Tankyrase 1 and Tankyrase 2 Are Essential but Redundant for Mouse Embryonic Development

Chiang, Y. Jeffrey; Hsiao, Susan J.; Yver, Dena R.; Cushman, Samuel W.; Tessarollo, Lino; Smith, Susan; Hodes, Richard J.

doi:10.1371/journal.pone.0002639

Cited by 137 publications

(129 citation statements)

References 32 publications

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“…Tank1 is thus believed to disrupt a "telomere cohesion complex" that holds telomeres together till separation at anaphase [18] . Consistent with the in vitro observations, both Tank1 and Tank2 are found to be essential though redundant for mouse embryonic development [19] . In addition, Tank1/2 are also found to regulate the Wnt/β-cantenin pathway (see the following).…”

Section: Poly(adp-ribose) Polymerase Inhibitors As Promising Cancer Tsupporting

confidence: 86%

Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics

Yang

Miao

2010

Acta Pharmacol Sin

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The year of 2005 was a watershed in the history of poly(ADP-ribose) polymerase (PARP) inhibitors due to the important findings of selective killing in BRCA-deficient cancers by PARP inhibition. The findings made PARP inhibition one of the most promising new therapeutic approaches to cancers, especially to those with specific defects. With AZD2281 and BSI-201 entering phase III clinical trials, the final application of PARP inhibitors in clinic would come true soon. This current paper will review the major advances in targeting PARP for cancer therapy and discuss the existing questions, the answers to which may influence the future of PARP inhibitors as cancer therapeutics.

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Section: Poly(adp-ribose) Polymerase Inhibitors As Promising Cancer Tsupporting

confidence: 86%

Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics

Yang

Miao

2010

Acta Pharmacol Sin

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“…Similarly, no defects in Wntdependent processes were observed after treatment of fish with Tnks inhibitors during embryonic development (Huang et al, 2009), but these inhibitors disrupted the regeneration of adult fins following injury (Chen et al, 2009;Huang et al, 2009), a process that is dependent on Wnt and several other signaling pathways (Wehner and Weidinger, 2015). Finally, functional redundancy exists between the two Tnks homologs in mice (Chiang et al, 2008) and double mutants displayed embryonic lethality, but no overt Wnt-related phenotypes (see also Discussion in Qian et al, 2011). However, a mutation in mouse Axin2 that is predicted to disrupt Tnks-dependent ADP-ribosylation paradoxically resulted in both hyperactivating and inhibiting effects on Wnt signaling in the primitive streak that were dependent on developmental stage.…”

Section: Introductionmentioning

confidence: 99%

The ADP-ribose polymerase Tankyrase regulates adult intestinal stem cell proliferation during homeostasis in Drosophila

et al. 2016

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Wnt/β-catenin signaling controls intestinal stem cell (ISC) proliferation, and is aberrantly activated in colorectal cancer. Inhibitors of the ADP-ribose polymerase Tankyrase (Tnks) have become lead therapeutic candidates for Wnt-driven cancers, following the recent discovery that Tnks targets Axin, a negative regulator of Wnt signaling, for proteolysis. Initial reports indicated that Tnks is important for Wnt pathway activation in cultured human cell lines. However, the requirement for Tnks in physiological settings has been less clear, as subsequent studies in mice, fish and flies suggested that Tnks was either entirely dispensable for Wntdependent processes in vivo, or alternatively, had tissue-specific roles. Here, using null alleles, we demonstrate that the regulation of Axin by the highly conserved Drosophila Tnks homolog is essential for the control of ISC proliferation. Furthermore, in the adult intestine, where activity of the Wingless pathway is graded and peaks at each compartmental boundary, Tnks is dispensable for signaling in regions where pathway activity is high, but essential where pathway activity is relatively low. Finally, as observed previously for Wingless pathway components, Tnks activity in absorptive enterocytes controls the proliferation of neighboring ISCs non-autonomously by regulating JAK/STAT signaling. These findings reveal the requirement for Tnks in the control of ISC proliferation and suggest an essential role in the amplification of Wnt signaling, with relevance for development, homeostasis and cancer.

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“…GENES & DEVELOPMENT Chiang et al 2008), suggesting that TNKS1 and TNKS2 have redundant functions during embryonic development. These findings are in agreement with our observations.…”

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confidence: 99%

Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth

Zhang

Han³

et al. 2014

Genes Dev.

114

126

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PTEN [phosphatidylinositol (3,4,5)-trisphosphate phosphatase and tensin homolog deleted from chromosome 10], a phosphatase and critical tumor suppressor, is regulated by numerous post-translational modifications, including phosphorylation, ubiquitination, acetylation, and SUMOylation, which affect PTEN localization and protein stability. Here we report ADP-ribosylation as a new post-translational modification of PTEN. We identified PTEN as a novel substrate of tankyrases, which are members of the poly(ADP-ribose) polymerases (PARPs). We showed that tankyrases interact with and ribosylate PTEN, which promotes the recognition of PTEN by a PAR-binding E3 ubiquitin ligase, RNF146, leading to PTEN ubiquitination and degradation. Double knockdown of tankyrase1/2 stabilized PTEN, resulting in the subsequent down-regulation of AKT phosphorylation and thus suppressed cell proliferation and glycolysis in vitro and tumor growth in vivo. Furthermore, tankyrases were up-regulated and negatively correlated with PTEN expression in human colon carcinomas. Together, our study revealed a new regulation of PTEN and highlighted a role for tankyrases in the PTEN-AKT pathway that can be explored further for cancer treatment.

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Tankyrase 1 and Tankyrase 2 Are Essential but Redundant for Mouse Embryonic Development

Cited by 137 publications

References 32 publications

Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics

Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics

The ADP-ribose polymerase Tankyrase regulates adult intestinal stem cell proliferation during homeostasis in Drosophila

Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth

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