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Geun Hye Hwang, So Mi Park, Ho Jae Han, Joong Sun Kim, Seung Pil Yun, Jung Min Ryu, Ho Jin Lee, Woochul Chang, Su-Jin Lee, Jeong-Hee Choi, Jin-Sung Choi, Min Young Lee
In order to realize the practical use of human pluripotent stem cell (hPSC)-derived cardiomyocytes for the purpose of clinical use or cardiovascular research, the generation of large numbers of highly purified cardiomyocytes should be achieved. Here, we show an efficient method for cardiac differentiation of human induced pluripotent stem cells (hiPSCs) in chemically defined conditions and purification of hiPSC-derived cardiomyocytes using a reporter system. Regulation of the Wnt/β-catenin signaling pathway is implicated in the induction of the cardiac differentiation of hPSCs...
January 7, 2017: Journal of Cellular Physiology
Ann-Gerd Thorsell, Torun Ekblad, Tobias Karlberg, Mirjam Löw, Ana Filipa Pinto, Lionel Trésaugues, Martin Moche, Michael S Cohen, Herwig Schüler
Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective...
December 21, 2016: Journal of Medicinal Chemistry
Yinglan Pu, Shuqun Zhang, Zhe Chang, Yunqin Zhang, Dong Wang, Li Zhang, Yan Li, Zhili Zuo
Tankyrases (TNKS), key transmitters in the Wnt signaling pathway which is very conservative in evolution, are vital targets as they are overexpressed widely in many cancers. In this work, 5 inhibitors with novel structures have been discovered and validated using the ligand-based (pharmacophore) virtual screening, docking study, and Luciferase reporter assays for Wnt signaling. Among them, PYL-1, in particular, was the most potent inhibitor with an IC50 value of 9.56 μM against Wnt signaling. The analysis of binding modes was performed to further understand the vital interactions between inhibitors and TNKS 2, and the five hits belong to dual site inhibitors...
December 20, 2016: Molecular BioSystems
Ekta Tripathi, Susan Smith
Timely resolution of sister chromatid cohesion in G2/M is essential for genome integrity. Resolution at telomeres requires the poly(ADP-ribose) polymerase tankyrase 1, but the mechanism that times its action is unknown. Here, we show that tankyrase 1 activity at telomeres is controlled by a ubiquitination/deubiquitination cycle depending on opposing ubiquitin ligase and deubiquitinase activities. In late S/G2 phase, the DNA damage-responsive E3 ligase RNF8 conjugates K63-linked ubiquitin chains to tankyrase 1, while in G1 phase such ubiquitin chains are removed by BRISC, an ABRO1/BRCC36-containing deubiquitinase complex...
December 19, 2016: EMBO Journal
Amit Nathubhai, Teemu Haikarainen, Jarkko Koivunen, Sudarshan Murthy, Françoise Koumanov, Matthew D Lloyd, Geoffrey D Holman, Taina Pihlajaniemi, David Tosh, Lari Lehtiö, Michael D Threadgill
Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward inhibiting tankyrases (TNKSs) than the "standard" inhibitor 1 (XAV939)(5), i.e., IC50 = 100 pM vs TNKS2 and IC50 = 6.5 μM vs PARP1 for 14. In cellular assays, 13 and 14 inhibited Wnt-signaling, enhanced insulin-stimulated glucose uptake, and inhibited the proliferation of DLD-1 colorectal adenocarcinoma cells to a greater extent than 1.
January 9, 2017: Journal of Medicinal Chemistry
Zhenghan Wang, Ofelia Tacchelly-Benites, Eungi Yang, Yashi Ahmed
Deregulation of the Wnt signal transduction pathway underlies numerous congenital disorders and cancers. Axin, a concentration-limiting scaffold protein, facilitates assembly of a "destruction complex" that prevents signaling in the unstimulated state and a plasma membrane-associated "signalosome" that activates signaling following Wnt stimulation. In the classical model, Axin is cytoplasmic under basal conditions, but relocates to the cell membrane after Wnt exposure; however, due to the very low levels of endogenous Axin, this model is based largely on examination of Axin at supraphysiological levels...
December 2016: PLoS Genetics
Ming-Wei Zhou, Wei-Tian Yin, Ri-Hua Jiang, Jin-Hyup Lee, Chang-Deok Kim, Jeung-Hoon Lee, Ming Ji Zhu, Tae-Jin Yoon
AIMS: Keloid is a benign tumor that is characterized by the hyperproliferation of dermal fibroblasts and excessive deposition of extracellular matrix (ECM) especially the collagen. Aberrant activation of Wnt/β-catenin signaling is implicated in the pathogenesis of keloid. In this study, we investigated the effects of IWR-1, a small molecule inhibitor for Wnt/β-catenin signaling via the inhibition of tankyrase, on production of collagen and matrix metalloproteinase (MMP) in dermal fibroblasts...
December 7, 2016: Life Sciences
Mathilde Gay-Bellile, Pierre Romero, Anne Cayre, Lauren Véronèse, Maud Privat, Shalini Singh, Patricia Combes, Fabrice Kwiatkowski, Catherine Abrial, Yves-Jean Bignon, Philippe Vago, Frédérique Penault-Llorca, Andreï Tchirkov
Dysfunctional telomeres and DNA damage repair (DDR) play important roles in cancer progression. Studies have reported correlations between these factors and tumour aggressiveness and clinical outcome in breast cancer. We studied the characteristics of telomeres and expression of ERCC1, a protein involved in a number of DNA repair pathways and in telomere homeostasis, to assess their prognostic value, alone or in combination, in 90 residual breast tumours after treatment with neoadjuvant chemotherapy (NCT). ERCC1 status was investigated at different molecular levels (protein and gene expression and gene copy-number variations) by immunohistochemistry, qRT-PCR and quantitative multiplex fluorescent-PCR (QMF-PCR)...
October 2016: Journal of Pathology. Clinical Research
Sebastian Guettler
The poly(ADP-ribose)polymerase (PARP) Tankyrase uses ankyrin repeat modules to capture substrates via Tankyrase-binding peptide motifs. In this issue of Structure, Eisemann et al. (2016) describe how the signaling protein AXIN can access and conformationally adapt the multivalent ankyrin repeat region of Tankyrase and discuss potential implications for enzymatic substrate modification.
October 4, 2016: Structure
Hannah A Scarborough, Barbara A Helfrich, Matias Casás-Selves, Alwin G Schuller, Shaun E Grosskurth, Jihye Kim, Aik-Choon Tan, Daniel C Chan, Zhiyong Zhang, Vadym Zaberezhnyy, Paul A Bunn, James DeGregori
PURPOSE: The emergence of EGFR inhibitors such as gefitinib, erlotinib, and osimertinib has provided novel treatment opportunities in EGFR-driven non-small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors...
September 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ludovic Zimmerlin, Tea Soon Park, Jeffrey S Huo, Karan Verma, Sarshan R Pather, C Conover Talbot, Jasmin Agarwal, Diana Steppan, Yang W Zhang, Michael Considine, Hong Guo, Xiufeng Zhong, Christian Gutierrez, Leslie Cope, M Valeria Canto-Soler, Alan D Friedman, Stephen B Baylin, Elias T Zambidis
The derivation and maintenance of human pluripotent stem cells (hPSCs) in stable naïve pluripotent states has a wide impact in human developmental biology. However, hPSCs are unstable in classical naïve mouse embryonic stem cell (ESC) WNT and MEK/ERK signal inhibition (2i) culture. We show that a broad repertoire of conventional hESC and transgene-independent human induced pluripotent stem cell (hiPSC) lines could be reverted to stable human preimplantation inner cell mass (ICM)-like naïve states with only WNT, MEK/ERK, and tankyrase inhibition (LIF-3i)...
December 1, 2016: Development
Tim Koopmans, Stijn Crutzen, Mark H Menzen, Andrew J Halayko, Tillie-Louise Hackett, Darryl A Knight, Reinoud Gosens
BACKGROUND AND PURPOSE: Asthma is a heterogeneous chronic inflammatory disease, characterized by the development of structural changes (airway remodelling). β-catenin, a transcriptional co-activator is fundamentally involved in airway smooth muscle growth, and may be a potential target in the treatment of airway smooth muscle remodelling. EXPERIMENTAL APPROACH: Using small-molecule compounds that selectively target β-catenin breakdown or its interactions with transcriptional co-activators, we assessed their ability to inhibit airway smooth muscle remodelling in vitro and in vivo...
September 15, 2016: British Journal of Pharmacology
Guillaume Renner, Fanny Noulet, Marie-Cécile Mercier, Laurence Choulier, Nelly Etienne-Selloum, Jean-Pierre Gies, Maxime Lehmann, Isabelle Lelong-Rebel, Sophie Martin, Monique Dontenwill
The Wnt/beta catenin pathway has been highlighted as an important player of brain tumors aggressiveness and resistance to therapies. Increasing knowledges of the regulation of beta-catenin transactivation point out its hub position in different pathophysiological outcomes in glioma such as survival and migration. Crosstalks between integrins and beta-catenin pathways have been suggested in several tumor tissues. As we demonstrated earlier that α5β1 integrin may be considered as a therapeutic target in high grade glioma through its contribution to glioma cell migration and resistance to chemotherapy, we addressed here the potential relationship between α5β1 integrin and beta-catenin activation in glioma cells...
September 20, 2016: Oncotarget
Travis Eisemann, Michael McCauley, Marie-France Langelier, Kushol Gupta, Swati Roy, Gregory D Van Duyne, John M Pascal
The poly(ADP-ribose) polymerase enzyme Tankyrase-1 (TNKS) regulates multiple cellular processes and interacts with diverse proteins using five ankyrin repeat clusters (ARCs). There are limited structural insights into functional roles of the multiple ARCs of TNKS. Here we present the ARC1-3 crystal structure and employ small-angle X-ray scattering (SAXS) to investigate solution conformations of the complete ankyrin repeat domain. Mutagenesis and binding studies using the bivalent TNKS binding domain of Axin1 demonstrate that only certain ARC combinations function together...
October 4, 2016: Structure
Jesung Moon, James F Amatruda
The activity of tankyrase (Tnks) enzymes modulates the activity of the β-catenin destruction complex in the Wnt/β-catenin signaling pathway. Here, we describe a method for determining the accessibility of various zebrafish tissues in vivo and in vitro to small molecule inhibitors of Tankyrase enzymes. This biochemical assay will facilitate chemically based studies focused on understanding the role of Tankyrase in cell fate reprogramming and tissue homeostasis and provide insights into the potential role of Wnt/β-catenin signaling in these processes...
2016: Methods in Molecular Biology
Jasminka Boskovic, Jaime Martinez-Gago, Marinela Mendez-Pertuz, Alberto Buscato, Jorge Luis Martinez-Torrecuadrada, Maria A Blasco
Telomeres are specific DNA-protein structures found at both ends of eukaryotic chromosomes that protect the genome from degradation and from being recognized as double-stranded breaks. In vertebrates, telomeres are composed of tandem repeats of the TTAGGG sequence that are bound by a six-subunit complex called shelterin. Molecular mechanisms of telomere functions remain unknown in large part due to lack of structural data on shelterins, shelterin complex, and its interaction with the telomeric DNA repeats. TRF1 is one of the best studied shelterin components; however, the molecular architecture of the full-length protein remains unknown...
October 7, 2016: Journal of Biological Chemistry
F Linke, M Harenberg, M M Nietert, S Zaunig, F von Bonin, A Arlt, M Szczepanowski, H A Weich, S Lutz, C Dullin, P Janovská, M Krafčíková, L Trantírek, P Ovesná, W Klapper, T Beissbarth, F Alves, V Bryja, L Trümper, J Wilting, D Kube
The interaction between vascular endothelial cells (ECs) and cancer cells is of vital importance to understand tumor dissemination. A paradigmatic cancer to study cell-cell interactions is classical Hodgkin Lymphoma (cHL) owing to its complex microenvironment. The role of the interplay between cHL and ECs remains poorly understood. Here we identify canonical WNT pathway activity as important for the mutual interactions between cHL cells and ECs. We demonstrate that local canonical WNT signaling activates cHL cell chemotaxis toward ECs, adhesion to EC layers and cell invasion using not only the Wnt-inhibitor Dickkopf, tankyrases and casein kinase 1 inhibitors but also knockdown of the lymphocyte enhancer binding-factor 1 (LEF-1) and β-catenin in cHL cells...
October 4, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Craig I Campbell, Payman Samavarchi-Tehrani, Miriam Barrios-Rodiles, Alessandro Datti, Anne-Claude Gingras, Jeffrey L Wrana
The Crumbs complex is an important determinant of epithelial apical-basal polarity that functions in regulation of tight junctions, resistance to epithelial-to-mesenchymal transitions and as a tumour suppressor. Although the functional role of the Crumbs complex is being elucidated, its regulation is poorly understood. Here, we show that suppression of RNF146, an E3 ubiquitin ligase that recognizes ADP-ribosylated substrates, and tankyrase, a poly(ADP-ribose) polymerase, disrupts the junctional Crumbs complex and disturbs the function of tight junctions...
September 15, 2016: Journal of Cell Science
Zhongming Jia, Yan Liu, Qiang Gao, Yong Han, Guoqiang Zhang, Shujian Xu, Kai Cheng, Weiwei Zou
Identification of key genes driving the aggressiveness of triple-negative breast cancer (TNBC) is important to develop effective therapies. In this study, we examined the expression and biological roles of microRNA (miR)-490-3p in TNBC. Our data showed that miR-490-3p-3p was underexpressed in TNBC compared with non-TNBC tissues (P=0.0021). Similarly, this miRNA was expressed at lower levels in TNBC cell lines than in non-TNBC cell lines. Gain-of-function studies revealed that miR-490-3p-3p overexpression inhibited cell growth and invasion in both MDA-MB-231 and MDA-MB-436 TNBC cells and impaired tumorigenesis of MDA-MB-231 cells in nude mice...
November 15, 2016: Gene
Amanda A Riccio, Michael McCauley, Marie-France Langelier, John M Pascal
Tankyrase-1 (TNKS1/PARP-5a) is a poly(ADP-ribose) polymerase (PARP) enzyme that regulates multiple cellular processes creating a poly(ADP-ribose) posttranslational modification that can lead to target protein turnover. TNKS1 thereby controls protein levels of key components of signaling pathways, including Axin1, the limiting component of the destruction complex in canonical Wnt signaling that degrades β-catenin to prevent its coactivator function in gene expression. There are limited molecular level insights into TNKS1 regulation in cell signaling pathways...
September 6, 2016: Structure
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