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https://www.readbyqxmd.com/read/28208209/the-emergence-of-tnik-inhibitors-in-cancer-therapeutics
#1
REVIEW
Tesshi Yamada, Mari Masuda
The outcome of patients with metastatic colorectal cancer remains unsatisfactory. To improve patient prognosis, it will be necessary to identify new drug targets based on molecules that are essential for colorectal carcinogenesis, and to develop therapeutics that target such molecules. The great majority of colorectal cancers (>90%) have mutations in at least one Wnt signaling pathway gene. Aberrant activation of Wnt signaling is a major force driving colorectal carcinogenesis. Several therapeutics targeting Wnt pathway molecules, including porcupine, frizzled receptors, and tankyrases, have been developed, but none of them have yet been incorporated into clinical practice...
February 16, 2017: Cancer Science
https://www.readbyqxmd.com/read/28202517/tankyrase-binding-protein-tnks1bp1-regulates-actin-cytoskeleton-rearrangement-and-cancer-cell-invasion
#2
Tomokazu Ohishi, Haruka Yoshida, Masamichi Katori, Toshiro Migita, Yukiko Muramatsu, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Shun-Ichiro Iemura, Tohru Natsume, Hiroyuki Seimiya
Tankyrase, a poly(ADP-ribose) polymerase (PARP) that promotes telomere elongation and Wnt/β-catenin signaling, has various binding partners, suggesting that it has as-yet unidentified functions. Here we report that the tankyrase-binding protein TNKS1BP1 regulates actin cytoskeleton and cancer cell invasion, which is closely associated with cancer progression. TNKS1BP1 colocalized with actin filaments and negatively regulated cell invasion. In TNKS1BP1-depleted cells, actin filament dynamics, focal adhesion, and lamellipodia ruffling were increased with activation of the ROCK-LIMK-cofilin pathway...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28179481/apc-mutations-as-a-potential-biomarker-for-sensitivity-to-tankyrase-inhibitors-in-colorectal-cancer
#3
Noritaka Tanaka, Tetsuo Mashima, Anna Mizutani, Ayana Sato, Aki Aoyama, Bo Gong, Haruka Yoshida, Yukiko Muramatsu, Kento Nakata, Masaaki Matsuura, Ryohei Katayama, Satoshi Nagayama, Naoya Fujita, Yoshikazu Sugimoto, Hiroyuki Seimiya
In most colorectal cancers (CRCs), Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli (APC) gene and plays a critical role in tumorigenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a negative regulator of β-catenin, and upregulate β-catenin signaling. Tankyrase inhibitors downregulate β-catenin and are expected to be promising therapeutics for CRC. However, CRC cells are not always sensitive to tankyrase inhibitors, and predictive biomarkers for the drug sensitivity remain elusive...
February 8, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28120389/modulating-the-wnt-signaling-pathway-with-small-molecules
#4
REVIEW
Freddi Huan Tran, Jie J Zheng
Wnt signaling is a critical component during embryonic development and also plays an important role in regulating adult tissue homeostasis. Abnormal activation of Wnt signaling has been implicated in many cancers, while reduced activity of Wnt signaling leads to poor wound healing and structural formations. Thus, extensive efforts have been focused on developing small molecules that have potential to either inhibit or activate the pathway, hoping these molecules can offer leads for novel approaches in treating different human diseases...
January 25, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28119762/synthesis-spectroscopic-dielectric-molecular-docking-and-dft-studies-of-3e-3-4-methylbenzylidene-3-4-dihydro-2h-chromen-2-one-an-anticancer-agent
#5
T Beena, L Sudha, A Nataraj, V Balachandran, D Kannan, M N Ponnuswamy
BACKGROUND: Coumarin (2H-chromen-2-one) and its derivatives have a wide range of biological and pharmaceutical activities. They possess antitumor, anti-HIV, anticoagulant, antimicrobial, antioxidant, and anti-inflammatory activities. Synthesis and isolation of coumarins from different species have attracted the attention of medicinal chemists. Herein, we report the synthesis, molecular structure, dielectric, anticancer activity and docking studies with the potential target protein tankyrase...
2017: Chemistry Central Journal
https://www.readbyqxmd.com/read/28107521/differential-roles-of-axin1-and-axin2-in-tankyrase-inhibitor-induced-formation-of-degradasomes-and-%C3%AE-catenin-degradation
#6
Tor Espen Thorvaldsen, Nina Marie Pedersen, Eva Maria Wenzel, Harald Stenmark
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 degradasomes, which promote degradation of β-catenin and reduced Wnt signaling activity in colorectal cancer cells. AXIN1 and AXIN2/Conductin, the rate-limiting factors for the stability and function of endogenous destruction complexes, are stabilized upon TNKS inhibition due to abrogated degradation of AXIN by the proteasome. Since the role of AXIN1 versus AXIN2 as scaffolding proteins in the Wnt signaling pathway still remains incompletely understood, we sought to elucidate their relative contribution in the formation of degradasomes, as these protein assemblies most likely represent the morphological and functional correlates of endogenous β-catenin destruction complexes...
2017: PloS One
https://www.readbyqxmd.com/read/28101169/role-of-wnt-%C3%AE-catenin-wnt-c-jun-n-terminal-kinase-and-wnt-ca-2-pathways-in-cisplatin-induced-chemoresistance-in-ovarian-cancer
#7
Lu Huang, Ye Jin, Shujun Feng, Yuqing Zou, Sainan Xu, Shuang Qiu, Ling Li, Jianhua Zheng
The aim of the present study was to explore the expression of Wnt signaling proteins β-catenin, c-Jun N-terminal kinase (JNK) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in ovarian cancer cells, and assess the correlation between this expression and cisplatin-induced chemoresistance. SKOV3 ovarian carcinoma cells and SKOV3/DDP (cisplatin resistant) cells were treated with cisplatin in the absence or presence of a Wnt signaling activator (CHIR-99021, glycogen synthase kinase 3β inhibitor) or inhibitor (XAV-939, tankyrase inhibitor)...
December 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28063225/purification-of-small-molecule-induced-cardiomyocytes-from-human-induced-pluripotent-stem-cells-using-a-reporter-system
#8
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
https://www.readbyqxmd.com/read/28001384/structural-basis-for-potency-and-promiscuity-in-poly-adp-ribose-polymerase-parp-and-tankyrase-inhibitors
#9
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
https://www.readbyqxmd.com/read/27995250/discovery-of-new-dual-binding-tnks-inhibitors-of-wnt-signaling-inhibition-by-pharmacophore-modeling-molecular-docking-and-bioassay
#10
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
https://www.readbyqxmd.com/read/27993934/cell-cycle-regulated-ubiquitination-of-tankyrase-1-by-rnf8-and-abro1-brcc36-controls-the-timing-of-sister-telomere-resolution
#11
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
https://www.readbyqxmd.com/read/27983846/highly-potent-and-isoform-selective-dual-site-binding-tankyrase-wnt-signaling-inhibitors-that-increase-cellular-glucose-uptake-and-have-antiproliferative-activity
#12
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 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27959917/dual-roles-for-membrane-association-of-drosophila-axin-in-wnt-signaling
#13
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
https://www.readbyqxmd.com/read/27939785/inhibition-of-collagen-synthesis-by-iwr-1-in-normal-and-keloid-derived-skin-fibroblasts
#14
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
https://www.readbyqxmd.com/read/27785368/ercc1-and-telomere-status-in-breast-tumours-treated-with-neoadjuvant-chemotherapy-and-their-association-with-patient-prognosis
#15
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
https://www.readbyqxmd.com/read/27705813/axin-shapes-tankyrase-architecture
#16
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
https://www.readbyqxmd.com/read/27663586/az1366-an-inhibitor-of-tankyrase-and-the-canonical-wnt-pathway-that-limits-the-persistence-of-non-small-cell-lung-cancer-cells-following-egfr-inhibition
#17
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
https://www.readbyqxmd.com/read/27660325/tankyrase-inhibition-promotes-a-stable-human-na%C3%A3-ve-pluripotent-state-with-improved-functionality
#18
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
https://www.readbyqxmd.com/read/27629364/selective-targeting-of-cbp-%C3%AE-catenin-inhibits-growth-of-and-extracellular-matrix-remodelling-by-airway-smooth-muscle
#19
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
https://www.readbyqxmd.com/read/27613837/expression-activation-of-%C3%AE-5%C3%AE-1-integrin-is-linked-to-the-%C3%AE-catenin-signaling-pathway-to-drive-migration-in-glioma-cells
#20
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
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