• BMB Reports
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• v.47 no.8
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• pp.424-432
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• 2014

The defining feature of Parkinson's disease is a progressive and selective demise of dopaminergic neurons. A recent report on Parkinson's disease animal model demonstrates that poly (ADP-ribose) (PAR) dependent cell death, also named parthanatos, is accountable for selective dopaminergic neuronal loss. Parthanatos is a programmed necrotic cell death, characterized by PARP1 activation, apoptosis inducing factor (AIF) nuclear translocation, and large scale DNA fragmentation. Besides cell death regulation via interaction with AIF, PAR molecule mediates diverse cellular processes including genomic stability, cell division, transcription, epigenetic regulation, and stress granule formation. In this review, we will discuss the roles of PARP1 activation and PAR molecules in the pathological processes of Parkinson's disease. Potential interaction between PAR molecule and Parkinson's disease protein interactome are briefly introduced. Finally, we suggest promising points of therapeutic intervention in the pathological PAR signaling cascade to halt progression in Parkinson's disease.

• Biomedical Science Letters
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• v.11 no.4
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• pp.441-446
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• 2005

The molecular mechanism of ischemia/reperfusion injury remains unclear. Reactive oxygen species (ROS) are implicated in cell death caused by ischemia/reperfusion in vivo or hypoxia in vitro. Poly (ADP-ribose) polymerase (PARP) activation has been reported to be involved in hydrogen peroxide-induced cell death in renal epithelial cells. This study was therefore undertaken to evaluate the role of P ARP activation in chemical hypoxia in opossum kidney (OK) cells. Chemical hypoxia was induced by incubating cells with antimycin A, an inhibitor of mitochondrial electron transport. Exposure of OK cells to chemical hypoxia resulted in a time-dependent cell death. In OK cells subjected to chemical hypoxia, the generation of ROS was increased, and this increase was prevented by the $H_2O_2$ scavenger catalase. Chemical hypoxia increased P ARP activity and chemical hypoxia-induced cell death was prevented by the inhibitor of PARP activation 3-aminobenzamide. Catalase prevented OK cell death induced by chemical hypoxia. $H_2O_2$ caused PARP activation and $H_2O_2-induced$ cell death was prevented by 3-aminobenzamide. Taken together, these results indicate that chemical hypoxia-induced cell injury is mediated by PARP activation through H202 generation in renal epithelial cells.

• Korean Journal of Food Science and Technology
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• v.51 no.5
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• pp.499-502
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• 2019

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which is activated in response to DNA damage, and which mediates DNA repair. PARP inhibitors can be used to reduce resistance of cancer cells to anticancer treatments. The objective of this study was to investigate the effects of selected phytochemicals and fruit extracts on PARP activation in MCF-7 breast cancer cells subjected to oxidative stress. Pre-incubation with epigallocatechin gallate (EGCG), apple extract (AE), cranberry extract (CE), or grape extract (GE) for 2 hours at test concentrations reduced PARP activity induced upon treatment with hydrogen peroxide in a dose-dependent manner (p<0.05). GE was found to be the most efficient PARP inhibitor among the fruit extracts examined. These results suggest that phytochemicals of fruit extracts might be used as PARP inhibitors in order to assist anticancer agents.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2002.07a
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• pp.113-113
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• 2002

Phylogenetically conserved Bcl-2 family proteins play a pivotal role in the regulation of apoptosis from virus to human. Members of the Bcl-2 family consist of antiapoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-w, and proapoptotic proteins such as BAD, Bax, BOD, and Bok. It has been proposed that anti- and proapoptotic Bcl-2 proteins regulate cell death by binding to each other and forming heterodimers. A delicate balance between anti- and proapoptotic Bcl-2 family members exists in each cell and the relative concentration of these two groups of proteins determines whether the cell survives or undergoes apoptosis. Mcl-1 (Myeloid cell :leukemia-1) is a member of the Bcl-2 family proteins and was originally cloned as a differentiation-induced early gene that was activated in the human myeloblastic leukemia cell line, ML-1 . Mcl-1 is expressed in a wide variety of tissues and cells including neoplastic ones. We recently identified a short splicing variant of Mcl-1 short (Mcl-IS) and designated the known Mcl-1 as Mcl-1 long (Mcl-lL). Mcl-lL protein exhibits antiapoptotic activity and possesses the BH (Bcl-2 homology) 1, BH2, BH3, and transmembrane (TM) domains found in related Bcl-2 proteins. In contrast, Mcl-1 S is a BH3 domain-only proapoptotic protein that heterodimerizes with Mcl-lL. Although both Mc1-lL and Mcl-lS proteins contain BH domains fecund in other Bcl-2 family proteins, they are distinguished by their unusually long N-terminal sequences containing PEST (proline, glutamic acid, serine, and threonine) motifs, four pairs of arginine residues, and alanine- and glycine-rich regions. In addition, the expression pattern of Mcl-1 protein is different from that of Bcl-2 suggesting a unique role (or Mcl-1 in apoptosis regulation. Tankyrasel (TRF1-interacting, ankyrin-related ADP-related polymerasel) was originally isolated based on its binding to TRF 1 (telomeric repeat binding factor-1) and contains the sterile alpha motif (SAM) module, 24 ankyrin (ANK) repeats, and the catalytic domain of poly(adenosine diphosphate-ribose) polymerase (PARP). Previous studies showed that tankyrasel promotes telomere elongation in human cells presumably by inhibiting TRFI though its poly(ADP-ribosyl)action by tankyrasel . In addition, tankyrasel poly(ADP-ribosyl)ates Insulin-responsive amino peptidase (IRAP), a resident protein of GLUT4 vesicles, and insulin stimulates the PARP activity of tankyrase1 through its phosphorylation by mitogen-activated protein kinase (MAPK). ADP-ribosylation is a posttranslational modification that usually results in a loss of protein activity presumably by enhancing protein turnover. However, little information is available regarding the physiological function(s) of tankyrase1 other than as a PARP enzyme. In the present study, we found tankyrasel as a specific-binding protein of Mcl-1 Overexpression of tankyrasel led to the inhibition of both the apoptotic activity of Mel-lS and the survival action of Mcl-lL in mammalian cells. Unlike other known tankyrasel-interacting proteins, tankyrasel did not poly(ADP-ribosyl)ate either of the Mcl-1 proteins despite its ability to decrease Mcl-1 proteins expression following coexpression. Therefore, this study provides a novel mechanism to regulate Mcl-1-modulated apoptosis in which tankyrasel downregulates the expression of Mcl-1 proteins without the involvement of its ADP-ribosylation activity.

• Biomedical Science Letters
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• v.24 no.3
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• pp.150-156
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• 2018

Tankyrases are multifunctional poly (ADP-ribose) polymerases that regulate a variety of cellular processes including WNT signaling, telomere maintenance, regulation of mitosis, and many others. Tankyrases interact with target proteins and regulate their interactions and stability through poly (ADP-ribosyl) ation. In addition to their roles in telomere maintenance and regulation of mitosis, tankyrase proteins regulate tumor suppressors such as AXIN, PTEN, and AMOT. Therefore, tankyrases can be effective targets for cancer treatment. Tankyrase inhibitors could affect a variety of pathways that are carcinogenic (essential for the unlimited proliferation of human cancer cells), including WNT, AKT, YAP, telomere maintenance, and regulation of mitosis. Recently, new aspects of the function and mechanism of tankyrases have been reported and several tankyrase inhibitors have been identified. Also, it has been proposed that the combination of conventional chemotherapy agents with tankyrase inhibitors may have synergistic anti-cancer effects. Based on this, it is expected that more advanced and improved tankyrase inhibitors will be developed, enabling new therapeutic strategies against cancer and other tankyrase linked diseases. This review discusses tankyrase function and the role of tankyrase inhibitors in the treatment of cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6429-6436
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• 2014

Poly-ADP-ribosylation (PAR) is a post-translational modification of mainly chromosomal proteins. It is known to be strongly involved in several molecular events, including nucleosome-remodelling and carcinogenesis. In this investigation, it was attempted to evaluate PAR level as a reliable biomarker for early detection of cancer in blood lymphocyte histones. PAR of isolated histone proteins was monitored in normal and dimethylnitrosamine (DMN)-exposed mice tissues using a novel ELISA-based immuno-probe assay developed in our laboratory. An inverse relationship was found between the level of PAR and period of DMN exposure in various histone proteins of blood lymphocytes and spleen cells. With the increase in the DMN exposure period, there was reduction in the PAR level of individual histones in both cases. It was also observed that the decrease in the level of PAR of histones resulted in progressive relaxation of genomic DNA, perhaps triggering activation of genes that are involved in initiation of transformation. The observed effect of carcinogen on the PAR of blood lymphocyte histones provided us with a handy tool for monitoring biochemical or physiological status of individuals exposed to carcinogens without obtaining biopsies of cancerous tissues, which involves several medical and ethical issues. Obtaining blood from any patient and separating blood lymphocytes are routine medical practices involving virtually no medical intervention, post-procedure medical care or trauma to a patient. Moreover, the immuno-probe assay is very simple, sensitive, reliable and cost-effective. Therefore, combined with the ease of preparation of blood lymphocytes and the simplicity of the technique, immuno-probe assay of PAR has the potential to be applied for mass screening of cancer. It appears to be a promising step in the ultimate goal of making cancer detection simple, sensitive and reliable in the near future.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2002.07a
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• pp.199-199
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• 2002

• Proceedings of the Zoological Society Korea Conference
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• 2000.10a
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• pp.246.1-246
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• 2000

No Abstract, See Full Text

• Bulletin of the Korean Chemical Society
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• v.32 no.5
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• pp.1650-1656
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• 2011

A series of potent tricyclic derivatives with a non-aromatic amide as potent PARP-1 inhibitors were successfully synthesized and their PARP-1 inhibitory activity was evaluated. Among the derivatives, 2-(1-propylpiperidin-4-yloxy)-7,8,9,10-tetrahydrophenanthridin-6(5H)-one 23c displayed potent activity in a PARP-1 enzymatic assay and cell-based assay ($IC_{50}$ = 0.142 ${\mu}M$, $ED_{50}$ = 0.90 ${\mu}M$) with good water solubility. Further, molecular modeling studies confirmed the obtained biological results.

• Journal of Nutrition and Health
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• v.36 no.4
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• pp.382-388
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• 2003

(-)-Epigallocatechin-3-gallate (EGCG) is a polyphenolic compound found in peen tea leaves, and has been known to be one of the most potent catechin species which inhibits cell growth most possibly through an apoptotic cell death. We investigated the apoptotic activity of (-)-EGCG on the human myeloid leukemia cell line, HL-60. Our results of MTT test indicated that (-)-EGCG had a significant antiproliferation effect in HL-60 cells with $IC_{50}$/ (50% inhibition concentration) value of 65 $\mu$M. Giemsa statining of HL-60 cells treated with (-)-EGCG (100 $\mu$M) for 6hrs showed a typical apoptosis-specific morphological change including shrinkage of the cytoplasm, membrane blobbing and compaction of the nuclear chromatin. The DNA fragmentation was observed from the agarose gel electrophoresis of cells treated with (-)-EGCG for 3hrs or longer, and was progressed to a greater degree as treatment time increases. Treatment of the cells with (-)-EGCG (100 $\mu$M) resulted in a rapid release of mitochondrial cytochrome c into the cytosol, and a subsequent cleavage of caspase-3 to an active form in a treatment-time dependent manner. (-)-EGCG (100 $\mu$M) also stimulated proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP) to an active form in HL-60 cells. Tlken together, (-)-EGCG appears to induce the apoptosis in human myeloid leukemia cells via a caspase-dependent pathway. These results suggest the possible application of (-)-EGCG, the major active compound in green tea, as an antiproliferative agent for cancer prevention.