Crystal Structure of a Tankyrase-Axin Complex and Its Implications for Axin Turnover and Tankyrase Substrate Recruitment
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Rat Anti-TERF1 Monoclonal Antibody, Clone 683D (CABT-RM172) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
Rat Anti-TERF1 monoclonal antibody, clone 683D (CABT-RM172) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Specificity Specifically detects murine Telomeric repeat-binding factor 1 (TRF1). Target TERF1 Immunogen His-tagged full-length recombinant mouse Telomeric repeat-binding factor 1 (TRF1). Isotype IgG1, κ Source/Host Rat Species Reactivity Mouse Clone 683D Purification Protein G purified Conjugate unconjugated Applications FC, ICC, IF, WB Molecular Weight ~51 kDa observed; 48.22 kDa calculated. Uncharacterized bands may be observed in some lysate(s). Format Liquid Size 100 μg, 25 μg Buffer 0.1 M Tris-Glycine (pH 7.4), 150 mM NaCl Preservative 0.05% sodium azide Storage Stable for 1 year at 2-8°C from date of receipt. Warnings Unless otherwise stated in our catalog or other company documentation accompanying the product(s), our products are intended for research use only and are not to be used for any other purpose, which includes but is not limited to, unauthorized commercial uses, in vitro diagnostic uses, ex vivo or in vivo therapeutic uses or any type of consumption or application to humans or animals. 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 1 © Creative Diagnostics All Rights Reserved BACKGROUND Introduction Telomeric repeat-binding factor 1 is encoded by the Terf1 gene in murine species. TRF1 is a component of the shelterin complex that is involved in the regulation of telomere length and protection. It binds to telomeric DNA as a homodimer and protects telomeres. -
Whole Proteome Analysis of Human Tankyrase Knockout Cells Reveals Targets of Tankyrase- Mediated Degradation
ARTICLE DOI: 10.1038/s41467-017-02363-w OPEN Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase- mediated degradation Amit Bhardwaj1, Yanling Yang2, Beatrix Ueberheide2 & Susan Smith1 Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that function in pathways critical to cancer cell growth. Tankyrase-mediated PARylation marks protein targets for proteasomal 1234567890 degradation. Here, we generate human knockout cell lines to examine cell function and interrogate the proteome. We show that either tankyrase 1 or 2 is sufficient to maintain telomere length, but both are required to resolve telomere cohesion and maintain mitotic spindle integrity. Quantitative analysis of the proteome of tankyrase double knockout cells using isobaric tandem mass tags reveals targets of degradation, including antagonists of the Wnt/β-catenin signaling pathway (NKD1, NKD2, and HectD1) and three (Notch 1, 2, and 3) of the four Notch receptors. We show that tankyrases are required for Notch2 to exit the plasma membrane and enter the nucleus to activate transcription. Considering that Notch signaling is commonly activated in cancer, tankyrase inhibitors may have therapeutic potential in targeting this pathway. 1 Kimmel Center for Biology and Medicine at the Skirball Institute, Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. 2 Proteomics Laboratory, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. Correspondence and requests for materials should be addressed to S.S. (email: [email protected]) NATURE COMMUNICATIONS | 8: 2214 | DOI: 10.1038/s41467-017-02363-w | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-017-02363-w ankyrases function in cellular pathways that are critical to function in human cells will provide insights into the clinical cancer cell growth including telomere cohesion and length utility of tankyrase inhibitors. -
Mayer-Rokitansky-Küster- Hauser Syndrome
Morcel et al. Orphanet Journal of Rare Diseases 2011, 6:9 http://www.ojrd.com/content/6/1/9 RESEARCH Open Access Utero-vaginal aplasia (Mayer-Rokitansky-Küster- Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge-like loci Karine Morcel1,2*†, Tanguy Watrin1†, Laurent Pasquier1,3, Lucie Rochard1, Cédric Le Caignec4,5, Christèle Dubourg1,6, Philippe Loget7, Bernard-Jean Paniel8, Sylvie Odent1,3, Véronique David1,6, Isabelle Pellerin1, Claude Bendavid1,6 and Daniel Guerrier1 Abstract Background: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. The uterovaginal aplasia is either isolated (type I) or more frequently associated with other malformations (type II or Müllerian Renal Cervico-thoracic Somite (MURCS) association), some of which belong to the malformation spectrum of DiGeorge phenotype (DGS). Its etiology remains poorly understood. Thus the phenotypic manifestations of MRKH and DGS overlap suggesting a possible genetic link. This would potentially have clinical consequences. Methods: We searched DiGeorge critical chromosomal regions for chromosomal anomalies in a cohort of 57 subjects with uterovaginal aplasia (55 women and 2 aborted fetuses). For this candidate locus approach, we used a multiplex ligation-dependent probe amplification (MLPA) assay based on a kit designed for investigation of the chromosomal regions known to be involved in DGS. The deletions detected were validated by Duplex PCR/liquid chromatography (DP/LC) and/or array-CGH analysis. Results: We found deletions in four probands within the four chromosomal loci 4q34-qter, 8p23.1, 10p14 and 22q11.2 implicated in almost all cases of DGS syndrome. -
APC Mutations As a Potential Biomarker for Sensitivity To
Published OnlineFirst February 8, 2017; DOI: 10.1158/1535-7163.MCT-16-0578 Companion Diagnostics and Cancer Biomarkers Molecular Cancer Therapeutics APC Mutations as a Potential Biomarker for Sensitivity to Tankyrase Inhibitors in Colorectal Cancer Noritaka Tanaka1,2, Tetsuo Mashima1, Anna Mizutani1, Ayana Sato1,3, Aki Aoyama3,4, Bo Gong3,4, Haruka Yoshida1, Yukiko Muramatsu1, Kento Nakata1,5, Masaaki Matsuura6, Ryohei Katayama4, Satoshi Nagayama7, Naoya Fujita3,4,5, Yoshikazu Sugimoto2, and Hiroyuki Seimiya1,3,5 Abstract In most colorectal cancers, Wnt/b-catenin signaling is acti- "short" truncated APCs lacking all seven b-catenin-binding vated by loss-of-function mutations in the adenomatous polyposis 20-amino acid repeats (20-AARs). In contrast, the drug-resistant coli (APC) gene and plays a critical role in tumorigenesis. cells possessed "long" APC retaining two or more 20-AARs. Knock- Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a neg- down of the long APCs with two 20-AARs increased b-catenin, ative regulator of b-catenin, and upregulate b-catenin signaling. Tcf/LEF transcriptional activity and its target gene AXIN2 expres- Tankyrase inhibitors downregulate b-catenin and are expected sion. Under these conditions, tankyrase inhibitors were able to to be promising therapeutics for colorectal cancer. However, downregulate b-catenin in the resistant cells. These results indicate colorectal cancer cells are not always sensitive to tankyrase that the long APCs are hypomorphic mutants, whereas they exert inhibitors, and predictive biomarkers for the drug sensitivity a dominant-negative effect on Axin-dependent b-catenin degra- remain elusive. Here we demonstrate that the short-form APC dation caused by tankyrase inhibitors. -
Discovery of a Novel Triazolopyridine Derivative As a Tankyrase Inhibitor
International Journal of Molecular Sciences Article Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor Hwani Ryu 1, Ky-Youb Nam 2, Hyo Jeong Kim 1, Jie-Young Song 1 , Sang-Gu Hwang 1 , Jae Sung Kim 1 , Joon Kim 3,* and Jiyeon Ahn 1,* 1 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; [email protected] (H.R.); [email protected] (H.J.K.); [email protected] (J.-Y.S.); [email protected] (S.-G.H.); [email protected] (J.S.K.) 2 Department of Research Center, Pharos I&BT Co., Ltd., Anyang 14059, Korea; [email protected] 3 Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul 02841, Korea * Correspondence: [email protected] (J.K.); [email protected] (J.A.); Tel.: +82-2-970-1311 (J.A.) Abstract: More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/β-catenin activation. Tankyrase (TNKS) mediates the release of active β-catenin, which occurs regardless of the ligand that translocates into the nucleus by AXIN degradation via the ubiquitin-proteasome pathway. Therefore, TNKS inhibition has emerged as an attractive strategy for cancer therapy. In this study, we identified pyridine derivatives by evaluating in vitro TNKS enzyme activity and investigated N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2- cyanophenyl)piperidine-4-carboxamide (TI-12403) as a novel TNKS inhibitor. TI-12403 stabilized β β AXIN2, reduced active -catenin, and downregulated -catenin target genes in COLO320DM and DLD-1 cells. -
Structural Basis and Sequence Rules for Substrate Recognition by Tankyrase Explain the Basis for Cherubism Disease
Structural Basis and Sequence Rules for Substrate Recognition by Tankyrase Explain the Basis for Cherubism Disease Sebastian Guettler,1,2 Jose LaRose,3 Evangelia Petsalaki,1,2 Gerald Gish,1 Andy Scotter,3 Tony Pawson,1,2,* Robert Rottapel,3,4,* and Frank Sicheri1,2,* 1Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada 2Department of Molecular Genetics, University of Toronto, 1 Kings College Circle, Toronto, Ontario M5S 1A8, Canada 3Ontario Cancer Institute and the Campbell Family Cancer Research Institute, 101 College Street, Room 8-703, Toronto Medical Discovery Tower, University of Toronto, Toronto, Ontario M5G 1L7, Canada 4Division of Rheumatology, Department of Medicine, Saint Michael’s Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada *Correspondence: [email protected] (T.P.), [email protected] (R.R.), [email protected] (F.S.) DOI 10.1016/j.cell.2011.10.046 SUMMARY asparagine, arginine, lysine, cysteine, phosphoserine, and diph- thamide residues (reviewed in Hottiger et al., 2010). As a large The poly(ADP-ribose)polymerases Tankyrase 1/2 posttranslational modification of substantial negative charge, (TNKS/TNKS2) catalyze the covalent linkage of protein poly(ADP-ribosyl)ation (PARsylation) can influence pro- ADP-ribose polymer chains onto target proteins, tein fate through several mechanisms, including a direct effect regulating their ubiquitylation, stability, and function. on protein activity, recruitment of binding partners -
ADP-Ribosyl)Hydrolases: Structure, Function, and Biology
Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press SPECIAL SECTION: REVIEW (ADP-ribosyl)hydrolases: structure, function, and biology Johannes Gregor Matthias Rack,1,3 Luca Palazzo,2,3 and Ivan Ahel1 1Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; 2Institute for the Experimental Endocrinology and Oncology, National Research Council of Italy, 80145 Naples, Italy ADP-ribosylation is an intricate and versatile posttransla- Diversification of NAD+ signaling is particularly apparent tional modification involved in the regulation of a vast in vertebrata, being linked to evolutionary optimization of variety of cellular processes in all kingdoms of life. Its NAD+ biosynthesis and increased (ADP-ribosyl) signaling complexity derives from the varied range of different (Bockwoldt et al. 2019). ADP-ribosylation is used by or- chemical linkages, including to several amino acid side ganisms from all kingdoms of life and some viruses chains as well as nucleic acids termini and bases, it can (Perina et al. 2014; Aravind et al. 2015) and controls a adopt. In this review, we provide an overview of the differ- wide range of cellular processes such as DNA repair, tran- ent families of (ADP-ribosyl)hydrolases. We discuss their scription, cell division, protein degradation, and stress re- molecular functions, physiological roles, and influence sponse to name a few (Bock and Chang 2016; Gupte et al. on human health and disease. Together, the accumulated 2017; Palazzo et al. 2017; Rechkunova et al. 2019). In ad- data support the increasingly compelling view that (ADP- dition to proteins, several in vitro observations strongly ribosyl)hydrolases are a vital element within ADP-ribosyl suggest that nucleic acids, both DNA and RNA, can be signaling pathways and they hold the potential for novel targets of ADP-ribosylation (Nakano et al. -
Identification of Genomic Targets of Krüppel-Like Factor 9 in Mouse Hippocampal
Identification of Genomic Targets of Krüppel-like Factor 9 in Mouse Hippocampal Neurons: Evidence for a role in modulating peripheral circadian clocks by Joseph R. Knoedler A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Neuroscience) in the University of Michigan 2016 Doctoral Committee: Professor Robert J. Denver, Chair Professor Daniel Goldman Professor Diane Robins Professor Audrey Seasholtz Associate Professor Bing Ye ©Joseph R. Knoedler All Rights Reserved 2016 To my parents, who never once questioned my decision to become the other kind of doctor, And to Lucy, who has pushed me to be a better person from day one. ii Acknowledgements I have a huge number of people to thank for having made it to this point, so in no particular order: -I would like to thank my adviser, Dr. Robert J. Denver, for his guidance, encouragement, and patience over the last seven years; his mentorship has been indispensable for my growth as a scientist -I would also like to thank my committee members, Drs. Audrey Seasholtz, Dan Goldman, Diane Robins and Bing Ye, for their constructive feedback and their willingness to meet in a frequently cold, windowless room across campus from where they work -I am hugely indebted to Pia Bagamasbad and Yasuhiro Kyono for teaching me almost everything I know about molecular biology and bioinformatics, and to Arasakumar Subramani for his tireless work during the home stretch to my dissertation -I am grateful for the Neuroscience Program leadership and staff, in particular -
Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor-Induced Formation of Degradasomes and Β-Catenin Degradation
RESEARCH ARTICLE Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor-Induced Formation of Degradasomes and β-Catenin Degradation Tor Espen Thorvaldsen1,2☯, Nina Marie Pedersen1,2☯, Eva Maria Wenzel1,2*, Harald Stenmark1,2* 1 Centre for Cancer Biomedicine, Faculty of Medicine, Oslo University Hospital, Oslo, Norway, 2 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway a1111111111 ☯ These authors contributed equally to this work. a1111111111 * [email protected] (EMW); [email protected] (HS) a1111111111 a1111111111 a1111111111 Abstract Inhibition of the tankyrase enzymes (TNKS1 and TNKS2) has recently been shown to induce highly dynamic assemblies of β-catenin destruction complex components known as OPEN ACCESS degradasomes, which promote degradation of β-catenin and reduced Wnt signaling activity Citation: Thorvaldsen TE, Pedersen NM, Wenzel in colorectal cancer cells. AXIN1 and AXIN2/Conductin, the rate-limiting factors for the sta- EM, Stenmark H (2017) Differential Roles of AXIN1 bility and function of endogenous destruction complexes, are stabilized upon TNKS inhibi- and AXIN2 in Tankyrase Inhibitor-Induced tion due to abrogated degradation of AXIN by the proteasome. Since the role of AXIN1 Formation of Degradasomes and β-Catenin versus AXIN2 as scaffolding proteins in the Wnt signaling pathway still remains incompletely Degradation. PLoS ONE 12(1): e0170508. doi:10.1371/journal.pone.0170508 understood, we sought to elucidate their relative contribution in the formation of degrada- somes, as these protein assemblies most likely represent the morphological and functional Editor: Masaru Katoh, National Cancer Center, JAPAN correlates of endogenous β-catenin destruction complexes. In SW480 colorectal cancer cells treated with the tankyrase inhibitor (TNKSi) G007-LK we found that AXIN1 was not Received: September 20, 2016 required for degradasome formation. -
Gene Expression Mechanism and Repertoire of ASC-Mediated
The Journal of Immunology Mechanism and Repertoire of ASC-Mediated Gene Expression1 Mizuho Hasegawa,2* Ryu Imamura,* Kou Motani,* Takumi Nishiuchi,† Norihiko Matsumoto,* Takeshi Kinoshita,* and Takashi Suda3* Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adaptor molecule that mediates inflammatory and apoptotic signals. Although the role of ASC in caspase-1-mediated IL-1 and IL-18 maturation is well known, ASC also induces NF-B activation and cytokine gene expression in human cells. In this study, we investigated the molecular mechanism and repertoire of ASC-induced gene expression in human cells. We found that the specific activation of ASC induced AP-1 activity, which was required for optimal IL8 promoter activity. ASC activation also induced STAT3-, but not STAT1-, IFN-stimulated gene factor 3- or NF-AT-dependent reporter gene expression. The ASC-mediated AP-1 activation was NF-B-independent and primarily cell-autonomous response, whereas the STAT3 activation required NF-B activation and was mediated by a factor that can act in a paracrine manner. ASC-mediated AP-1 activation was inhibited by chemical or protein inhibitors for caspase-8, caspase-8-targeting small-interfering RNA, and p38 and JNK inhibitors, but not by a caspase-1 inhibitor, caspase-9 or Fas-associated death domain protein (FADD) dominant-negative mutants, FADD- or RICK-targeting small-interfering RNAs, or a MEK inhibitor, indicating that the ASC-induced AP-1 activation is mediated by caspase-8, p38, and JNK, but does not require caspase-1, caspase-9, FADD, RICK, or ERK. DNA microarray analyses identified 75 genes that were induced by ASC activation. -
Axin Family of Scaffolding Proteins in Development
Journal of Developmental Biology Review Axin Family of Scaffolding Proteins in Development: Lessons from C. elegans Avijit Mallick 1 , Shane K. B. Taylor 1, Ayush Ranawade 2 and Bhagwati P. Gupta 1,* 1 Department of Biology, McMaster University, Hamilton, ON L8S-4K1, Canada; [email protected] (A.M.); [email protected] (S.K.B.T.) 2 Department of Bioengineering, Northeastern University, Boston, MA 02115, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-905-525-9140 (ext. 26451); Fax: +1-905-522-6066 Received: 12 August 2019; Accepted: 11 October 2019; Published: 15 October 2019 Abstract: Scaffold proteins serve important roles in cellular signaling by integrating inputs from multiple signaling molecules to regulate downstream effectors that, in turn, carry out specific biological functions. One such protein, Axin, represents a major evolutionarily conserved scaffold protein in metazoans that participates in the WNT pathway and other pathways to regulate diverse cellular processes. This review summarizes the vast amount of literature on the regulation and functions of the Axin family of genes in eukaryotes, with a specific focus on Caenorhabditis elegans development. By combining early studies with recent findings, the review is aimed to serve as an updated reference for the roles of Axin in C. elegans and other model systems. Keywords: Axin; C. elegans; pry-1; axl-1; WNT signaling; scaffolding protein; signal transduction; development Axin was first discovered as a negative regulator of WNT (wingless and int-1) signaling in mice while deciphering its role in embryonic axis formation [1]. This protein is the product of the mouse Fu (Fused) gene [2–4] and was named Axin for its initial discovered role in inhibiting axis formation (Axis inhibition). -
Autocrine IFN Signaling Inducing Profibrotic Fibroblast Responses By
Downloaded from http://www.jimmunol.org/ by guest on September 23, 2021 Inducing is online at: average * The Journal of Immunology , 11 of which you can access for free at: 2013; 191:2956-2966; Prepublished online 16 from submission to initial decision 4 weeks from acceptance to publication August 2013; doi: 10.4049/jimmunol.1300376 http://www.jimmunol.org/content/191/6/2956 A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Autocrine IFN Signaling Feng Fang, Kohtaro Ooka, Xiaoyong Sun, Ruchi Shah, Swati Bhattacharyya, Jun Wei and John Varga J Immunol cites 49 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2013/08/20/jimmunol.130037 6.DC1 This article http://www.jimmunol.org/content/191/6/2956.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 23, 2021. The Journal of Immunology A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Inducing Autocrine IFN Signaling Feng Fang,* Kohtaro Ooka,* Xiaoyong Sun,† Ruchi Shah,* Swati Bhattacharyya,* Jun Wei,* and John Varga* Activation of TLR3 by exogenous microbial ligands or endogenous injury-associated ligands leads to production of type I IFN.