Tankyrase

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Susan Smith - One of the best experts on this subject based on the ideXlab platform.

  • Whole proteome analysis of human Tankyrase knockout cells reveals targets of Tankyrase-mediated degradation.
    Nature Communications, 2017
    Co-Authors: Amit Bhardwaj, Yanling Yang, Beatrix Ueberheide, Susan Smith
    Abstract:

    Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that function in pathways critical to cancer cell growth. Tankyrase-mediated PARylation marks protein targets for proteasomal degradation. Here, we generate human knockout cell lines to examine cell function and interrogate the proteome. We show that either Tankyrase 1 or 2 is sufficient to maintain telomere length, but both are required to resolve telomere cohesion and maintain mitotic spindle integrity. Quantitative analysis of the proteome of Tankyrase double knockout cells using isobaric tandem mass tags reveals targets of degradation, including antagonists of the Wnt/β-catenin signaling pathway (NKD1, NKD2, and HectD1) and three (Notch 1, 2, and 3) of the four Notch receptors. We show that Tankyrases are required for Notch2 to exit the plasma membrane and enter the nucleus to activate transcription. Considering that Notch signaling is commonly activated in cancer, Tankyrase inhibitors may have therapeutic potential in targeting this pathway.

  • cell cycle regulated ubiquitination of Tankyrase 1 by rnf8 and abro1 brcc36 controls the timing of sister telomere resolution
    The EMBO Journal, 2017
    Co-Authors: Ekta Tripathi, Susan Smith
    Abstract:

    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. We show that K63‐linked ubiquitin chains accumulate on Tankyrase 1 in late S/G2 to promote its stabilization, association with telomeres, and resolution of cohesion. Timing of this posttranslational modification coincides with the ATM‐mediated DNA damage response that occurs on functional telomeres following replication in G2. Removal of ubiquitin chains is controlled by ABRO1/BRCC36 and occurs as cells exit mitosis and enter G1, ensuring that telomere cohesion is not resolved prematurely in S phase. Our studies suggest that a cell cycle‐regulated posttranslational mechanism couples resolution of telomere cohesion with completion of telomere replication to ensure genome integrity. ![][1] Timely resolution of sister chromatid cohesion at telomeres by the poly(ADP‐ribose) polymerase Tankyrase 1 is essential for genome integrity, but its timing mechanism is unknown. Here, we describe a K63‐linked ubiquitination cycle that ensures telomeres are resolved in the G2/M window of the cell cycle. [1]: /embed/graphic-1.gif

  • Tankyrase 1 regulates centrosome function by controlling CPAP stability
    EMBO reports, 2012
    Co-Authors: Mi Kyung Kim, Charles Dudognon, Susan Smith
    Abstract:

    CPAP—a gene mutated in primary microcephaly—is required for procentriole formation. Here we show that CPAP degradation and function is controlled by the poly(ADP-ribose) polymerase Tankyrase 1. CPAP is PARsylated by Tankyrase 1 in vitro and in vivo. Overexpression of Tankyrase 1 leads to CPAP proteasomal degradation, preventing centriole duplication, whereas depletion of Tankyrase 1 stabilizes CPAP in G1, generating elongated procentrioles and multipolarity. Tankyrase 1 localizes to centrosomes exclusively in G1, coinciding with CPAP degradation. Hence, Tankyrase 1-mediated PARsylation regulates CPAP levels during the cell cycle to limit centriole elongation and ensure normal centrosome function.

  • GDP-Mannose-4,6-Dehydratase Is a Cytosolic Partner of Tankyrase 1 That Inhibits Its Poly(ADP-Ribose) Polymerase Activity
    Molecular and Cellular Biology, 2012
    Co-Authors: Kamlesh Bisht, William G. Chang, Charles Dudognon, Ethan S. Sokol, Alejandro F. Ramírez, Susan Smith
    Abstract:

    Tankyrase 1 is a poly(ADP-ribose) polymerase (PARP) that participates in a broad range of cellular activities due to interaction with multiple binding partners. Tankyrase 1 recognizes a linear six-amino-acid degenerate motif and, hence, has hundreds of potential target proteins. Binding of partner proteins to Tankyrase 1 usually results in their poly(ADP-ribosyl)ation (PARsylation) and can lead to ubiquitylation and proteasomal degradation. However, it is not known how Tankyrase 1 PARP activity is regulated. Here we identify GDP-mannose 4,6-dehydratase (GMD) as a binding partner of Tankyrase 1. GMD is a cytosolic protein required for the first step of fucose synthesis. We show that GMD is complexed to Tankyrase 1 in the cytosol throughout interphase, but its association with Tankyrase 1 is reduced upon entry into mitosis, when Tankyrase 1 binds to its other partners TRF1 (at telomeres) and NuMA (at spindle poles). In contrast to other binding partners, GMD is not PARsylated by Tankyrase 1. Indeed, we show that GMD inhibits Tankyrase 1 PARP activity in vitro, dependent on the GMD Tankyrase 1 binding motif. In vivo, depletion of GMD led to degradation of Tankyrase 1, dependent on the catalytic PARP activity of Tankyrase 1. We speculate that association of Tankyrase 1 with GMD in the cytosol sequesters Tankyrase 1 in an inactive stable form that can be tapped by other target proteins as needed.

  • Tankyrase 1 and Tankyrase 2 are essential but redundant for mouse embryonic development.
    PLoS ONE, 2008
    Co-Authors: Y. Jeffrey Chiang, Susan J. Hsiao, Dena R. Yver, Samuel W. Cushman, Lino Tessarollo, Susan Smith, Richard J. Hodes
    Abstract:

    Tankyrases are proteins with poly(ADP-ribose) polymerase activity. Human Tankyrases post-translationally modify multiple proteins involved in processes including maintenance of telomere length, sister telomere association, and trafficking of glut4-containing vesicles. To date, however, little is known about in vivo functions for Tankyrases. We recently reported that body size was significantly reduced in mice deficient for Tankyrase 2, but that these mice otherwise appeared developmentally normal. In the present study, we report generation of Tankyrase 1-deficient and Tankyrase 1 and 2 double-deficient mice, and use of these mutant strains to systematically assess candidate functions of Tankyrase 1 and Tankyrase 2 in vivo. No defects were observed in development, telomere length maintenance, or cell cycle regulation in Tankyrase 1 or Tankyrase 2 knockout mice. In contrast to viability and normal development of mice singly deficient in either Tankyrase, deficiency in both Tankyrase 1 and Tankyrase 2 results in embryonic lethality by day 10, indicating that there is substantial redundancy between Tankyrase 1 and Tankyrase 2, but that Tankyrase function is essential for embryonic development.

Yukiko Muramatsu - One of the best experts on this subject based on the ideXlab platform.

  • design and discovery of an orally efficacious spiroindolinone based Tankyrase inhibitor for the treatment of colon cancer
    Journal of Medicinal Chemistry, 2020
    Co-Authors: Fumiyuki Shirai, Anna Mizutani, Yukiko Muramatsu, Takeshi Tsumura, Yoko Yashiroda, Hitomi Yuki, Hideaki Niwa, Tsubasa Chikada, Yuko Kano, Shin Sato
    Abstract:

    Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent Tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and β-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.

  • rk 287107 a potent and specific Tankyrase inhibitor blocks colorectal cancer cell growth in a preclinical model
    Cancer Science, 2018
    Co-Authors: Anna Mizutani, Yukiko Muramatsu, Haruka Yoshida, Fumiyuki Shirai, Takeshi Tsumura, Yoko Yashiroda, Tsubasa Chikada, Masayuki Okue, Takehiro Fukami, Minoru Yoshida
    Abstract:

    Aberrant activation of Wnt/β-catenin signaling causes tumorigenesis and promotes the proliferation of colorectal cancer cells. Porcupine inhibitors, which block secretion of Wnt ligands, may have only limited clinical impact for the treatment of colorectal cancer, because most colorectal cancer is caused by loss-of-function mutations of the tumor suppressor adenomatous polyposis coli (APC) downstream of Wnt ligands. Tankyrase poly(ADP-ribosyl)ates (PARylates) Axin, a negative regulator of β-catenin. This post-translational modification causes ubiquitin-dependent degradation of Axin, resulting in β-catenin accumulation. Tankyrase inhibitors downregulate β-catenin and suppress the growth of APC-mutated colorectal cancer cells. Herein, we report a novel Tankyrase-specific inhibitor RK-287107, which inhibits Tankyrase-1 and -2 four- and eight-fold more potently, respectively, than G007-LK, a Tankyrase inhibitor that has been previously reported as effective in mouse xenograft models. RK-287107 causes Axin2 accumulation and downregulates β-catenin, T-cell factor/lymphoid enhancer factor reporter activity and the target gene expression in colorectal cancer cells harboring the shortly truncated APC mutations. Consistently, RK-287107 inhibits the growth of APC-mutated (β-catenin-dependent) colorectal cancer COLO-320DM and SW403 cells but not the APC-wild (β-catenin-independent) colorectal cancer RKO cells. Intraperitoneal or oral administration of RK-287107 suppresses COLO-320DM tumor growth in NOD-SCID mice. Rates of tumor growth inhibition showed good correlation with the behavior of pharmacodynamic biomarkers, such as Axin2 accumulation and MYC downregulation. These observations indicate that RK-287107 exerts a proof-of-concept antitumor effect, and thus may have potential for Tankyrase-directed molecular cancer therapy.

  • mTOR signaling mediates resistance to Tankyrase inhibitors in Wnt-driven colorectal cancer.
    Oncotarget, 2017
    Co-Authors: Tetsuo Mashima, Anna Mizutani, Yukiko Muramatsu, Noritaka Tanaka, Ayana Sato, Haruka Yoshida, Yoshikazu Sugimoto, Myungkyu Jang, Yoko Taneda, Hiroyuki Seimiya
    Abstract:

    // Tetsuo Mashima 1 , Yoko Taneda 1, 2 , Myung-Kyu Jang 1, 2 , Anna Mizutani 1 , Yukiko Muramatsu 1 , Haruka Yoshida 1 , Ayana Sato 1, 2 , Noritaka Tanaka 1, 3 , Yoshikazu Sugimoto 3 and Hiroyuki Seimiya 1, 2 1 Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan 2 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan 3 Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan Correspondence to: Hiroyuki Seimiya, email: hseimiya@jfcr.or.jp Keywords: Tankyrase, Wnt, colorectal cancer, resistance, mTOR Received: August 26, 2016     Accepted: May 03, 2017     Published: May 24, 2017 ABSTRACT 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. 320-IWR cells exhibited resistance to Tankyrase inhibitors, IWR-1 and G007-LK, but remained sensitive to a PARP-1/2 inhibitor, olaparib, and several anti-CRC agents. In 320-IWR cells, nuclear localization of active β-catenin was decreased and expression of β-catenin target genes was constitutively repressed, suggesting that these cells repressed the Wnt/β-catenin signaling and were dependent on alternative proliferation pathways. 320-IWR cells exhibited upregulated mTOR signaling and were more sensitive to mTOR inhibition than the parental cells. Importantly, mTOR inhibition reversed resistance to Tankyrase inhibitors and potentiated their anti-proliferative effects in 320-IWR cells as well as in CRC cell lines in which the mTOR pathway was intrinsically activated. These results indicate that mTOR signaling confers resistance to Tankyrase inhibitors in CRC cells and suggest that the combination of Tankyrase and mTOR inhibitors would be a useful therapeutic approach for a subset of CRCs.

  • Tankyrase binding protein tnks1bp1 regulates actin cytoskeleton rearrangement and cancer cell invasion
    Cancer Research, 2017
    Co-Authors: Tomokazu Ohishi, Yukiko Muramatsu, Haruka Yoshida, Shun-ichiro Iemura, Masamichi Katori, Toshiro Migita, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Tohru Natsume
    Abstract:

    Tankyrase, a poly(ADP-ribose) polymerase (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. TNKS1BP1 bound the actin capping protein CapZA2. TNKS1BP1 depletion dissociated CapZA2 from the cytoskeleton, leading to cofilin phosphorylation and enhanced cell invasion. Tankyrase overexpression increased cofilin phosphorylation, dissociated CapZA2 from cytoskeleton, and enhanced cell invasion in a PARP activity-dependent manner. In clinical samples of pancreatic cancer, TNKS1BP1 expression was reduced in invasive regions. We propose that the Tankyrase-TNKS1BP1 axis constitutes a post-translational modulator of cell invasion whose aberration promotes cancer malignancy.

  • Tankyrase binding protein tnks1bp1 regulates actin cytoskeleton rearrangement and cancer cell invasion
    Cancer Research, 2017
    Co-Authors: Tomokazu Ohishi, Yukiko Muramatsu, Haruka Yoshida, Shun-ichiro Iemura, Masamichi Katori, Toshiro Migita, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Tohru Natsume
    Abstract:

    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. TNKS1BP1 bound the actin-capping protein CapZA2. TNKS1BP1 depletion dissociated CapZA2 from the cytoskeleton, leading to cofilin phosphorylation and enhanced cell invasion. Tankyrase overexpression increased cofilin phosphorylation, dissociated CapZA2 from cytoskeleton, and enhanced cell invasion in a PARP activity-dependent manner. In clinical samples of pancreatic cancer, TNKS1BP1 expression was reduced in invasive regions. We propose that the Tankyrase-TNKS1BP1 axis constitutes a posttranslational modulator of cell invasion whose aberration promotes cancer malignancy. Cancer Res; 77(9); 2328-38. ©2017 AACR.

Jo Waaler - One of the best experts on this subject based on the ideXlab platform.

  • Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.
    Journal of Medicinal Chemistry, 2020
    Co-Authors: Jo Waaler, Sven T. Sowa, Albert Galera-prat, Ruben Gerardus George Leenders, Shoshy Alam Brinch, Max Lycke, Piotr Nieczypor, Sjoerd Aertssen, Sudarshan Murthy, Eddy Damen
    Abstract:

    Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed Tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the Tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these Tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC50 inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.

  • the Tankyrase inhibitor g007 lk inhibits small intestine lgr5 stem cell proliferation without altering tissue morphology
    Biological Research, 2018
    Co-Authors: Jens Henrik Norum, Raoul Kuiper, Jo Waaler, Stefan Krauss, Ellen Skarpen, Andreas Brech, Therese Sørlie
    Abstract:

    The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes Tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the Tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5+ stem cell proliferation was reversible. We show that the Tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5+ intestinal stem cells was inhibited. Our observations suggest the presence of a Tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5+ intestinal epithelial stem cells.

  • The Tankyrase inhibitor G007-LK inhibits small intestine LGR5^+ stem cell proliferation without altering tissue morphology
    Biological Research, 2018
    Co-Authors: Jens Henrik Norum, Raoul Kuiper, Jo Waaler, Stefan Krauss, Ellen Skarpen, Andreas Brech, Therese Sørlie
    Abstract:

    Background The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes Tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5^+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. Results We treated Lgr5 - EGFP - Ires - CreERT2;R26R - Confetti mice with the Tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5^+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5^+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5^+ stem cell proliferation was reversible. Conclusion We show that the Tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5^+ intestinal stem cells was inhibited. Our observations suggest the presence of a Tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5^+ intestinal epithelial stem cells.

  • the Tankyrase inhibitor g007 lk inhibits small intestine lgr5 stem cell proliferation without altering tissue morphology
    Biological Research, 2018
    Co-Authors: Jens Henrik Norum, Raoul Kuiper, Jo Waaler, Stefan Krauss, Ellen Skarpen, Andreas Brech, Therese Sørlie
    Abstract:

    The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes Tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the Tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5+ stem cell proliferation was reversible. We show that the Tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5+ intestinal stem cells was inhibited. Our observations suggest the presence of a Tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5+ intestinal epithelial stem cells.

  • abstract a18 the Tankyrase inhibitor g007 lk inhibits small intestine lgr5 stem cell proliferation without altering tissue morphology
    Cancer Research, 2016
    Co-Authors: Jens Henrik Norum, Raoul Kuiper, Jo Waaler, Stefan Krauss, Ellen Skarpen, Andreas Brech, Therese Sørlie
    Abstract:

    Tankyrase enzymes play crucial roles in the Wnt signaling pathway, involved in the regulation of intestinal stem cells and tissue homeostasis. Aberrant Wnt signaling is known to cause intestinal cancers and the Tankyrase inhibitor G007-LK has previously been shown to inhibit tumor growth in an APC-mutant colorectal cancer xenograft model. We have used in vivo models to address the effect of G007-LK on small intestine tissue homeostasis. The mice were treated for up to 3 weeks with the Tankyrase inhibitor, without affecting the body mass or observed clinical condition of the mice. HE 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A18.

Tohru Natsume - One of the best experts on this subject based on the ideXlab platform.

  • MERIT40-dependent recruitment of Tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs.
    Oncotarget, 2018
    Co-Authors: Keiji Okamoto, Tomokazu Ohishi, Mika Kuroiwa, Shun-ichiro Iemura, Tohru Natsume, Hiroyuki Seimiya
    Abstract:

    Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, regulates various intracellular responses, such as telomere maintenance, Wnt/β-catenin signaling and cell cycle progression through its interactions with multiple target proteins. Tankyrase contains a long stretch of 24 ankyrin repeats that are further divided into five subdomains, called ANK repeat clusters (ARCs). Each ARC works as an independent ligand-binding unit, which implicates Tankyrase as a platform for multiple protein-protein interactions. Furthermore, Tankyrase distributes to various intracellular loci, suggesting potential distinct but yet unidentified physiological functions. To explore the novel functions of Tankyrase, we performed liquid chromatography-mass spectrometry analysis and identified the BRE-BRCC36-MERIT40 complex, a regulator of homologous recombination, as Tankyrase-binding proteins. Among the complex components, MERIT40 was directly associated with Tankyrase via a Tankyrase-binding consensus motif, as previously reported. In X-ray-irradiated non-small cell lung cancer cells, Tankyrase localized to DNA double-stranded break sites in a MERIT40-dependent manner. MERIT40 knockdown increased the cell sensitivity to X-ray, whereas the wild-type, but not the Tankyrase-unbound mutant, MERIT40 rescued the phenotype of the knockdown cells. Tankyrase inhibitors, such as G007-LK and XAV939, increased the cellular sensitivity to X-ray irradiation and anticancer drugs that induce DNA double-stranded breaks. These observations suggest that Tankyrase plays a role in the DNA damage repair response and implicates a potential therapeutic utility of Tankyrase inhibitors in combination treatments with DNA-damaging anticancer drugs.

  • Tankyrase binding protein tnks1bp1 regulates actin cytoskeleton rearrangement and cancer cell invasion
    Cancer Research, 2017
    Co-Authors: Tomokazu Ohishi, Yukiko Muramatsu, Haruka Yoshida, Shun-ichiro Iemura, Masamichi Katori, Toshiro Migita, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Tohru Natsume
    Abstract:

    Tankyrase, a poly(ADP-ribose) polymerase (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. TNKS1BP1 bound the actin capping protein CapZA2. TNKS1BP1 depletion dissociated CapZA2 from the cytoskeleton, leading to cofilin phosphorylation and enhanced cell invasion. Tankyrase overexpression increased cofilin phosphorylation, dissociated CapZA2 from cytoskeleton, and enhanced cell invasion in a PARP activity-dependent manner. In clinical samples of pancreatic cancer, TNKS1BP1 expression was reduced in invasive regions. We propose that the Tankyrase-TNKS1BP1 axis constitutes a post-translational modulator of cell invasion whose aberration promotes cancer malignancy.

  • Tankyrase binding protein tnks1bp1 regulates actin cytoskeleton rearrangement and cancer cell invasion
    Cancer Research, 2017
    Co-Authors: Tomokazu Ohishi, Yukiko Muramatsu, Haruka Yoshida, Shun-ichiro Iemura, Masamichi Katori, Toshiro Migita, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Tohru Natsume
    Abstract:

    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. TNKS1BP1 bound the actin-capping protein CapZA2. TNKS1BP1 depletion dissociated CapZA2 from the cytoskeleton, leading to cofilin phosphorylation and enhanced cell invasion. Tankyrase overexpression increased cofilin phosphorylation, dissociated CapZA2 from cytoskeleton, and enhanced cell invasion in a PARP activity-dependent manner. In clinical samples of pancreatic cancer, TNKS1BP1 expression was reduced in invasive regions. We propose that the Tankyrase-TNKS1BP1 axis constitutes a posttranslational modulator of cell invasion whose aberration promotes cancer malignancy. Cancer Res; 77(9); 2328-38. ©2017 AACR.

Tomokazu Ohishi - One of the best experts on this subject based on the ideXlab platform.

  • MERIT40-dependent recruitment of Tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs.
    Oncotarget, 2018
    Co-Authors: Keiji Okamoto, Tomokazu Ohishi, Mika Kuroiwa, Shun-ichiro Iemura, Tohru Natsume, Hiroyuki Seimiya
    Abstract:

    Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, regulates various intracellular responses, such as telomere maintenance, Wnt/β-catenin signaling and cell cycle progression through its interactions with multiple target proteins. Tankyrase contains a long stretch of 24 ankyrin repeats that are further divided into five subdomains, called ANK repeat clusters (ARCs). Each ARC works as an independent ligand-binding unit, which implicates Tankyrase as a platform for multiple protein-protein interactions. Furthermore, Tankyrase distributes to various intracellular loci, suggesting potential distinct but yet unidentified physiological functions. To explore the novel functions of Tankyrase, we performed liquid chromatography-mass spectrometry analysis and identified the BRE-BRCC36-MERIT40 complex, a regulator of homologous recombination, as Tankyrase-binding proteins. Among the complex components, MERIT40 was directly associated with Tankyrase via a Tankyrase-binding consensus motif, as previously reported. In X-ray-irradiated non-small cell lung cancer cells, Tankyrase localized to DNA double-stranded break sites in a MERIT40-dependent manner. MERIT40 knockdown increased the cell sensitivity to X-ray, whereas the wild-type, but not the Tankyrase-unbound mutant, MERIT40 rescued the phenotype of the knockdown cells. Tankyrase inhibitors, such as G007-LK and XAV939, increased the cellular sensitivity to X-ray irradiation and anticancer drugs that induce DNA double-stranded breaks. These observations suggest that Tankyrase plays a role in the DNA damage repair response and implicates a potential therapeutic utility of Tankyrase inhibitors in combination treatments with DNA-damaging anticancer drugs.

  • Tankyrase binding protein tnks1bp1 regulates actin cytoskeleton rearrangement and cancer cell invasion
    Cancer Research, 2017
    Co-Authors: Tomokazu Ohishi, Yukiko Muramatsu, Haruka Yoshida, Shun-ichiro Iemura, Masamichi Katori, Toshiro Migita, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Tohru Natsume
    Abstract:

    Tankyrase, a poly(ADP-ribose) polymerase (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. TNKS1BP1 bound the actin capping protein CapZA2. TNKS1BP1 depletion dissociated CapZA2 from the cytoskeleton, leading to cofilin phosphorylation and enhanced cell invasion. Tankyrase overexpression increased cofilin phosphorylation, dissociated CapZA2 from cytoskeleton, and enhanced cell invasion in a PARP activity-dependent manner. In clinical samples of pancreatic cancer, TNKS1BP1 expression was reduced in invasive regions. We propose that the Tankyrase-TNKS1BP1 axis constitutes a post-translational modulator of cell invasion whose aberration promotes cancer malignancy.

  • Tankyrase binding protein tnks1bp1 regulates actin cytoskeleton rearrangement and cancer cell invasion
    Cancer Research, 2017
    Co-Authors: Tomokazu Ohishi, Yukiko Muramatsu, Haruka Yoshida, Shun-ichiro Iemura, Masamichi Katori, Toshiro Migita, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Tohru Natsume
    Abstract:

    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. TNKS1BP1 bound the actin-capping protein CapZA2. TNKS1BP1 depletion dissociated CapZA2 from the cytoskeleton, leading to cofilin phosphorylation and enhanced cell invasion. Tankyrase overexpression increased cofilin phosphorylation, dissociated CapZA2 from cytoskeleton, and enhanced cell invasion in a PARP activity-dependent manner. In clinical samples of pancreatic cancer, TNKS1BP1 expression was reduced in invasive regions. We propose that the Tankyrase-TNKS1BP1 axis constitutes a posttranslational modulator of cell invasion whose aberration promotes cancer malignancy. Cancer Res; 77(9); 2328-38. ©2017 AACR.

  • Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer
    Oncogene, 2009
    Co-Authors: Nuala Mccabe, Hiroyuki Seimiya, Christopher J. Lord, Tomokazu Ohishi, Maria Antonietta Cerone, Alan Ashworth
    Abstract:

    The BRCA1 and BRCA2 proteins are involved in the maintenance of genome stability and germ-line loss-of-function mutations in either BRCA1 or BRCA2 strongly predispose carriers to cancers of the breast and other organs. It has been demonstrated previously that inhibiting elements of the cellular DNA maintenance pathways represents a novel therapeutic approach to treating tumors in these individuals. Here, we show that inhibition of the telomere-associated protein, Tankyrase 1, is also selectively lethal with BRCA deficiency. We also demonstrate that the selectivity caused by inhibition of Tankyrase 1 is associated with an exacerbation of the centrosome amplification phenotype associated with BRCA deficiency. We propose that inhibition of Tankyrase 1 could be therapeutically exploited in BRCA-associated cancers.

  • Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics
    Cancer Cell, 2005
    Co-Authors: Hiroyuki Seimiya, Yukiko Muramatsu, Tomokazu Ohishi, Takashi Tsuruo
    Abstract:

    Telomere elongation by telomerase is repressed in cis by the telomeric protein TRF1. Tankyrase 1 poly(ADP-ribosyl)ates TRF1 and releases it from telomeres, allowing access of telomerase to telomeres. Here we demonstrate that Tankyrase 1 inhibition in human cancer cells enhances telomere shortening by a telomerase inhibitor and hastens cell death. Conversely, either Tankyrase 1 upregulation or telomere shortening, each of which decreased TRF1 loading on a chromosome end, attenuated the impact of telomerase inhibition. These results are consistent with the idea that telomeres having fewer TRF1s increase the efficiency of their elongation by telomerase. This study implies that both enzyme activity and accessibility to telomeres can be targets for telomerase inhibition.