. Dr. Sabine Werner Zürich, 2018 Summary ........................................................................................................................... 3 Zusammenfassung ............................................................................................................ 5 Introduction ...................................................................................................................... 7 Review ............................................................................................................................ 10 Pharmacological interventions in the Wnt pathway: Inhibition of Wnt secretion versus disrupting the protein-protein interfaces of nuclear factors ..................................................... 10 Manuscripts .................................................................................................................... 22 WNT ligands control initiation and progression of human papilloma-virus-driven squamous cell carcinoma ................................................................................................................................ 22 Pax6-dependent, but b-catenin-independent, function of Bcl9 proteins in mouse lens development ............................................................................................................................ 50 Mutations in the Wnt/b-catenin cofactors Bcl9 and Pygo Cause Congenital Heart Malformations ................................................................................................................................................ 58 A regulatory receptor network directs range and output of the Wingless signal ..................... 101 Brief summaries, discussions and outlooks .................................................................... 113 WNT ligands control initiation and progression of human papilloma-virus-driven squamous cell carcinoma .............................................................................................................................. 113 Pax6-dependent, but β-catenin-independent function of Bcl9 proteins in mouse lens development .......................................................................................................................... 115 Mutations in the Wnt/b-catenin cofactors Bcl9 and Pygo Cause Congenital Heart Malformations .............................................................................................................................................. 115 A regulatory receptor network directs the range and output of the Wingless signal ............... 118 Conclusion ..................................................................................................................... 120 Appendix ....................................................................................................................... 122 1 A regulatory receptor network directs the range and output of the Wingless signal ............................................................................................................... 118 Conclusion ........................................................................................................... 120 Appendix ............................................................................................................. 122 β-catenin binding to either C- or N-terminal co-factors alone is sufficient to drive Wnt/β-catenin signaling in hair follicle regeneration ........................................ 122 β-catenin’s signaling function is necessary for HPV-induced cSCC growth ......... 129 Appendix Materials and Methods .................................................................... 133 Bibliography ........................................................................................................ 134 Acknowledgments ............................................................................................... 136 2 Summary The discovery of the connection between Wnt/β-catenin signaling, APC and colon cancer two decades ago created fertile ground for research in the field of Wnt/β-catenin signaling. The hope was that by elucidating all the elements of the cascade, one might discover inhibitors of this pathway that help treating cancer patients. This work has revealed a picture of Wnt/β-catenin signaling’s pivotal involvement in virtually every developmental process as well as in adult tissue homeostasis; moreover, Wnt-signaling is involved in many forms of cancer. Unfortunately, one aspect that also became clear over the years was that targeting the pathway is not a simple matter. Apart from the fact, that inhibition of the pathway is associated with severe side effects due to its crucial role in gut homeostasis, it is also a notoriously difficult cascade to target. This difficulty arises mainly because there are no pathway specific kinases known against which an inhibitor could be developed. Another problematic aspect is the dual role the main pathway effector b-catenin has in transducing the Wnt signal as well as maintaining adherens junctions. Nevertheless, the last years have shown several possible ways to tackle these issues. Besides the discovery of Porcupine inhibitors, which hinder palmitoylation of the Wnt ligands, thereby blocking secretion and shutting down the pathway, the idea to block b-catenin’s interaction with transcriptional co- factors has gained some merit. In this work, we set out to test the advantages and draw- backs of Porcupine inhibitors. Furthermore, we wanted to clarify the tissue specific roles of b-catenin’s transcriptional co-factors with regards to their ability to transduce the signal. This information will be crucial to judge the feasibility of using an inhibitor in a specific setting. Here we show that Porcupine is overexpressed in a murine cutaneous squamous cell carcinoma model (cSCC) model, as well as in human cSCCs. This gave us the incentive to test Porcupine inhibitors in this cSCC model, where we found that this hinders tumor development and reduces the cancer stem cell compartment of established tumors. This leads to increased differentiation and a reduction of markers for tumor invasiveness. 3 In an effort to further characterize the specific roles of b-catenin’s transcriptional co-factors, we used mouse models with specific domain deletions inhibiting the binding of b-catenin to the N-terminal co-factors (Bcl9 and Pygopus) and the co-factors to each other. We found that the integrity of these interactions is specifically needed in the development of the embryonic heart and limbs. Loss of Bcl9-Pygo-b-catenin binding in mouse embryos phenocopies human congenital heart disorders by disrupting a molecular cascade necessary for the correct specification of the heart outflow tract and valves. We thus uncovered a novel role for Wnt/b-catenin signaling in heart development and possibly human congenital heart disorders. 4 Zusammenfassung Die Erkenntnis in den Neunzigerjahren, dass zwischen der Wnt/b-catenin Signalkaskade, APC und Darmkrebs ein Zusammenhang besteht, liess die Forschung im Wnt/b-catenin Gebiet aufleben. Das Ziel dieser Forschungstätigkeit war, durch besseres Verständnis aller Elemente der Signalkaskade neue Inhibitoren zu entdecken, um Darmkrebs zu heilen. Die Studien damals haben gezeigt, dass die Wnt/b-catenin Signalkaskade in praktisch allen entwicklungsbiologischen Schritten als auch in der Gewebehomöostase eine Rolle spielt. Unglücklicherweise wurde auch immer klarer, dass es nicht einfach werden würde diese Signalkaskade zu inhibieren. Abgesehen davon, dass die Inhibition der Kaskade schwere Nebenwirkungen hervorrufen kann wegen der wichtigen Rolle, die die Wnt/b-catenin Signalkaskade in der Homöostase des Darmes spielt, ist es generell eXtrem schwierig diese Kaskade zu inhibieren. Dies kommt vor allem daher, dass keine Kaskaden-spezifischen Kinasen bekannt sind, welche als Ziel eines Inhibitors verwendet werden könnten. Ein anderer sehr problematischer Aspekt der Kaskade ist die Doppelrolle des Haupteffektors b- catenin als Signalgeber sowie als Teil der Adhärenzverbindungen zwischen zwei Zellen. Trotzdem wurden in den letzten Jahren verschiedene Möglichkeiten gezeigt, wie das Problem angegangen werden könnte. Einerseits wäre da die Entdeckung von Porcupine Inhibitoren zu erwähnen, welche die Palmytoylierung der Wnt-Liganden verhindern, was zur kompletten Blockade jeglicher Sekretion der Wnt-Moleküle führt, womit die Kaskade blockiert wird. Des Weiteren wird die Idee in Erwägung gezogen, die Bindung von b-catenin
Load more

Recommended publications
  • Constitutive Scaffolding of Multiple Wnt Enhanceosome Components By
    RESEARCH ARTICLE Constitutive scaffolding of multiple Wnt enhanceosome components by Legless/ BCL9 Laurens M van Tienen, Juliusz Mieszczanek, Marc Fiedler, Trevor J Rutherford, Mariann Bienz* MRC Laboratory of Molecular Biology, Cambridge, United Kingdom Abstract Wnt/b-catenin signaling elicits context-dependent transcription switches that determine normal development and oncogenesis. These are mediated by the Wnt enhanceosome, a multiprotein complex binding to the Pygo chromatin reader and acting through TCF/LEF- responsive enhancers. Pygo renders this complex Wnt-responsive, by capturing b-catenin via the Legless/BCL9 adaptor. We used CRISPR/Cas9 genome engineering of Drosophila legless (lgs) and human BCL9 and B9L to show that the C-terminus downstream of their adaptor elements is crucial for Wnt responses. BioID proximity labeling revealed that BCL9 and B9L, like PYGO2, are constitutive components of the Wnt enhanceosome. Wnt-dependent docking of b-catenin to the enhanceosome apparently causes a rearrangement that apposes the BCL9/B9L C-terminus to TCF. This C-terminus binds to the Groucho/TLE co-repressor, and also to the Chip/LDB1-SSDP enhanceosome core complex via an evolutionary conserved element. An unexpected link between BCL9/B9L, PYGO2 and nuclear co-receptor complexes suggests that these b-catenin co-factors may coordinate Wnt and nuclear hormone responses. DOI: 10.7554/eLife.20882.001 *For correspondence: mb2@mrc- Introduction lmb.cam.ac.uk The Wnt/b-catenin signaling cascade is an ancient cell communication pathway that operates con- Competing interests: The text-dependent transcriptional switches to control animal development and tissue homeostasis authors declare that no (Cadigan and Nusse, 1997).
    [Show full text]
  • Inhibition of Nuclear Wnt Signaling: Challenges of an Elusive Target for Cancer Therapy
    1 Inhibition of Nuclear Wnt Signaling: Challenges of an Elusive Target for Cancer Therapy Yung Lyou1*, Amber N. Habowski2, George T. Chen2, Marian L. Waterman2*. 1University of California Irvine Medical Center, Department of Medicine, Division of Hematology Oncology, 101 The City Drive South, Orange, CA, USA, 92868; 2University of California Irvine, Department of Microbiology and Molecular Genetics, Irvine, CA, USA, 92697. *Co-corresponding authors 2 Abstract The highly conserved Wnt signaling pathway plays an important role in embryonic development and disease pathogenesis, most notably cancer. The “canonical,” or - catenin-dependent Wnt signal initiates at the cell plasma membrane with the binding of Wnt proteins to Frizzled:LRP5/LRP6 receptor complexes, and is mediated by the translocation of the transcription co-activator protein, -catenin, into the nucleus. -catenin then forms a complex with TCF/LEF transcription factors to regulate multiple gene programs. These programs play roles in cell proliferation, migration, vasculogenesis, survival, and metabolism. Mutations in Wnt signaling pathway components that lead to constitutively active Wnt signaling drive aberrant expression of these programs and development of cancer. It has been a longstanding and challenging goal to develop therapies that can interfere with the TCF/LEF--catenin transcriptional complex. This review will focus on the i) structural considerations for targeting the TCF/LEF--catenin and co-regulatory complexes in the nucleus, ii) current molecules that directly target
    [Show full text]
  • The Role of Pygopus 2 in Neural Crest
    The role of Pygopus 2 in Neural Crest KEVIN ROBERT GILLINDER A Thesis submitted for the Degree of Doctor of Philosophy Institute of Genetic Medicine Newcastle University April 2012 Abstract Epidermal neural crest stem cells (EPI-NCSC) are remnants of the embryonic neural crest that reside in a postnatal location, the bulge of rodent and human hair follicles. They are multipotent stem cells and are easily accessible in the hairy skin. They do not form tumours after transplantation, and because they can be expanded in vitro, these cells are promising candidates for autologous transplantation in cell replacement therapy and biomedical engineering. Pygopus 2 (Pygo2) is a signature gene of EPI-NCSC being specifically expressed in embryonic neural crest stem cells (NCSC) and hair follicle-derived EPI-NCSC, but not in other known skin-resident stem cells. Pygo2 is particularly interesting, as it is an important transducer of the Wnt signaling pathway, known to play key roles in the regulation of NCSC migration, proliferation, and differentiation. This study focuses on the role of Pygo2 in the development of the neural crest (NC) in vertebrates during development. Three loss-of-function models were utilized to determine the role Pygo2 in mouse and zebrafish development, and EPI-NCSC ex vivo. A Wnt1-specific loss of Pygo2 in mice causes multi-organ birth defects in multiple NC derived organs. In addition, morpholino (MO) knockdown of pygo homologs within zebrafish leads to NC related craniofacial abnormalities, together with a gastrulation defect during early embryogenesis. While ex vivo studies using EPI-NCSC suggest a role for Pygo2 in cellular proliferation.
    [Show full text]
  • Agricultural University of Athens
    ΓΕΩΠΟΝΙΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΣΧΟΛΗ ΕΠΙΣΤΗΜΩΝ ΤΩΝ ΖΩΩΝ ΤΜΗΜΑ ΕΠΙΣΤΗΜΗΣ ΖΩΙΚΗΣ ΠΑΡΑΓΩΓΗΣ ΕΡΓΑΣΤΗΡΙΟ ΓΕΝΙΚΗΣ ΚΑΙ ΕΙΔΙΚΗΣ ΖΩΟΤΕΧΝΙΑΣ ΔΙΔΑΚΤΟΡΙΚΗ ΔΙΑΤΡΙΒΗ Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων ΕΙΡΗΝΗ Κ. ΤΑΡΣΑΝΗ ΕΠΙΒΛΕΠΩΝ ΚΑΘΗΓΗΤΗΣ: ΑΝΤΩΝΙΟΣ ΚΟΜΙΝΑΚΗΣ ΑΘΗΝΑ 2020 ΔΙΔΑΚΤΟΡΙΚΗ ΔΙΑΤΡΙΒΗ Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων Genome-wide association analysis and gene network analysis for (re)production traits in commercial broilers ΕΙΡΗΝΗ Κ. ΤΑΡΣΑΝΗ ΕΠΙΒΛΕΠΩΝ ΚΑΘΗΓΗΤΗΣ: ΑΝΤΩΝΙΟΣ ΚΟΜΙΝΑΚΗΣ Τριμελής Επιτροπή: Aντώνιος Κομινάκης (Αν. Καθ. ΓΠΑ) Ανδρέας Κράνης (Eρευν. B, Παν. Εδιμβούργου) Αριάδνη Χάγερ (Επ. Καθ. ΓΠΑ) Επταμελής εξεταστική επιτροπή: Aντώνιος Κομινάκης (Αν. Καθ. ΓΠΑ) Ανδρέας Κράνης (Eρευν. B, Παν. Εδιμβούργου) Αριάδνη Χάγερ (Επ. Καθ. ΓΠΑ) Πηνελόπη Μπεμπέλη (Καθ. ΓΠΑ) Δημήτριος Βλαχάκης (Επ. Καθ. ΓΠΑ) Ευάγγελος Ζωίδης (Επ.Καθ. ΓΠΑ) Γεώργιος Θεοδώρου (Επ.Καθ. ΓΠΑ) 2 Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων Περίληψη Σκοπός της παρούσας διδακτορικής διατριβής ήταν ο εντοπισμός γενετικών δεικτών και υποψηφίων γονιδίων που εμπλέκονται στο γενετικό έλεγχο δύο τυπικών πολυγονιδιακών ιδιοτήτων σε κρεοπαραγωγικά ορνίθια. Μία ιδιότητα σχετίζεται με την ανάπτυξη (σωματικό βάρος στις 35 ημέρες, ΣΒ) και η άλλη με την αναπαραγωγική
    [Show full text]
  • Bcl9 and Pygo Synergise Downstream of Apc to Effect Intestinal Neoplasia in FAP Mouse Models
    ARTICLE https://doi.org/10.1038/s41467-018-08164-z OPEN Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models Juliusz Mieszczanek1, Laurens M. van Tienen1, Ashraf E.K. Ibrahim1, Douglas J. Winton2 & Mariann Bienz 1 Bcl9 and Pygo are Wnt enhanceosome components that effect β-catenin-dependent tran- scription. Whether they mediate β-catenin-dependent neoplasia is unclear. Here we assess their roles in intestinal tumourigenesis initiated by Apc loss-of-function (ApcMin), or by 1322T 1234567890():,; Apc encoding a partially-functional Apc truncation commonly found in colorectal carci- nomas. Intestinal deletion of Bcl9 extends disease-free survival in both models, and essen- tially cures Apc1322T mice of their neoplasia. Loss-of-Bcl9 synergises with loss-of-Pygo to shift gene expression within Apc-mutant adenomas from stem cell-like to differentiation along Notch-regulated secretory lineages. Bcl9 loss also promotes tumour retention in ApcMin mice, apparently via relocating nuclear β-catenin to the cell surface, but this undesirable effect is not seen in Apc1322T mice whose Apc truncation retains partial function in regulating β- catenin. Our results demonstrate a key role of the Wnt enhanceosome in β-catenin- dependent intestinal tumourigenesis and reveal the potential of BCL9 as a therapeutic target during early stages of colorectal cancer. 1 MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK. 2 Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre,, Robinson Way, Cambridge CB2 0RE, UK. These authors contributed equally: Juliusz Mieszczanek, Laurens M. van Tienen.
    [Show full text]
  • Supplementary Material Localizing Regions in the Genome
    Supplementary Material Localizing regions in the genome contributing to ADHD, aggressive and antisocial behavior Running title: Genetic overlap between ADHD, aggression and antisocial behavior Mariana Lizbeth Rodríguez López1, Barbara Franke1,2*, Marieke Klein1,3 1 Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands 2 Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Psychiatry, Nijmegen, The Netherlands 3 University Medical Center Utrecht, UMC Utrecht Brain Center, Department of Psychiatry, Utrecht, the Netherlands Supplementary Tables: 5 Supplementary Figures: 2 Supplementary Table 1 | Category traits from LDHub GWAS-ss database. Category Number of traits Aging 3 Anthropometric 22 Autoimmune 11 Bone 5 Brain Volume 7 Cancer 5 Cardiometabolic 2 Cognitive 1 Education 5 Glycemic 8 Haemotological 3 Hormone 2 Kidney 6 Lipids 4 Lung Function 8 Metabolites 107 Metal 2 Neurological 3 Other 1 Personality 4 Psychiatric 11 Reproductive 4 Sleeping 5 Smoking 4 Behaviour Uric Acid 1 Total 234 A list of all categories from all the traits LDHub platform. We performed genetic correlation analyses for all traits with both AGG and ASB, giving a total of 234 rg scores for each one of our two traits. Supplementary Table 2 | Summary of data from GTEx project (https://gtexportal.org/home/). GTEx - Gene expression in 12 brain-related tissues Anterior Caudate Frontal cingulate (basal Cerebellar Cortex Nucleus Substantia
    [Show full text]
  • The Pygo2-H3k4me2/3 Interaction Is Dispensable for Mouse
    RESEARCH ARTICLE 2377 Development 140, 2377-2386 (2013) doi:10.1242/dev.093591 © 2013. Published by The Company of Biologists Ltd The Pygo2-H3K4me2/3 interaction is dispensable for mouse development and Wnt signaling-dependent transcription Claudio Cantù1, Tomas Valenta1, George Hausmann1, Nathalie Vilain2, Michel Aguet2 and Konrad Basler1,* SUMMARY Pygopus has been discovered as a fundamental Wnt signaling component in Drosophila. The mouse genome encodes two Pygopus homologs, Pygo1 and Pygo2. They serve as context-dependent β-catenin coactivators, with Pygo2 playing the more important role. All Pygo proteins share a highly conserved plant homology domain (PHD) that allows them to bind di- and trimethylated lysine 4 of histone H3 (H3K4me2/3). Despite the structural conservation of this domain, the relevance of histone binding for the role of Pygo2 as a Wnt signaling component and as a reader of chromatin modifications remains speculative. Here we generate a knock-in mouse line, homozygous for a Pygo2 mutant defective in chromatin binding. We show that even in the absence of the potentially redundant Pygo1, Pygo2 does not require the H3K4me2/3 binding activity to sustain its function during mouse development. Indeed, during tissue homeostasis, Wnt/β-catenin-dependent transcription is largely unaffected. However, the Pygo2-chromatin interaction is relevant in testes, where, importantly, Pygo2 binds in vivo to the chromatin in a PHD-dependent manner. Its presence on regulatory regions does not affect the transcription of nearby genes; rather, it is important for the recruitment of the histone acetyltransferase Gcn5 to chromatin, consistent with a testis-specific and Wnt-unrelated role for Pygo2 as a chromatin remodeler.
    [Show full text]
  • Pan-Cancer Multi-Omics Analysis and Orthogonal Experimental Assessment of Epigenetic Driver Genes
    Downloaded from genome.cshlp.org on October 9, 2021 - Published by Cold Spring Harbor Laboratory Press Resource Pan-cancer multi-omics analysis and orthogonal experimental assessment of epigenetic driver genes Andrea Halaburkova, Vincent Cahais, Alexei Novoloaca, Mariana Gomes da Silva Araujo, Rita Khoueiry,1 Akram Ghantous,1 and Zdenko Herceg1 Epigenetics Group, International Agency for Research on Cancer (IARC), 69008 Lyon, France The recent identification of recurrently mutated epigenetic regulator genes (ERGs) supports their critical role in tumorigen- esis. We conducted a pan-cancer analysis integrating (epi)genome, transcriptome, and DNA methylome alterations in a cu- rated list of 426 ERGs across 33 cancer types, comprising 10,845 tumor and 730 normal tissues. We found that, in addition to mutations, copy number alterations in ERGs were more frequent than previously anticipated and tightly linked to ex- pression aberrations. Novel bioinformatics approaches, integrating the strengths of various driver prediction and multi- omics algorithms, and an orthogonal in vitro screen (CRISPR-Cas9) targeting all ERGs revealed genes with driver roles with- in and across malignancies and shared driver mechanisms operating across multiple cancer types and hallmarks. This is the largest and most comprehensive analysis thus far; it is also the first experimental effort to specifically identify ERG drivers (epidrivers) and characterize their deregulation and functional impact in oncogenic processes. [Supplemental material is available for this article.] Although it has long been known that human cancers harbor both gression, potentially acting as oncogenes or tumor suppressors genetic and epigenetic changes, with an intricate interplay be- (Plass et al. 2013; Vogelstein et al. 2013).
    [Show full text]
  • Mutations in Bcl9 and Pygo Genes Cause Congenital Heart Defects by Tissue-Specific Perturbation of Wnt/Β-Catenin Signaling
    bioRxiv preprint doi: https://doi.org/10.1101/249680; this version posted January 17, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/-catenin signaling Claudio Cantù1,†, Anastasia Felker1,†, Dario Zimmerli1,†, Elena Chiavacci1, Elena María Cabello1, Lucia Kirchgeorg1, Tomas Valenta1, George Hausmann1, Jorge Ripoll2, Natalie Vilain3, Michel Aguet3, Konrad Basler1,*, Christian Mosimann1,* 1 Institute of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland. 2 Department of Bioengineering and Aerospace Engineering, Universidad Carlos III de Madrid, 28911 Madrid, Spain. 3 Swiss Institute for Experimental Cancer Research (ISREC), École Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland. † contributed equally to this work * correspondence to: [email protected]; [email protected] Abstract Genetic alterations in human BCL9 genes have repeatedly been found in congenital heart disease (CHD) with as-of-yet unclear causality. BCL9 proteins and their Pygopus (Pygo) co-factors can participate in canonical Wnt signaling via binding to β-catenin. Nonetheless, their contributions to vertebrate heart development remain uncharted. Here, combining zebrafish and mouse genetics, we document tissue- specific functions in canonical Wnt signaling for BCL9 and Pygo proteins during heart development. In a CRISPR-Cas9-based genotype-phenotype association screen, we uncovered that zebrafish mutants for bcl9 and pygo genes largely retain β-catenin activity, yet develop cardiac malformations.
    [Show full text]
  • Identification of Small Molecule Inhibitors Targeting Truncated
    IDENTIFICATION OF SMALL MOLECULE INHIBITORS TARGETING TRUNCATED ADENOMATOUS POLYPOSIS COLI (APC) AS A NOVEL THERAPEUTIC STRATEGY IN COLORECTAL CANCER APPROVED BY SUPERVISORY COMMITTEE Jerry W. Shay, Ph.D., Mentor Woodring E. Wright, M.D., Ph.D., Mentor Ralph Deberardinis, M.D., Ph.D., Chair Michael Roth, Ph.D. Michael White, Ph.D. ACKNOWLEDGMENTS I would like to express my deepest gratitude to my mentors Dr. Jerry Shay and Dr. Woodring Wright, for their support, encouragement, valuable guidance and instrumental criticism throughout my graduate study. Thank you for sharing your knowledge with me and providing me a strong foundation for my future career as a research scientist. I would like to thank my thesis committee members, Dr. Ralph Deberardinis, Dr. Michael Roth and Dr. Michael White for their invaluable suggestions and constructive feedbacks. I would also like to thank all the current and former lab members of the Shay/Wright lab. In particular, I would like to thank my colleagues Dr. Sang Bum Kim, Dr. Ugur Eskiocak and Dr. Guido Stadler for their experimental guidance and assistance. Likewise, thanks to Sze Wong, Ilgen Mender, Ejun Huang and Gaoxiang Jia for their kind friendship and encouragement. Special thanks to Kevin Kennon for his administrative support. Finally, I would like to thank my parents, Jie Wang and Bin Zhang, and my husband Wenhao Chen for their unconditional support, encouragement and everlasting love. Thank you for being with me every step throughout my life. IDENTIFICATION OF SMALL MOLECULE INHIBITORS TARGETING
    [Show full text]
  • Functional in Vivo Screen Identifies Pygo2 As a Putative Gene to Promote Prostate Cancer
    The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 5-2015 FUNCTIONAL IN VIVO SCREEN IDENTIFIES PYGO2 AS A PUTATIVE GENE TO PROMOTE PROSTATE CANCER Xiaolu Pan Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Medicine and Health Sciences Commons Recommended Citation Pan, Xiaolu, "FUNCTIONAL IN VIVO SCREEN IDENTIFIES PYGO2 AS A PUTATIVE GENE TO PROMOTE PROSTATE CANCER" (2015). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 587. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/587 This Thesis (MS) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. FUNCTIONAL IN VIVO SCREEN IDENTIFIES PYGO2 AS A PUTATIVE GENE TO PROMOTE PROSTATE CANCER by Xiaolu Pan, MB APPROVED: ______________________________ Ronald DePinho, MD Advisory Professor ______________________________
    [Show full text]
  • Nuclear Regulation of Wnt/-Catenin Signaling
    G C A T T A C G G C A T genes Review Nuclear Regulation of Wnt/β-Catenin Signaling: It’s a Complex Situation Christin C. Anthony 1 , David J. Robbins 2, Yashi Ahmed 3 and Ethan Lee 1,4,* 1 Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; [email protected] 2 Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; [email protected] 3 Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755, USA; [email protected] 4 Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA * Correspondence: [email protected] Received: 14 July 2020; Accepted: 31 July 2020; Published: 4 August 2020 Abstract: Wnt signaling is an evolutionarily conserved metazoan cell communication pathway required for proper animal development. Of the myriad of signaling events that have been ascribed to cellular activation by Wnt ligands, the canonical Wnt/β-catenin pathway has been the most studied and best understood. Misregulation of Wnt/β-catenin signaling has been implicated in developmental defects in the embryo and major diseases in the adult. Despite the latter, no drugs that inhibit the Wnt/β-catenin pathway have been approved by the FDA. In this review, we explore the least understood step in the Wnt/β-catenin pathway—nuclear regulation of Wnt target gene transcription. We initially describe our current understanding of the importation of β-catenin into the nucleus.
    [Show full text]