Base de dados : MEDLINE
Pesquisa : D08.811.913.400.725.115.690.840 [Categoria DeCS]
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  1 / 268 MEDLINE  
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[PMID]:28877210
[Au] Autor:Jia J; Qiao Y; Pilo MG; Cigliano A; Liu X; Shao Z; Calvisi DF; Chen X
[Ad] Endereço:Department of Oncology and Hematology, The Second Hospital, Jilin University, Changchun, China.
[Ti] Título:Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade.
[So] Source:PLoS One;12(9):e0184068, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous data indicate that Tankyrase inhibitors exert anti-growth functions in many cancer cell lines due to their ability to inactivate the YAP protooncogene. In the present manuscript, we investigated the effect of Tankyrase inhibitors on the growth of hepatocellular carcinoma (HCC) cell lines and the molecular mechanisms involved. For this purpose, we performed cell proliferation assay by colony-forming ability in seven human HCC cells subjected to XAV-939 and G007-LK Tankyrase inhibitors. Noticeably, the two Tankyrase inhibitors suppressed the HCC cell growth in a dose-dependent manner. Furthermore, we found that Tankyrase inhibitors synergized with MEK and AKT inhibitors to suppress HCC cell proliferation. At the molecular level, Tankyrase inhibitors significantly decreased YAP protein levels, reduced the expression of YAP target genes, and inhibited YAP/TEAD luciferase reporter activity. In addition, Tankyrase inhibitors administration was accompanied by upregulation of Angiomotin-like 1 (AMOTL1) and Angiomotin-like 2 (AMOTL2) proteins, two major negative regulators of YAP. Altogether, the present data indicate that XAV-939 and G007-LK Tankyrase inhibitors could suppress proliferation of hepatocellular carcinoma cells and downregulate YAP/TAZ by stabilizing AMOTL1 and AMOTL2 proteins, thus representing new potential anticancer drugs against hepatocellular carcinoma.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Carcinoma Hepatocelular/tratamento farmacológico
Compostos Heterocíclicos com 3 Anéis/uso terapêutico
Neoplasias Hepáticas/tratamento farmacológico
Sulfonas/uso terapêutico
Tanquirases/antagonistas & inibidores
Triazóis/uso terapêutico
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Apoptose/efeitos dos fármacos
Western Blotting
Proteínas de Transporte/metabolismo
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Proteínas de Membrana/metabolismo
Fosfoproteínas/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AMOTL1 protein, human); 0 (AMOTL2 protein, human); 0 (Adaptor Proteins, Signal Transducing); 0 (Antineoplastic Agents); 0 (Carrier Proteins); 0 (G007-LK); 0 (Heterocyclic Compounds, 3-Ring); 0 (Membrane Proteins); 0 (Phosphoproteins); 0 (Sulfones); 0 (Triazoles); 0 (XAV939); 0 (YAP1 (Yes-associated) protein, human); EC 2.4.2.30 (Tankyrases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184068


  2 / 268 MEDLINE  
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[PMID]:28659575
[Au] Autor:Kang DH; Lee DJ; Lee S; Lee SY; Jun Y; Kim Y; Kim Y; Lee JS; Lee DK; Lee S; Jho EH; Yu DY; Kang SW
[Ad] Endereço:Department of Life Science, Ewha Womans University, Seoul, 120-750, Korea.
[Ti] Título:Interaction of tankyrase and peroxiredoxin II is indispensable for the survival of colorectal cancer cells.
[So] Source:Nat Commun;8(1):40, 2017 06 28.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo: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/ß-catenin axis and thereby promotes survival. In human colorectal cancer cells with APC mutations, PrxII depletion consistently reduces the ß-catenin levels and the expression of ß-catenin target genes. Essentially, PrxII depletion hampers the PARP-dependent Axin1 degradation through tankyrase inactivation. Direct binding of PrxII to tankyrase ARC4/5 domains seems to be crucial for protecting tankyrase from oxidative inactivation. Furthermore, a chemical compound targeting PrxII inhibits the expansion of APC-mutant colorectal cancer cells in vitro and in vivo tumor xenografts. Collectively, this study reveals a redox mechanism for regulating tankyrase activity and implicates PrxII as a targetable antioxidant enzyme in APC-mutation-positive colorectal cancer.2-Cys peroxiredoxin (Prx) enzymes are highly expressed in most cancers but how they promote cancer progression is unclear. Here the authors show that in colorectal cancers with APC mutation, PrxII binds to tankyrase and prevents its oxidative inactivation, thereby preventing Axin1-dependent degradation of ²b-catenin.
[Mh] Termos MeSH primário: Neoplasias Colorretais/metabolismo
Regulação Enzimológica da Expressão Gênica/fisiologia
Regulação Neoplásica da Expressão Gênica/fisiologia
Peroxirredoxinas/metabolismo
Tanquirases/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Neoplasias Colorretais/genética
Seres Humanos
Camundongos
Neoplasias Experimentais
Peroxirredoxinas/genética
Tanquirases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 1.11.1.15 (Peroxiredoxins); EC 2.4.2.30 (Tankyrases); EC 2.4.4.30 (TNKS protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-00054-0


  3 / 268 MEDLINE  
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[PMID]:28619731
[Au] Autor:Xu D; Liu J; Fu T; Shan B; Qian L; Pan L; Yuan J
[Ad] Endereço:Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Pudong, Shanghai 201210, China.
[Ti] Título:USP25 regulates Wnt signaling by controlling the stability of tankyrases.
[So] Source:Genes Dev;31(10):1024-1035, 2017 May 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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 ß-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 ß-catenin. Thus, regulation of the levels and activity of tankyrases is mechanistically important in controlling Wnt signaling. Here, we identify ubiquitin-specific protease 25 (USP25) as a positive regulator of Wnt/ß-catenin signaling. We found that USP25 directly interacted with tankyrases to promote their deubiquitination and stabilization. We demonstrated that USP25 deficiency could promote the degradation of tankyrases and consequent stabilization of Axin to antagonize Wnt signaling. We further characterized the interaction between TNKS1 and USP25 by X-ray crystal structure determination. Our results provide important new insights into the molecular mechanism that regulates the turnover of tankyrases and the possibility of targeting the stability of tankyrases by antagonizing their interaction with USP25 to modulate the Wnt/ß-catenin pathway.
[Mh] Termos MeSH primário: Estabilidade Enzimática/genética
Tanquirases/metabolismo
Ubiquitina Tiolesterase/metabolismo
Via de Sinalização Wnt/fisiologia
[Mh] Termos MeSH secundário: Repetição de Anquirina
Proteína Axina/metabolismo
Linhagem Celular
Cristalografia por Raios X
Células HCT116
Células HEK293
Seres Humanos
Mutação
Ligação Proteica
Tanquirases/química
Ubiquitina Tiolesterase/química
Ubiquitina Tiolesterase/genética
Via de Sinalização Wnt/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Axin Protein); EC 2.4.2.30 (Tankyrases); EC 2.4.4.30 (TNKS protein, human); EC 3.1.2.15 (USP25 protein, human); EC 3.4.19.12 (Ubiquitin Thiolesterase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1101/gad.300889.117


  4 / 268 MEDLINE  
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[PMID]:28591512
[Au] Autor:Thomson DW; Wagner AJ; Bantscheff M; Benson RE; Dittus L; Duempelfeld B; Drewes G; Krause J; Moore JT; Mueller K; Poeckel D; Rau C; Salzer E; Shewchuk L; Hopf C; Emery JG; Muelbaier M
[Ad] Endereço:Cellzome GmbH, A GlaxoSmithKline Company , Meyerhofstraße 1, 69117 Heidelberg, Germany.
[Ti] Título:Discovery of a Highly Selective Tankyrase Inhibitor Displaying Growth Inhibition Effects against a Diverse Range of Tumor Derived Cell Lines.
[So] Source:J Med Chem;60(13):5455-5471, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Descoberta de Drogas
Inibidores Enzimáticos/farmacologia
Quinoxalinas/farmacologia
Tanquirases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Seres Humanos
Ligantes
Modelos Moleculares
Estrutura Molecular
Quinoxalinas/síntese química
Quinoxalinas/química
Relação Estrutura-Atividade
Tanquirases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Ligands); 0 (Quinoxalines); 0 (tetrazoloquinoxaline); EC 2.4.2.30 (Tankyrases); EC 2.4.4.30 (TNKS protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170608
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00137


  5 / 268 MEDLINE  
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[PMID]:28179481
[Au] Autor:Tanaka N; Mashima T; Mizutani A; Sato A; Aoyama A; Gong B; Yoshida H; Muramatsu Y; Nakata K; Matsuura M; Katayama R; Nagayama S; Fujita N; Sugimoto Y; Seimiya H
[Ad] Endereço:Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
[Ti] Título: Mutations as a Potential Biomarker for Sensitivity to Tankyrase Inhibitors in Colorectal Cancer.
[So] Source:Mol Cancer Ther;16(4):752-762, 2017 Apr.
[Is] ISSN:1538-8514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In most colorectal cancers, Wnt/ß-catenin signaling is activated by loss-of-function mutations in the ( ) gene and plays a critical role in tumorigenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a negative regulator of ß-catenin, and upregulate ß-catenin signaling. Tankyrase inhibitors downregulate ß-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. Here we demonstrate that the short-form mutations predict the sensitivity of colorectal cancer cells to tankyrase inhibitors. By using well-established colorectal cancer cell lines, we found that tankyrase inhibitors downregulated ß-catenin in the drug-sensitive, but not resistant, colorectal cancer cells. The drug-sensitive cells showed higher Tcf/LEF transcriptional activity than the resistant cells and possessed "short" truncated APCs lacking all seven ß-catenin-binding 20-amino acid repeats (20-AARs). In contrast, the drug-resistant cells possessed "long" APC retaining two or more 20-AARs. Knockdown of the long APCs with two 20-AARs increased ß-catenin, Tcf/LEF transcriptional activity and its target gene expression. Under these conditions, tankyrase inhibitors were able to downregulate ß-catenin in the resistant cells. These results indicate that the long APCs are hypomorphic mutants, whereas they exert a dominant-negative effect on Axin-dependent ß-catenin degradation caused by tankyrase inhibitors. Finally, we established 16 patient-derived colorectal cancer cells and confirmed that the tankyrase inhibitor-responsive cells harbor the short-form APC mutations. These observations exemplify the predictive importance of mutations, the most common genetic alteration in colorectal cancers, for molecular targeted therapeutics. .
[Mh] Termos MeSH primário: Proteína da Polipose Adenomatosa do Colo/genética
Biomarcadores Tumorais/genética
Neoplasias Colorretais/genética
Inibidores Enzimáticos/farmacologia
Tanquirases/antagonistas & inibidores
Via de Sinalização Wnt/efeitos dos fármacos
[Mh] Termos MeSH secundário: Proteína da Polipose Adenomatosa do Colo/metabolismo
Sítios de Ligação
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Neoplasias Colorretais/tratamento farmacológico
Neoplasias Colorretais/enzimologia
Células HCT116
Células HT29
Compostos Heterocíclicos com 3 Anéis/farmacologia
Seres Humanos
Imidas/farmacologia
Ligação Proteica
Quinolinas/farmacologia
Sulfonas/farmacologia
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APC protein, human); 0 (Adenomatous Polyposis Coli Protein); 0 (Biomarkers, Tumor); 0 (Enzyme Inhibitors); 0 (G007-LK); 0 (Heterocyclic Compounds, 3-Ring); 0 (IWR-1 compound); 0 (Imides); 0 (Quinolines); 0 (Sulfones); 0 (Triazoles); 0 (XAV939); EC 2.4.2.30 (Tankyrases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1158/1535-7163.MCT-16-0578


  6 / 268 MEDLINE  
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[PMID]:28160604
[Au] Autor:Yang L; Sun L; Teng Y; Chen H; Gao Y; Levine AS; Nakajima S; Lan L
[Ad] Endereço:School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.
[Ti] Título:Tankyrase1-mediated poly(ADP-ribosyl)ation of TRF1 maintains cell survival after telomeric DNA damage.
[So] Source:Nucleic Acids Res;45(7):3906-3921, 2017 Apr 20.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Oxidative DNA damage triggers telomere erosion and cellular senescence. However, how repair is initiated at telomeres is largely unknown. Here, we found unlike PARP1-mediated Poly-ADP-Ribosylation (PARylation) at genomic damage sites, PARylation at telomeres is mainly dependent on tankyrase1 (TNKS1). TNKS1 is recruited to damaged telomeres via its interaction with TRF1, which subsequently facilitates the PARylation of TRF1 after damage. TNKS inhibition abolishes the recruitment of the repair proteins XRCC1 and polymerase ß at damaged telomeres, while the PARP1/2 inhibitor only has such an effect at non-telomeric damage sites. The ANK domain of TNKS1 is essential for the telomeric damage response and TRF1 interaction. Mutation of the tankyrase-binding motif (TBM) on TRF1 (13R/18G to AA) disrupts its interaction with TNKS1 concomitant recruitment of TNKS1 and repair proteins after damage. Either TNKS1 inhibition or TBM mutated TRF1 expression markedly sensitizes cells to telomere oxidative damage as well as XRCC1 inhibition. Together, our data reveal a novel role of TNKS1 in facilitating SSBR at damaged telomeres through PARylation of TRF1, thereby protecting genome stability and cell viability.
[Mh] Termos MeSH primário: Reparo do DNA
Tanquirases/metabolismo
Telômero/enzimologia
Proteína 1 de Ligação a Repetições Teloméricas/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Sobrevivência Celular
Dano ao DNA
Instabilidade Genômica
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Telomeric Repeat Binding Protein 1); EC 2.4.2.30 (Tankyrases); EC 2.4.4.30 (TNKS protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170205
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx083


  7 / 268 MEDLINE  
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[PMID]:28158503
[Au] Autor:Sun L; Nakajima S; Teng Y; Chen H; Yang L; Chen X; Gao B; Levine AS; Lan L
[Ad] Endereço:School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.
[Ti] Título:WRN is recruited to damaged telomeres via its RQC domain and tankyrase1-mediated poly-ADP-ribosylation of TRF1.
[So] Source:Nucleic Acids Res;45(7):3844-3859, 2017 Apr 20.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Werner syndrome (WS) is a progeroid-like syndrome caused by WRN gene mutations. WS cells exhibit shorter telomere length compared to normal cells, but it is not fully understood how WRN deficiency leads directly to telomere dysfunction. By generating localized telomere-specific DNA damage in a real-time fashion and a dose-dependent manner, we found that the damage response of WRN at telomeres relies on its RQC domain, which is different from the canonical damage response at genomic sites via its HRDC domain. We showed that in addition to steady state telomere erosion, WRN depleted cells are also sensitive to telomeric damage. WRN responds to site-specific telomeric damage via its RQC domain, interacting at Lysine 1016 and Phenylalanine1037 with the N-terminal acidic domain of the telomere shelterin protein TRF1 and demonstrating a novel mechanism for WRN's role in telomere protection. We also found that tankyrase1-mediated poly-ADP-ribosylation of TRF1 is important for both the interaction between WRN and TRF1 and the damage recruitment of WRN to telomeres. Mutations of potential tankyrase1 ADP-ribosylation sites within the RGCADG motif of TRF1 strongly diminish the interaction with WRN and the damage response of WRN only at telomeres. Taken together, our results reveal a novel mechanism as to how WRN protects telomere integrity from damage and telomere erosion.
[Mh] Termos MeSH primário: Reparo do DNA
Tanquirases/metabolismo
Telômero/enzimologia
Proteína 1 de Ligação a Repetições Teloméricas/metabolismo
Helicase da Síndrome de Werner/metabolismo
[Mh] Termos MeSH secundário: Animais
Sobrevivência Celular
Células Cultivadas
Dano ao DNA
Seres Humanos
Oxirredução
Domínios e Motivos de Interação entre Proteínas
Espécies Reativas de Oxigênio/metabolismo
Telômero/metabolismo
Proteína 1 de Ligação a Repetições Teloméricas/química
Helicase da Síndrome de Werner/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species); 0 (Telomeric Repeat Binding Protein 1); EC 2.4.2.30 (Tankyrases); EC 2.4.4.30 (TNKS protein, human); EC 3.6.4.12 (WRN protein, human); EC 3.6.4.12 (Werner Syndrome Helicase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170204
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx065


  8 / 268 MEDLINE  
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[PMID]:28107521
[Au] Autor:Thorvaldsen TE; Pedersen NM; Wenzel EM; Stenmark H
[Ad] Endereço:Centre for Cancer Biomedicine, Faculty of Medicine, Oslo University Hospital, Oslo, Norway.
[Ti] Título:Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor-Induced Formation of Degradasomes and ß-Catenin Degradation.
[So] Source:PLoS One;12(1):e0170508, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Inhibition of the tankyrase enzymes (TNKS1 and TNKS2) has recently been shown to induce highly dynamic assemblies of ß-catenin destruction complex components known as degradasomes, which promote degradation of ß-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 ß-catenin destruction complexes. In SW480 colorectal cancer cells treated with the tankyrase inhibitor (TNKSi) G007-LK we found that AXIN1 was not required for degradasome formation. In contrast, the formation of degradasomes as well as their capacity to degrade ß-catenin were considerably impaired in G007-LK-treated cells depleted of AXIN2. These findings give novel insights into differential functional roles of AXIN1 versus AXIN2 in the ß-catenin destruction complex.
[Mh] Termos MeSH primário: Proteína Axina/fisiologia
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Western Blotting
Linhagem Celular Tumoral
Neoplasias Colorretais/fisiopatologia
Vesículas Citoplasmáticas/fisiologia
Seres Humanos
Complexo de Endopeptidases do Proteassoma/fisiologia
Proteólise
Sulfonas/farmacologia
Tanquirases/antagonistas & inibidores
Triazóis/farmacologia
Via de Sinalização Wnt/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AXIN1 protein, human); 0 (AXIN2 protein, human); 0 (Axin Protein); 0 (G007-LK); 0 (Sulfones); 0 (Triazoles); 0 (beta Catenin); EC 2.4.2.30 (Tankyrases); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170823
[Lr] Data última revisão:
170823
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170121
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0170508


  9 / 268 MEDLINE  
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[PMID]:28001384
[Au] Autor:Thorsell AG; Ekblad T; Karlberg T; Löw M; Pinto AF; Trésaugues L; Moche M; Cohen MS; Schüler H
[Ti] Título:Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
[So] Source:J Med Chem;60(4):1262-1271, 2017 Feb 23.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Inibidores de Poli(ADP-Ribose) Polimerases/química
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Tanquirases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Benzimidazóis/química
Benzimidazóis/farmacologia
Células HEK293
Seres Humanos
Indazóis/química
Indazóis/farmacologia
Modelos Moleculares
Fenantrenos/química
Fenantrenos/farmacologia
Ftalazinas/química
Ftalazinas/farmacologia
Piperazinas/química
Piperazinas/farmacologia
Piperidinas/química
Piperidinas/farmacologia
Poli(ADP-Ribose) Polimerases/metabolismo
Tanquirases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzimidazoles); 0 (Enzyme Inhibitors); 0 (Indazoles); 0 (N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride); 0 (Phenanthrenes); 0 (Phthalazines); 0 (Piperazines); 0 (Piperidines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 01O4K0631N (veliparib); 9QHX048FRV (talazoparib); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 2.4.2.30 (Tankyrases); HMC2H89N35 (niraparib); WOH1JD9AR8 (olaparib)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b00990


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[PMID]:27995250
[Au] Autor:Pu Y; Zhang S; Chang Z; Zhang Y; Wang D; Zhang L; Li Y; Zuo Z
[Ad] Endereço:School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong, China and State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. zuozhili@mail.kib.ac.cn.
[Ti] Título:Discovery of new dual binding TNKS inhibitors of Wnt signaling inhibition by pharmacophore modeling, molecular docking and bioassay.
[So] Source:Mol Biosyst;13(2):363-370, 2017 Jan 31.
[Is] ISSN:1742-2051
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo: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 IC 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. This work could be helpful for the design and development of novel dual binders as TNKS inhibitors.
[Mh] Termos MeSH primário: Simulação de Acoplamento Molecular
Simulação de Dinâmica Molecular
Inibidores de Poli(ADP-Ribose) Polimerases/química
Tanquirases/química
[Mh] Termos MeSH secundário: Análise por Conglomerados
Simulação por Computador
Descoberta de Drogas
Concentração Inibidora 50
Ligantes
Conformação Molecular
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Ligação Proteica
Relação Quantitativa Estrutura-Atividade
Tanquirases/antagonistas & inibidores
Via de Sinalização Wnt/efeitos dos fármacos
Fluxo de Trabalho
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Poly(ADP-ribose) Polymerase Inhibitors); EC 2.4.2.30 (Tankyrases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161221
[St] Status:MEDLINE
[do] DOI:10.1039/c6mb00712k



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