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https://www.readbyqxmd.com/read/28731148/molecular-genetics-and-targeted-therapy-of-wnt-related-human-diseases-review
#1
Masuko Katoh, Masaru Katoh
Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription...
September 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28723574/proteomic-analysis-of-the-human-tankyrase-protein-interaction-network-reveals-its-role-in-pexophagy
#2
Xu Li, Han Han, Mao-Tian Zhou, Bing Yang, Albert Paul Ta, Nan Li, Junjie Chen, Wenqi Wang
Tankyrase 1 (TNKS) and tankyrase 2 (TNKS2) belong to the poly(ADP-ribose) polymerase family of proteins, which use nicotinamide adenine dinucleotide to modify substrate proteins with ADP-ribose modifications. Emerging evidence has revealed the pathological relevance of TNKS and TNKS2, and identified these two enzymes as potential drug targets. However, the cellular functions and regulatory mechanisms of TNKS/2 are still largely unknown. Through a proteomic analysis, we defined the protein-protein interaction network for human TNKS/2 and revealed more than 100 high-confidence interacting proteins with numerous biological functions in this network...
July 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28695526/identifying-and-validating-tankyrase-binders-and-substrates-a-candidate-approach
#3
Katie Pollock, Michael Ranes, Ian Collins, Sebastian Guettler
The poly(ADP-ribose)polymerase (PARP) enzyme tankyrase (TNKS/ARTD5, TNKS2/ARTD6) uses its ankyrin repeat clusters (ARCs) to recognize degenerate peptide motifs in a wide range of proteins, thereby recruiting such proteins and their complexes for scaffolding and/or poly(ADP-ribosyl)ation. Here, we provide guidance for predicting putative tankyrase-binding motifs, based on the previously delineated peptide sequence rules and existing structural information. We present a general method for the expression and purification of tankyrase ARCs from Escherichia coli and outline a fluorescence polarization assay to quantitatively assess direct ARC-TBM peptide interactions...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28683851/survival-of-apc-mutant-colorectal-cancer-cells-requires-interaction-between-tankyrase-and-a-thiol-peroxidase-peroxiredoxin-ii
#4
Dong Hoon Kang, Joanna H S Lee, Sang Won Kang
Overexpression of mammalian 2-Cys peroxiredoxin (Prx) enzymes is observed in most cancer tissues. Nevertheless, their specific role in colorectal cancer progression has yet to be fully elucidated. Here, a novel molecular mechanism by which PrxII/TNKS interaction mediates survival of APC-mutant CRC cells was explored. In mice with inactivating APC mutation, a model of spontaneous intestinal tumorigenesis, deletion of PrxII reduces intestinal adenomatous polyposis and thereby increases survival. In APC mutation-derived human CRC cells, PrxII depletion hinders the PARP-dependent Axin1 degradation through TNKS inactivation...
July 7, 2017: BMB Reports
https://www.readbyqxmd.com/read/28678390/natural-product-withanolide-inspired-small-molecules-as-potent-inhibitors-of-wnt-signaling
#5
Herbert Waldmann, Michael Sheremet, Shobhna Kapoor, Peter Schröder, Kamal Kumar, Slava Ziegler
Wnt signaling is a fundamental pathway that drives embryonic development and is essential for stem cell maintenance and tissue homeostasis. Dysregulation of Wnt signaling is linked to various diseases and a constitutively active Wnt pathway drives tumorigenesis. Thus, disruption of the Wnt response is deemed a promising strategy for cancer drug discovery. However, only few clinical drug candidates that target Wnt signaling are available so far and new small molecules modulators of Wnt-related processes are in high demand...
July 5, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28659575/interaction-of-tankyrase-and-peroxiredoxin-ii-is-indispensable-for-the-survival-of-colorectal-cancer-cells
#6
Dong Hoon Kang, Doo Jae Lee, Sunmi Lee, So-Young Lee, Yukyung Jun, Yerin Kim, Youngeun Kim, Ju-Seog Lee, Dae-Kee Lee, Sanghyuk Lee, Eek-Hoon Jho, Dae-Yeul Yu, Sang Won Kang
Mammalian 2-Cys peroxiredoxin (Prx) enzymes are overexpressed in most cancer tissues, but their specific signaling role in cancer progression is poorly understood. Here we demonstrate that Prx type II (PrxII) plays a tumor-promoting role in colorectal cancer by interacting with a poly(ADP-ribose) polymerase (PARP) tankyrase. PrxII deletion in mice with inactivating mutation of adenomatous polyposis coli (APC) gene reduces intestinal adenomatous polyposis via Axin/β-catenin axis and thereby promotes survival...
June 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28628258/tankyrase-inhibition-regulates-corpus-luteum-development-and-luteal-function-in-gonadotropin-treated-rats
#7
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
#8
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...
May 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28615517/mtor-signaling-mediates-resistance-to-tankyrase-inhibitors-in-wnt-driven-colorectal-cancer
#9
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...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28611108/wnt-%C3%AE-catenin-signaling-contributes-to-tumor-malignancy-and-is-targetable-in-gastrointestinal-stromal-tumor
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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, 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 colorectal cancer. However, colorectal cancer cells are not always sensitive to tankyrase inhibitors, and predictive biomarkers for the drug sensitivity remain elusive...
April 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28120389/modulating-the-wnt-signaling-pathway-with-small-molecules
#19
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
#20
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
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