Journal ArticleDOI
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
Shih Min A Huang,Yuji Mishina,Shanming Liu,Atwood K. Cheung,Frank Stegmeier,Gregory A. Michaud,Olga Charlat,Elizabeth Wiellette,Yue Zhang,Stephanie Wiessner,Marc Hild,Xiaoying Shi,Christine D. Wilson,Craig Mickanin,Vic E. Myer,Aleem Fazal,Ronald Tomlinson,Fabrizio C. Serluca,Wenlin Shao,Hong Cheng,Michael Shultz,Christina Rau,Markus Schirle,Judith Schlegl,Sonja Ghidelli,Stephen Fawell,Chris Lu,Daniel Curtis,Marc W. Kirschner,Christoph Lengauer,Peter Finan,John A. Tallarico,Tewis Bouwmeester,Jeffery A. Porter,Andreas Bauer,Feng Cong +35 more
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TLDR
This study uses a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits β-catenin-mediated transcription and reveals new mechanistic insights into the regulation of axin protein homeostasis, which presents new avenues for targeted Wnt pathway therapies.Abstract:
The stability of the Wnt pathway transcription factor -catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits -catenin-mediated transcription. XAV939 stimulates -catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.read more
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Journal ArticleDOI
Wnt/β-catenin signaling and disease.
Hans Clevers,Roel Nusse +1 more
TL;DR: An update of the core Wnt/β-catenin signaling pathway is provided, how its various components contribute to disease, and outstanding questions to be addressed in the future are discussed.
Journal ArticleDOI
Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.
Roel Nusse,Hans Clevers +1 more
TL;DR: The core Wnt/β-catenin signaling pathway is described, how it controls stem cells, and contributes to disease, and strategies for Wnt-based therapies are discussed.
Journal ArticleDOI
WNT signalling pathways as therapeutic targets in cancer
Jamie N. Anastas,Randall T. Moon +1 more
TL;DR: This work has shown that WNTs and their downstream effectors regulate various processes that are important for cancer progression, including tumour initiation, tumour growth, cell senescence, cell death, differentiation and metastasis, and improved drug-discovery platforms and new technologies have facilitated the discovery of agents that can alter WNT signalling in preclinical models.
Journal ArticleDOI
Wnt signaling in cancer.
TL;DR: Current insights into novel components of Wnt pathways are reviewed and how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control are described.
Journal ArticleDOI
Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
Mary F. Feitosa,Aldi T. Kraja,Daniel I. Chasman,Yun J. Sung,Thomas W. Winkler,Ioanna Ntalla,Xiuqing Guo,Nora Franceschini,Ching-Yu Cheng,Ching-Yu Cheng,Xueling Sim,Dina Vojinovic,Jonathan Marten,Solomon K. Musani,Changwei Li,Amy R. Bentley,Michael R. Brown,Karen Schwander,Melissa A. Richard,Raymond Noordam,Hugues Aschard,Hugues Aschard,Traci M. Bartz,Lawrence F. Bielak,Rajkumar Dorajoo,Virginia Fisher,Fernando Pires Hartwig,Fernando Pires Hartwig,Andrea R. V. R. Horimoto,Kurt Lohman,Alisa K. Manning,Tuomo Rankinen,Albert V. Smith,Salman M. Tajuddin,Mary K. Wojczynski,Maris Alver,Mathilde Boissel,Qiuyin Cai,Archie Campbell,Jin-Fang Chai,Xu Chen,Jasmin Divers,Chuan Gao,Anuj Goel,Yanick Hagemeijer,Sarah E. Harris,Meian He,Fang-Chi Hsu,Anne U. Jackson,Mika Kähönen,Anuradhani Kasturiratne,Pirjo Komulainen,Brigitte Kühnel,Federica Laguzzi,Jian'an Luan,Nana Matoba,Ilja M. Nolte,Sandosh Padmanabhan,Muhammad Riaz,Muhammad Riaz,Rico Rueedi,Antonietta Robino,M. Abdullah Said,Robert A. Scott,Tamar Sofer,Alena Stančáková,Fumihiko Takeuchi,Bamidele O. Tayo,Peter J. van der Most,Tibor V. Varga,Veronique Vitart,Yajuan Wang,Erin B. Ware,Helen R. Warren,Stefan Weiss,Wanqing Wen,Lisa R. Yanek,Weihua Zhang,Weihua Zhang,Jing Hua Zhao,Saima Afaq,Najaf Amin,Marzyeh Amini,Dan E. Arking,Tin Aung,Tin Aung,Eric Boerwinkle,Eric Boerwinkle,Ingrid B. Borecki,Ulrich Broeckel,Morris J. Brown,Marco Brumat,Gregory L. Burke,Mickaël Canouil,Aravinda Chakravarti,Sabanayagam Charumathi,Sabanayagam Charumathi,Yii-Der Ida Chen,John M. C. Connell,Adolfo Correa,Lisa de las Fuentes,Renée de Mutsert,H. Janaka de Silva,Xuan Deng,Jingzhong Ding,Qing Duan,Charles B. Eaton,Georg Ehret,Ruben N. Eppinga,Evangelos Evangelou,Evangelos Evangelou,Jessica D. Faul,Stephan B. Felix,Nita G. Forouhi,Terrence Forrester,Oscar H. Franco,Yechiel Friedlander,Ilaria Gandin,He Gao,Mohsen Ghanbari,Mohsen Ghanbari,Bruna Gigante,C. Charles Gu,Dongfeng Gu,Saskia P. Hagenaars,Göran Hallmans,Tamara B. Harris,Jiang He,Sami Heikkinen,Chew-Kiat Heng,Makoto Hirata,Barbara V. Howard,M. Arfan Ikram,Ulrich John,Tomohiro Katsuya,Chiea Chuen Khor,Chiea Chuen Khor,Tuomas O. Kilpeläinen,Tuomas O. Kilpeläinen,Woon-Puay Koh,José Eduardo Krieger,Stephen B. Kritchevsky,Michiaki Kubo,Johanna Kuusisto,Timo A. Lakka,Carl D. Langefeld,Claudia Langenberg,Lenore J. Launer,Benjamin Lehne,Cora E. Lewis,Yize Li,Shiow Lin,Jianjun Liu,Jianjun Liu,Jingmin Liu,Marie Loh,Marie Loh,Tin Louie,Reedik Mägi,Colin A. McKenzie,Thomas Meitinger,Andres Metspalu,Yuri Milaneschi,Lili Milani,Karen L. Mohlke,Yukihide Momozawa,Mike A. Nalls,Christopher P. Nelson,Christopher P. Nelson,Nona Sotoodehnia,Jill M. Norris,Jeffrey R. O'Connell,Nicholette D. Palmer,Thomas T. Perls,Nancy L. Pedersen,Annette Peters,Patricia A. Peyser,Neil Poulter,Leslie J. Raffel,Olli T. Raitakari,Kathryn Roll,Lynda M. Rose,Frits R. Rosendaal,Jerome I. Rotter,Carsten Oliver Schmidt,Pamela J. Schreiner,Nicole Schupf,William R. Scott,Peter S. Sever,Yuan Shi,Stephen Sidney,Mario Sims,Colleen M. Sitlani,Jennifer A. Smith,Harold Snieder,John M. Starr,Konstantin Strauch,Heather M. Stringham,Nicholas Y.Q. Tan,Hua Tang,Kent D. Taylor,Yik Ying Teo,Yik Ying Teo,Yih Chung Tham,Stephen Turner,André G. Uitterlinden,Peter Vollenweider,Melanie Waldenberger,Lihua Wang,Ya Xing Wang,Wen Bin Wei,Christine Williams,Jie Yao,Caizheng Yu,Jian-Min Yuan,Wei Zhao,Alan B. Zonderman,Diane M. Becker,Michael Boehnke,Donald W. Bowden,John C. Chambers,John C. Chambers,John C. Chambers,Ian J. Deary,Tõnu Esko,Tõnu Esko,Martin Farrall,Paul W. Franks,Paul W. Franks,Barry I. Freedman,Philippe Froguel,Philippe Froguel,Paolo Gasparini,Christian Gieger,Jost B. Jonas,Jost B. Jonas,Yoichiro Kamatani,Norihiro Kato,Jaspal S. Kooner,Jaspal S. Kooner,Zoltán Kutalik,Markku Laakso,Cathy C. Laurie,Karin Leander,Terho Lehtimäki,Patrik K. E. Magnusson,Albertine J. Oldehinkel,Brenda W.J.H. Penninx,Ozren Polasek,Ozren Polasek,David J. Porteous,Rainer Rauramaa,Nilesh J. Samani,Nilesh J. Samani,James Scott,Xiao-Ou Shu,Pim van der Harst,Lynne E. Wagenknecht,Nicholas J. Wareham,Hugh Watkins,David R. Weir,Ananda R. Wickremasinghe,Tangchun Wu,Wei Zheng,Claude Bouchard,Kaare Christensen,Michele K. Evans,Vilmundur Gudnason,Bernardo L. Horta,Sharon L.R. Kardia,Yongmei Liu,Alexandre C. Pereira,Bruce M. Psaty,Bruce M. Psaty,Paul M. Ridker,Rob M. van Dam,W. James Gauderman,Xiaofeng Zhu,Dennis O. Mook-Kanamori,Myriam Fornage,Charles N. Rotimi,L. Adrienne Cupples,L. Adrienne Cupples,Tanika N. Kelly,Ervin R. Fox,Caroline Hayward,Cornelia M. van Duijn,E. Shyong Tai,Tien Yin Wong,Tien Yin Wong,Charles Kooperberg,Walter Palmas,Kenneth Rice,Alanna C. Morrison,Paul Elliott,Mark J. Caulfield,Patricia B. Munroe,Dabeeru C. Rao,Michael A. Province,Daniel Levy +299 more
TL;DR: In insights into the role of alcohol consumption in the genetic architecture of hypertension, a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions is conducted.
References
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Journal ArticleDOI
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Journal ArticleDOI
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Journal ArticleDOI
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Journal ArticleDOI
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Marcus Bantscheff,Dirk Eberhard,Yann Abraham,Sonja Bastuck,Markus Boesche,Scott Hobson,Toby Mathieson,Jessica Perrin,Manfred Raida,Christina Rau,Valerie Reader,Gavain Sweetman,Andreas Bauer,Tewis Bouwmeester,Carsten Hopf,Ulrich Kruse,Gitte Neubauer,Nigel Ramsden,Jens Rick,Bernhard Kuster,Gerard Drewes +20 more
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