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https://www.readbyqxmd.com/read/28628258/tankyrase-inhibition-regulates-corpus-luteum-development-and-luteal-function-in-gonadotropin-treated-rats
#1
Accialini Paula, Irusta Griselda, Bechis Andres, Bas Diana, Parborell Fernanda, Abramovich Dalhia, Tesone Marta
Tankyrases are physiological regulators of Axin, a protein involved in several cellular processes, including Wnt signaling. Here, we investigated the effect of a specific Tankyrase inhibitor (XAV939) in follicular-luteal dynamics, and its possible relationship with ovarian vascular development. Studies were designed to analyze the effect of intrabursa administration of XAV939 in gonadotropin-treated prepubertal rats. In particular, we examined follicle and corpus luteum development, steroidogenesis, angiogenic markers, and apoptotic parameters...
June 19, 2017: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/28619731/usp25-regulates-wnt-signaling-by-controlling-the-stability-of-tankyrases
#2
Daichao Xu, Jianping Liu, Tao Fu, Bing Shan, Lihui Qian, Lifeng Pan, Junying Yuan
Aberrant activation of the Wnt signaling pathway plays an important role in human cancer development. Wnt signaling is negatively regulated by Axin, a scaffolding protein that controls a rate-limiting step in the destruction of β-catenin, the central activator of the Wnt pathway. In Wnt-stimulated cells, Axin is rapidly modified by tankyrase-mediated poly(ADP-ribosyl)ation, which promotes the proteolysis of Axin and consequent stabilization of β-catenin. Thus, regulation of the levels and activity of tankyrases is mechanistically important in controlling Wnt signaling...
June 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28615517/mtor-signaling-mediates-resistance-to-tankyrase-inhibitors-in-wnt-driven-colorectal-cancer
#3
Tetsuo Mashima, Yoko Taneda, Myung-Kyu Jang, Anna Mizutani, Yukiko Muramatsu, Haruka Yoshida, Ayana Sato, Noritaka Tanaka, Yoshikazu Sugimoto, Hiroyuki Seimiya
Activation of Wnt/β-catenin signaling is essential for colorectal carcinogenesis. Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, is a positive regulator of the Wnt/β-catenin signaling. Accordingly, tankyrase inhibitors are under preclinical development for colorectal cancer (CRC) therapy. However, Wnt-driven colorectal cancer cells are not equally sensitive to tankyrase inhibitors, and cellular factors that affect tankyrase inhibitor sensitivity remain elusive. Here, we established a tankyrase inhibitor-resistant cell line, 320-IWR, from Wnt/β-catenin-dependent CRC COLO-320DM cells...
May 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28611108/wnt-%C3%AE-catenin-signaling-contributes-to-tumor-malignancy-and-is-targetable-in-gastrointestinal-stromal-tumor
#4
Shan Zeng, Adrian M Seifert, Jennifer Q Zhang, Michael J Cavnar, Teresa S Kim, Vinod P Balachandran, Juan A Santamaria-Barria, Noah A Cohen, Michael J Beckman, Benjamin Medina, Ferdinand Rossi, Megan H Crawley, Jennifer K Loo, Joanna H Maltbaek, Peter Besmer, Cristina R Antonescu, Ronald P DeMatteo
Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. While the Wnt/b-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed b-catenin and contained active, dephosphorylated nuclear b-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4...
June 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28591512/discovery-of-a-highly-selective-tankyrase-inhibitor-displaying-growth-inhibition-effects-against-a-diverse-range-of-tumor-derived-cell-lines
#5
Douglas W Thomson, Anne J Wagner, Marcus Bantscheff, R Edward Benson, Lars Dittus, Birgit Duempelfeld, Gerard Drewes, Jana Krause, John T Moore, Katrin Mueller, Daniel Poeckel, Christina Rau, Elsa Salzer, Lisa Shewchuk, Carsten Hopf, John G Emery, Marcel Muelbaier
The availability of high quality probes for specific protein targets is fundamental to the investigation of their function and their validation as therapeutic targets. We report the utilization of a dedicated chemoproteomic assay platform combining affinity enrichment technology with high-resolution protein mass spectrometry to the discovery of a novel nicotinamide isoster, the tetrazoloquinoxaline 41, a highly potent and selective tankyrase inhibitor. We also describe the use of 41 to investigate the biology of tankyrase, revealing the compound induced growth inhibition of a number of tumor derived cell lines, demonstrating the potential of tankyrase inhibitors in oncology...
June 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28588489/fh535-suppresses-osteosarcoma-growth-in-vitro-and-inhibits-wnt-signaling-through-tankyrases
#6
Carl T Gustafson, Tewodros Mamo, Kristen L Shogren, Avudaiappan Maran, Michael J Yaszemski
Osteosarcoma (OS) is an aggressive primary bone tumor which exhibits aberrantly activated Wnt signaling. The canonical Wnt signaling cascade has been shown to drive cancer progression and metastasis through the activation of β-catenin. Hence, small molecule inhibitors of Wnt targets are being explored as primary or adjuvant chemotherapy. In this study, we have investigated the ability of FH535, an antagonist of Wnt signaling, to inhibit the growth of OS cells. We found that FH535 was cytotoxic in all OS cell lines which were tested (143b, U2OS, SaOS-2, HOS, K7M2) but well tolerated by normal human osteoblast cells...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28371398/targeting-tankyrase-to-fight-wnt-dependent-tumours
#7
REVIEW
Tor Espen Thorvaldsen
Aberrant WNT signalling activity is linked to various diseases due to the WNT dependency of fundamental processes during development and in adult tissue homeostasis. Mutations in components of the multi-protein β-catenin destruction complex promote excessive amounts of the main transcriptional activator β-catenin and are particularly common in colorectal cancer (CRC). The tankyrase enzymes were recently implicated as negative regulators of destruction complex activity by mediating degradation of the scaffolding protein AXIN...
April 2, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28337959/microrna-940-targets-inpp4a-or-gsk3%C3%AE-and-activates-the-wnt-%C3%AE-catenin-pathway-to-regulate-the-malignant-behavior-of-bladder-cancer-cells
#8
Rong Wang, Yunfeng Wu, Weihua Huang, Weijun Chen
We aimed to explore the roles and regulatory mechanism of microRNA-940 (miR-940) in bladder cancer development. The expressions of miR-940 in bladder cancer tissues and cells were measured. Then miR-940 mimics, miR-940 inhibitor mall interference RNA against INPP4A (si-INPP4A) and GSK3β (si-GSK3β) and their corresponding controls were transfected into cells. We then investigated that the effects of miR-940, INPP4A or GSK3β on cell proliferation, migration, invasion and apoptosis. Additionally, target prediction and luciferase reporter assay were performed to investigate the targets of miR-940...
March 23, 2017: Oncology Research
https://www.readbyqxmd.com/read/28240680/inhibition-of-wnt-signaling-reduces-differentiation-and-induces-sensitivity-to-doxorubicin-in-human-malignant-neuroblastoma-sh-sy5y-cells
#9
Junjira Suebsoonthron, Thiranut Jaroonwitchawan, Montarop Yamabhai, Parinya Noisa
Neuroblastoma is one of the most common cancers in infancy, arising from the neuroblasts during embryonic development. This cancer is difficult to treat and resistance to chemotherapy is often found; therefore, clinical trials of novel therapeutic approaches, such as targeted-cancer signaling, could be an alternative for a better treatment. WNT signaling plays significant roles in the survival, proliferation, and differentiation of human neuroblastoma. In this report, WNT signaling of a malignant human neuroblastoma cell line, SH-SY5Y cells, was inhibited by XAV939, a specific inhibitor of the Tankyrase enzyme...
June 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28208209/emergence-of-tnik-inhibitors-in-cancer-therapeutics
#10
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...
May 2017: Cancer Science
https://www.readbyqxmd.com/read/28202517/tankyrase-binding-protein-tnks1bp1-regulates-actin-cytoskeleton-rearrangement-and-cancer-cell-invasion
#11
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 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
#12
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
#13
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...
April 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
#14
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
#15
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
#16
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
#17
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
#18
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...
February 23, 2017: 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
#19
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
#20
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
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