Tankyrase, a positive regulator of telomere elongation, is over expressed in human breast cancer

Gelmini, Stefania; Poggesi, M.; Distante, V.; Bianchi, Simonetta; Simi, Lisa; Luconi, Michaela; Raggi, Claudia; Cataliotti, Luigi; Pazzagli, Mario; Orlando, Claudio

doi:10.1016/j.canlet.2004.05.010

Cited by 66 publications

(50 citation statements)

References 23 publications

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“…33,34 These findings suggesting that there could be an association between aberrant regulation of TNKS1 expression and human cancers. Importantly, a number of studies have also reported that Plk1 is highly upregulated in a wide range of human cancers and is often associated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Tankyrase-1 function at telomeres and during mitosis is regulated by Polo-like kinase-1-mediated phosphorylation

et al. 2011

Cell Death Differ

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Telomere length is critical for chromosome stability that affects cell proliferation and survival. Telomere elongation by telomerase is inhibited by the telomeric protein, TRF1. Tankyrase-1 (TNKS1) poly(ADP-ribosyl)ates TRF1 and releases TRF1 from telomeres, thereby allowing access of telomerase to the telomeres. TNKS1-mediated poly(ADP-ribosyl)ation also appears to be crucial for regulating the mitotic cell cycle. In searching for proteins that interact with polo-like kinase-1 (Plk1) by using complex proteomics, we identified TNKS1 as a novel Plk1-binding protein. Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. Taken together, our results provide evidence of a novel molecular mechanism in which phosphorylation of TNKS1 by Plk1 may help regulate mitotic spindle assembly and promote telomeric chromatin maintenance.

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Section: Discussionmentioning

confidence: 99%

Tankyrase-1 function at telomeres and during mitosis is regulated by Polo-like kinase-1-mediated phosphorylation

et al. 2011

Cell Death Differ

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“…This leads to decreased levels of β-catenin and increased levels of phosphorylated β-catenin causing inhibition of the Wnt/β-catenin-driven proliferation of cancer cells. 9 Tankyrases are overexpressed in several human cancers, including breast cancer, 10 colon cancer, 11 chronic myeloid leukemia, 12 brain tumors, 13 and gastric 14 and bladder cancers. 15 There is 85% sequence homology between TNKS-1 and TNKS-2 within the ankyrin repeat, sterile alpha motif, and the NAD + -binding catalytic domains; the catalytic domains are 86% identical.…”

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confidence: 99%

Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

Nathubhai

Wood

Lloyd

et al. 2013

ACS Med. Chem. Lett.

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Tankyrases (TNKSs) are poly(ADP-ribose)polymerases (PARPs) that are overexpressed in several clinical cancers. They regulate elongation of telomeres, regulate the Wnt system, and are essential for the function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been designed and identified as potent and selective TNKS inhibitors, some being more potent and selective than the lead inhibitor XAV939, with IC 50 = 3 nM vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the 4-position of the 2-phenyl group; electronic effects and H-bonding were irrelevant, but charge in the 4′-substituent must be avoided. Molecular modeling facilitated initial design of the compounds and rationalization of the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further development into anticancer drugs.

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“…It has been found that telomerase activity is increased in a variety of tumor tissues, such as well-differentiated non-Hodgkin's lymphoma, colon and liver cancer, and high expression of TNKS1 was detected simultaneously (19)(20)(21)(22)(23), suggesting that the expression of TNKS1 is positively correlated with telomerase activity. It was also reported that the presence of TNKS1 undermined the role of telomerase inhibitors, and consequently the telomere became more tolerant to telomerase inhibitors in the progressive process of telomere shortening (13).…”

Section: Discussionmentioning

confidence: 99%

XAV939 promotes apoptosis in a neuroblastoma cell line via telomere shortening

et al. 2014

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Abstract. Telomeres, telomerase and tankyrase (TNKS) have an extremely important and special association with human cell aging and cancer. Telomerase activity is abnormally high in cancer cells and is accompanied by the overexpression of tankyrase 1 (TNKS1). TNKS1 is a positive regulator of telomerase activation and telomere extension in the human body, indicating that TNKS1 may be a possible therapeutic target for cancer. XAV939 is a small-molecule inhibitor of TNKS1. The objective of the present study was to investigate the apoptotic effect of XAV939 on the neuroblastoma (NB) SH-SY5Y cell line, as well as the change in telomere length and telomerase activity and elucidate the mechanism from this perspective. In the present study, we initially treated SH-SY5Y cells with XAV939 and RNA interference (RNAi)-TNKS1, and subsequently chose the optimal sequence for RNAi-TNKS1. We then measured the telomere length using quantitative real-time polymerase chain reaction (qPCR) assay, detected the telomerase activity using the ELISA kit, observed apoptotic morphology by transmission electron microscopy, and detected the percentages of apoptotic cells using flow cytometry and Hoechst 33342 staining. We also determined the invasive ability by a cell invasion assay. The results showed that short hairpin RNA-2 (shRNA-2) was the optimal sequence for RNAi-TNKS1. Treatment with both XAV939 and RNAi-TNKS1 shortened the telomere length, promoted apoptosis and reduced the invasive ability of the SH-SY5Y cells, yet had no effect on telomerase activity. XAV939 promoted apoptosis and reduced the invasiveness of SH-SY5Y cells dependent on telomere shortening, and further research should be conducted to clarify the exact mechanisms. This research may contribute to the cure of malignant NB using multi-targeted therapy with small-molecule agents. IntroductionTelomeres, telomerase and tankyrase (TNKS) have an extremely important and special association with human 'cell aging' and 'immortalized cells', offering new opportunities for the research of senescence and cancer. Telomere is a short DNA-protein complex that presents in the linear chromosome ends of eukaryotic cells and constitutes a special hat-like structure along with telomere-binding proteins to maintain the integrity of chromosomes. Telomerase is a ribonucleoprotein complex of RNA and protein composition, and belongs to the reverse transcriptases. Subunits of the human telomerase gene include telomerase RNA (hTR), telomerase binding protein (hTP1) and telomerase activity catalytic unit (hTERT). The main function of telomerase is to maintain telomere length. Telomeres can use the 3' end as primers, their own RNA as a template to synthesize telomere repeat sequences of TTAGGG, and add these to chromosome ends to maintain the original length of the telomere. Telomerase activity has been found in germ and stem cells, which have self-renewal capacity, and in 80-95% of tumors, yet it is weak or has no activity in normal somatic cells (1). Telomerase activity gradually disappears with ...

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Tankyrase, a positive regulator of telomere elongation, is over expressed in human breast cancer

Cited by 66 publications

References 23 publications

Tankyrase-1 function at telomeres and during mitosis is regulated by Polo-like kinase-1-mediated phosphorylation

Tankyrase-1 function at telomeres and during mitosis is regulated by Polo-like kinase-1-mediated phosphorylation

Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

XAV939 promotes apoptosis in a neuroblastoma cell line via telomere shortening

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