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Statements

Subject Item
n2:RIV%2F68378050%3A_____%2F12%3A00383115%21RIV13-GA0-68378050
rdf:type
n5:Vysledek skos:Concept
dcterms: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.
dcterms: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
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
skos:notation
RIV/68378050:_____/12:00383115!RIV13-GA0-68378050
n5:predkladatel
n6:ico%3A68378050
n3:aktivita
n11:P n11:Z
n3:aktivity
P(2B06077), P(GAP305/12/2042), Z(AV0Z50520514)
n3:cisloPeriodika
11
n3:dodaniDat
n10:2013
n3:domaciTvurceVysledku
n14:8468559 n14:3517152 n14:7189346 n14:5427312
n3:druhVysledku
n20:J
n3:duvernostUdaju
n13:S
n3:entitaPredkladatele
n19:predkladatel
n3:idSjednocenehoVysledku
120485
n3:idVysledku
RIV/68378050:_____/12:00383115
n3:jazykVysledku
n17:eng
n3:klicovaSlova
beta-catenin; canonical Wnt signaling; tankyrase; inhibition
n3:klicoveSlovo
n4:canonical%20Wnt%20signaling n4:tankyrase n4:inhibition n4:beta-catenin
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[EE178C34427A]
n3:nazevZdroje
Cancer Research
n3:obor
n16:EB
n3:pocetDomacichTvurcuVysledku
4
n3:pocetTvurcuVysledku
14
n3:projekt
n7:2B06077 n7:GAP305%2F12%2F2042
n3:rokUplatneniVysledku
n10:2012
n3:svazekPeriodika
72
n3:tvurceVysledku
Voronkov, A. Paulsen, J. E. Kořínek, Vladimír Eide, T. J. Gradl, D. Machoň, Ondřej Tůmová, Lucie von Kries, J. P. Wilson, S. R. Dinh, H. Machoňová, Olga Pedersen, N. M. Krauss, S. Waaler, J.
n3:wos
000307348000015
n3:zamer
n15:AV0Z50520514
s:issn
0008-5472
s:numberOfPages
11
n18:doi
10.1158/0008-5472.CAN-11-3336