Poly(ADP-ribosyl)ation of p53 Contributes to TPEN-Induced Neuronal Apoptosis

Kim, Hyun-Lim; Ra, Hana; Kim, Ki-Ryeong; Lee, Jeong Min; Im, Hana; Kim, Yang‐Hee

doi:10.14348/molcells.2015.2142

Cited by 15 publications

(7 citation statements)

References 35 publications

(49 reference statements)

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“…Chemical inhibition of the PARP‐1 function suppresses the induction of P53 in response to ionizing radiation in MCF‐7 and BJ/TERT cells [Wieler et al, ]. Based on chemical inhibitor or genetic studies, PARP‐1 acts as an upstream modulator of post‐translational modification of P53 [Kim et al, ]. These data clearly suggest that PARP‐1 is a positive regulator of P53, and our results also show that PARP‐1 deficiency results in reduced P53 levels (Fig.…”

Section: Discussionsupporting

confidence: 73%

Bcl‐2 protects TK6 cells against hydroquinone‐induced apoptosis through PARP‐1 cytoplasm translocation and stabilizing mitochondrial membrane potential

Chen

Liang

et al. 2017

Environ and Mol Mutagen

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B cell leukemia/lymphoma-2 (Bcl-2) suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating mitochondrial membrane potential (MMP). This study aimed to investigate the role of Bcl-2 in controlling the mitochondrial pathway of apoptosis during hydroquinone (HQ)-induced TK6 cytotoxicity. In this study, HQ, one metabolite of benzene, decreased the MMP in a concentration-dependent manner and induced the generation of reactive oxygen species (ROS), the activation of the DNA damage marker g-H2AX, and production of the DNA damage-responsive enzyme poly(ADP-ribose)polymerase-1 (PARP-1). Exposure of TK6 cells to HQ leads to an increase in Bcl-2 and colocalization with PARP-1 in the cytoplasm. Inhibition of Bcl-2 using the BH3 mimetic, ABT-737, suppressed the PARP-1 nuclear to cytoplasm translocation and sensitized TK6 cells to HQ-induced apoptosis through depolarization of the MMP. Western blot analysis indicated that ABT-737 combined with HQ increased the levels of cleaved PARP and g-H2AX, but significantly decreased the level of P53. Thus, ABT-737 can influence PARP-1 translocation and induce apoptosis via mitochondria-mediated apoptotic pathway, independently of P53. In addition, we found that knockdown of PARP-1 attenuated the HQ-induced production of cleaved PARP and P53. These results identify Bcl-2 as a protective mediator of HQ-induced apoptosis and show that upregulation of Bcl-2 helps to localize PARP-1 to the cytoplasm and stabilize MMP. Environ. Mol. Mutagen. 59:49-59, 2018.V C 2017 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 73%

Bcl‐2 protects TK6 cells against hydroquinone‐induced apoptosis through PARP‐1 cytoplasm translocation and stabilizing mitochondrial membrane potential

Chen

Liang

et al. 2017

Environ and Mol Mutagen

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“…p53 activation and p53‐mediated apoptosis depend on the status of PARP‐1 and the degree of DNA strand breaks. For example, reduced p53 accumulation and activation were observed in PARP‐1 deficient cells upon treatment of N,N,N ′ ,N ′‐tetrakis(2‐pyridylmethyl)ethylenediamine (TPEN) and the alkylating agent 2′‐methyl‐2′‐nitrose‐urea (MNU) . It has been demonstrated that p53 activation transcriptionally upregulates death receptor proteins such as Fas, oncogene K‐RAS, and inhibits the antiapoptotic function of Bcl‐2, which might trigger the extrinsic pathway of apoptosis .…”

Section: Discussionmentioning

confidence: 99%

Hydroquinone induces TK6 cell growth arrest and apoptosis through PARP‐1/p53 regulatory pathway

Luo

Liang

Chen

et al. 2017

Environmental Toxicology

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Hydroquinone (HQ), one of the most important metabolites derived from benzene, induces cell cycle arrest and apoptosis. Poly(ADP-ribose) polymerase-1 (PARP-1) participates in various biological processes, including DNA repair and cell cycle regulation. To explore whether PARP-1 regulatory pathway mediated HQ-induced cell cycle arrest and apoptosis, we assessed the effect of PARP-1 suppression on induction of apoptosis analyzed by FACSCalibur flow cytometer in PARP-1 deficientTK6 cells (TK6-shPARP-1). We observed an increase in the fraction of cells in G1 phase by 7.6% and increased apoptosis by 4.5% in PARP-1-deficient TK6 cells (TK6-shPARP-1) compared to those negative control cells (TK6-shNC cells) in response to HQ treatment. Furthermore, HQ might activate the extrinsic pathways of apoptosis via up-regulation of Fas expression, followed by caspase-3 activation, apoptotic body, and sub G1 accumulation. Enhanced p53 expression was observed in TK6-shPARP-1 cells than in TK6-shNC cells after HQ treatment. In contrast, Fas expression was lower in TK6-shPARP-1 cells than in TK6-shNC cells. Therefore, we conclude that HQ may activate apoptotic signals via Fas up-regulation and p53-mediated apoptosis in TK6-shNC cells. The reduction of PARP-1 expression further intensified up-regulation of p53 in TK6-shPARP-1 cells, resulting in an increased G1→S phase cell arrest and apoptosis in TK6-shPARP-1 cells compared to TK6-shNC cells.

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“…Finally, we investigated whether these selected agents reduced the apoptosis when exposed to the following: (1) N , N , N ′, N ′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a cell-permeant zinc chelator; − (2) etoposide (ETPS), a topoisomerase II inhibitor; or (3) staurosporine (STSP), a potent cell-permeable inhibitor of various protein kinases (Figure C). Although STSP-induced apoptosis was attenuated by five compounds (1A09, 1D08, 1H10, 2G11, and 3A02) and by Cpd C (Figure C, right graph), agents 1H10 and 2G11 treatment protected from apoptosis in all three experimental conditions (Figure C).…”

Section: Results and Discussionmentioning

confidence: 99%

Identifying New AMP-Activated Protein Kinase Inhibitors That Protect against Ischemic Brain Injury

Eom

Kim

Seo

et al. 2019

ACS Chem. Neurosci.

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We recently reported that AMP-activated protein kinase (AMPK) contributes to zinc-induced neuronal death by inducing Bim, a pro-apoptotic Bcl-2 homology domain 3-only protein, in a liver kinase B1 (LKB1)-dependent manner. Current data suggest AMPK plays key roles in excitotoxicity and ischemic brain injury, with zinc neurotoxicity representing at least one mechanism of ischemic neuronal death. Inhibition of AMPK could be a viable therapeutic strategy to prevent ischemic brain injury following stroke. This prompted our search for novel inhibitors of AMPK activity and zinc-induced neuronal death using cultured mouse cortex and a rat model of brain injury after middle cerebral artery occlusion (MCAO). In structure-based virtual screening, 118 compounds were predicted to bind the active site of AMPK α2, and 40 showed in vitro AMPK α2 inhibitory activity comparable to compound C (a well-known, potent AMPK inhibitor). In mouse cortical neuronal cultures, 7 of 40 compound reduced zinc-induced neuronal death at levels comparable to compound C. Ultimately, only agents 2G11 and 1H10 significantly attenuated various types of neuronal death, including oxidative stress, excitotoxicity, and apoptosis. When administered as intracerebroventricular injections prior to permanent MCAO in rats, 2G11 and 1H10 reduced brain infarct volumes, whereas compound C did not. Therefore, these novel AMPK inhibitors could be drug development candidates to treat stroke.

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Poly(ADP-ribosyl)ation of p53 Contributes to TPEN-Induced Neuronal Apoptosis

Cited by 15 publications

References 35 publications

Bcl‐2 protects TK6 cells against hydroquinone‐induced apoptosis through PARP‐1 cytoplasm translocation and stabilizing mitochondrial membrane potential

Bcl‐2 protects TK6 cells against hydroquinone‐induced apoptosis through PARP‐1 cytoplasm translocation and stabilizing mitochondrial membrane potential

Hydroquinone induces TK6 cell growth arrest and apoptosis through PARP‐1/p53 regulatory pathway

Identifying New AMP-Activated Protein Kinase Inhibitors That Protect against Ischemic Brain Injury

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