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| rdf:type
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| Description
| - Increased nuclear accumulation of beta-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/beta-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the beta-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the beta-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl) ation activity by JW55 led to stabilization of AXIN2, a member of the beta-catenin destruction complex, followed by increased degradation of beta-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of beta-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/beta-catenin signaling through inhibiting the PARP domain of TNKS1/2.
- Increased nuclear accumulation of beta-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/beta-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the beta-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the beta-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl) ation activity by JW55 led to stabilization of AXIN2, a member of the beta-catenin destruction complex, followed by increased degradation of beta-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of beta-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/beta-catenin signaling through inhibiting the PARP domain of TNKS1/2. (en)
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| Title
| - A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice
- A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice (en)
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| skos:prefLabel
| - A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice
- A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice (en)
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| skos:notation
| - RIV/68378050:_____/12:00383115!RIV13-GA0-68378050
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| http://linked.open...avai/riv/aktivita
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| http://linked.open...avai/riv/aktivity
| - P(2B06077), P(GAP305/12/2042), Z(AV0Z50520514)
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| http://linked.open...iv/cisloPeriodika
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| http://linked.open...vai/riv/dodaniDat
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| http://linked.open...aciTvurceVysledku
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| http://linked.open.../riv/druhVysledku
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| http://linked.open...iv/duvernostUdaju
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| http://linked.open...titaPredkladatele
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| http://linked.open...dnocenehoVysledku
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| http://linked.open...ai/riv/idVysledku
| - RIV/68378050:_____/12:00383115
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| http://linked.open...riv/jazykVysledku
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| http://linked.open.../riv/klicovaSlova
| - beta-catenin; canonical Wnt signaling; tankyrase; inhibition (en)
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| http://linked.open.../riv/klicoveSlovo
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| http://linked.open...odStatuVydavatele
| - US - Spojené státy americké
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| http://linked.open...ontrolniKodProRIV
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| http://linked.open...i/riv/nazevZdroje
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| http://linked.open...in/vavai/riv/obor
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| http://linked.open...ichTvurcuVysledku
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| http://linked.open...cetTvurcuVysledku
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| http://linked.open...vavai/riv/projekt
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| http://linked.open...UplatneniVysledku
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| http://linked.open...v/svazekPeriodika
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| http://linked.open...iv/tvurceVysledku
| - Tůmová, Lucie
- Gradl, D.
- Kořínek, Vladimír
- Krauss, S.
- Machoň, Ondřej
- Dinh, H.
- Paulsen, J. E.
- Waaler, J.
- Wilson, S. R.
- von Kries, J. P.
- Eide, T. J.
- Machoňová, Olga
- Pedersen, N. M.
- Voronkov, A.
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| http://linked.open...ain/vavai/riv/wos
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| http://linked.open...n/vavai/riv/zamer
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| issn
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| number of pages
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| http://bibframe.org/vocab/doi
| - 10.1158/0008-5472.CAN-11-3336
|
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