Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenite (As3+) has long been known to induce cancer and other degenerative diseases. Arsenite exerts its toxicity in part by generating reactive oxygen species. Identification of genetic factors that contribute to arsenic mutagenicity and carcinogenicity is critical for the treatment and prevention of arsenic exposure in human population. As poly(ADP-ribose) polymerase (PARP) is critical for genomic DNA stability, role of PARP-1 was evaluated in arsenic-induced cytotoxic and genotoxic effects. Our study revealed that telomere attrition, probably owing to arsenite-induced oxidative stress, was much more pronounced in PARP-1-/- mouse embryonic fibroblasts (MEF; 40%) compared with PARP-1+/+ MEFs (10-20%). Correlation observed between telomere reduction and apoptotic death in PARP-1 null cells strongly indicates that the telomere attrition might be a trigger for enhanced apoptotic death after arsenite treatment. Elevated DNA damage detected by alkaline comet assay points to an impaired repair ability of arsenite-induced DNA lesions in PARP-1-/- MEFs. Consistent with elevated DNA damage, increased micronuclei induction reflecting gross genomic instability was also observed in arsenite-treated PARP-1-/- MEFs. Microarray analysis has revealed that arsenite treatment altered the expression of about 311 genes majority of which have known functions in cellular responses to stress/external stimulus and cell growth and/or maintenance. Our results suggest an important role for PARP-1 gene product in the maintenance of chromosome-genome stability in response to arsenite-induced DNA damage.
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PMID:Lack of poly(ADP-ribose) polymerase-1 gene product enhances cellular sensitivity to arsenite. 1632 46

Ultraviolet light (UV) inhibits translation initiation through activation of kinases that phosphorylate the alpha-subunit of eukaryotic initiation factor 2 (eIF2alpha). Two eIF2alpha kinases, PERK and GCN2, are known to phosphorylate the Serine-51 of eIF2alpha in response to UV-irradiation. In this report, we present evidence that phosphorylation of eIF2alpha plays a role in UV-induced apoptosis. Our data show that wild-type mouse embryo fibroblasts (MEF(s/s)) are less sensitive to UV-induced apoptosis than MEF(A/A) cells in which the phosphorylation site, Ser51, of eIF2alpha is replaced with a non-phosphorylatable Ala (Ser51Ala). PARP expression in MEF(A/A) cells is reduced without being cleaved after UV-irradiation. In contrast, PARP is cleaved without a significant decrease in parental PARP in MEF(S/S) cells after UV-irradiation. Our data also show that MEF(GCN2-/-) cells, in which GCN2 is knocked out, are more sensitive to UV-irradiation, agreeing with the observation from MEF(A/A) cells. However, MEF(PERK-/-) cells, in which PERK is knocked out, are less sensitive to UV-irradiation. In addition, MCF-7-PERKDeltaC cells, which are stably transfected with a kinase domain deleted mutant of PERK (PERKDeltaC), are more resistant to UV-induced apoptosis than parental MCF-7 cells. Overexpression of wild-type PERK sensitizes MCF-7 cells to UV-induced apoptosis without directly inducing cell death. These results suggest that the level of eIF2alpha phosphorylation impacts PARP expression upon UV-irradiation. The eIF2alpha kinases may mediate UV-induced apoptosis via an eIF2alpha dependent or independent signaling pathway.
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PMID:The roles of translation initiation regulation in ultraviolet light-induced apoptosis. 1678 87

Majority of chemotherapeutic agents inhibit tumor growth by inducing apoptosis or necrosis. The DNA alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), kills cells by necrosis through massive production of DNA strand breaks and subsequent over-activation of PARP. Inhibition of PARP, either through PARP1 genetic ablation or through small molecule PARP inhibitors, protected MNNG-induced cell death in certain cell types including MEF and primary cortical cultures. We report here that a potent PARP inhibitor, ABT-888, facilitates the induction of apoptotic cell death in HeLa cells treated with MNNG. Although the release of cytochrome c from mitochondria to cytosol was observed in HeLa cells treated with either MNNG alone or the combination of MNNG and ABT-888 (MNNG/ABT-888), apoptosis is observed only in HeLa cells treated with MNNG/ABT-888. Bcl-2 family proteins regulate the release of cytochrome c. Downregulation of Bax and Bak by their corresponding siRNAs or overexpression of Bcl-xl inhibited the release of cytochrome c from mitochondria to cytosol, and inhibited apoptosis induced by MNNG/ABT-888. Further examination indicates that ATP concentration is greatly reduced in HeLa cells treated with MNNG alone, but not in HeLa cells treated with MNNG/ABT-888. Reduction of ATP concentration by F0F1-ATP synthase inhibitor oligomycin A renders HeLa cells resistant to the apoptosis induction by treatment with MNNG/ABT-888. Unlike in HeLa cells, ABT-888 protected MNNG induced cell death in normal human fibroblasts. Our study provides evidence that PARP activity determines the fate of HeLa cells by regulating the level of ATP after treatment with MNNG.
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PMID:Poly (ADP-ribose) polymerase activity regulates apoptosis in HeLa cells after alkylating DNA damage. 1872 May 55

XIAP (X chromosome-linked inhibitor of apoptosis) is a member of the anti-apoptotic IAP gene family and an inhibitor of caspase-3. We show here that loss of XIAP renders cells highly sensitive to oxidative stress. Stimulation of XIAP(-/-) MEF with hydrogen peroxide, or other agents that generate reactive oxygen species (ROS) results in increased apoptosis assessed by caspase-3 activity and PARP cleavage. Furthermore, we observed increased levels of ROS and diminished expression of antioxidative genes, e.g., SOD1, -2, NQO1, HO-1, and Txn2 in XIAP(-/-) cells. In addition, stimulation of XIAP(-/-) MEF with hydrogen peroxide resulted in enhanced phosphorylation of JNK. Our findings reveal that XIAP, in addition to its well described caspase-inhibitory function, prevents prolonged JNK activation and is critically involved in modulating ROS levels through regulation of antioxidative genes, thereby inhibiting ROS-induced apoptosis.
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PMID:XIAP regulates intracellular ROS by enhancing antioxidant gene expression. 1869 82

Tumor-associated NADH oxidase (tNOX, also known as ENOX2) is a growth-related protein expressed in transformed cells. Previous reports have revealed that the inhibition of tNOX activity by the anti-cancer drug, capsaicin, correlates with a reduction in growth of cancer cells, indicating a close relationship between tNOX activity and cell growth. Moreover, the study of depleted tNOX expression by RNA interference in HeLa cells suggests that it may be associated with the ability of tumor cells to acquire an aggressive phenotype, particularly in relation to cell proliferation. A key role for tNOX in regulating cell growth is further supported by the observation that the growth rate of MEF cells from tNOX-overexpressing transgenic mice is approximately two-fold greater than that of wild-type cells. The purpose of this study was to investigate the anti-proliferative effect of capsaicin on tNOX expression level in stomach cancer cells. We showed that capsaicin induced cytotoxicity in SCM cells concomitantly with apoptosis, PARP cleavage, and down-regulation of tNOX protein.
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PMID:Effect of Ccapsaicin on tNOX (ENOX2) protein expression in stomach cancer cells. 1973 22

Molecular mechanisms accompanying ethanol-induced cytotoxicity remain to be defined. The renin-angiotensin system with its respective receptors, the angiotensin AT1 and AT2 receptor (AT1R and AT2R), has been implicated in these processes. The AT2R seems to counteract the pro-inflammatory, pro-hypertrophic, and pro-fibrotic actions of the AT1R and is involved in cellular differentiation and tissue repair. Recently, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a novel negative transcriptional regulator of the AT2R. However, the complex interactions between ethanol, PARP-1, and the AT2R are largely unknown. In this in vitro study, we aimed to clarify whether acute ethanol treatment modifies AT2R promoter activity or AT2R mRNA and protein levels and whether PARP-1 is involved in ethanol-mediated regulation of the AT2R. Murine fibroblasts of the R3T3 and MEF line (murine embryonic fibroblasts) were exposed to ethanol for 24h. AT2R promoter activity, mRNA and protein levels were analyzed with and without PARP-1 inhibition and in PARP-1 knockout MEF cells. Expression of PARP-1 was analyzed over course of time, and cell viability and DNA fragmentation were measured on single-cell level by flow cytometry. Ethanol exposition induced substantial downregulation of the AT2R on promoter, mRNA and protein levels in a dose-dependent manner. Pharmacological inhibition or ablation of PARP-1 completely abolished this effect. Ethanol treatment did not have any effect on AT1R mRNA and protein levels in MEF cells. Further, acute ethanol treatment promoted DNA fragmentation and caused transcriptional induction of PARP-1. Our findings reveal that PARP-1 is an upstream transcriptional regulator of the AT2 receptor in the context of ethanol exposure and represses the AT2R gene in fibroblasts in vitro. Variations in expression of the potentially tissue-protective AT2R might contribute to ethanol-mediated pathology.
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PMID:Ethanol-induced downregulation of the angiotensin AT2 receptor in murine fibroblasts is mediated by PARP-1. 2069 3

Tissue transglutaminase (TG2) activity has been implicated in inflammatory disease processes such as Celiac disease, infectious diseases, cancer, and neurodegenerative diseases, such as Huntington's disease. Furthermore, four distinct biochemical activities have been described for TG2 including protein crosslinking via transamidation, GTPase, kinase and protein disulfide isomerase activities. Although the enzyme plays a complex role in the regulation of cell death and autophagy, the molecular mechanisms and the putative biochemical activity involved in each is unclear. Therefore, the goal of the present study was to determine how TG2 modulates autophagy and/or apoptosis and which of its biochemical activities is involved in those processes. To address this question, immortalized embryonic fibroblasts obtained from TG2 knock-out mice were reconstituted with either wild-type TG2 or TG2 lacking its transamidating activity and these were subjected to different treatments to induce autophagy or apoptosis. We found that knock out of the endogenous TG2 resulted in a significant exacerbation of caspase 3 activity and PARP cleavage in MEF cells subjected to apoptotic stimuli. Interestingly, the same cells showed the accumulation of LC3 II isoform following autophagy induction. These findings strongly suggest that TG2 transamidating activity plays a protective role in the response of MEF cells to death stimuli, because the expression of the wild-type TG2, but not its transamidation inactive C277S mutant, resulted in a suppression of caspase 3 as well as PARP cleavage upon apoptosis induction. Additionally, the same mutant was unable to catalyze the final steps in autophagosome formation during autophagy. Our findings clearly indicate that the TG2 transamidating activity is the primary biochemical function involved in the physiological regulation of both apoptosis and autophagy. These data also indicate that TG2 is a key regulator of cross-talk between autophagy and apoptosis.
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PMID:TG2 transamidating activity acts as a reostat controlling the interplay between apoptosis and autophagy. 2147 26

An inherited deficiency in the frataxin protein causes neurodegeneration of the dorsal root ganglia and Friedreich's ataxia (FA). Frataxin deficiency leads to oxidative stress and inflammatory changes in cell and animal models; however, the cause of the inflammatory changes, and especially what causes brain microglial activation is unclear. Here we investigated: 1) the mechanism by which frataxin deficiency activates microglia, 2) whether a brain-localized inflammatory stimulus provokes a greater microglial response in FA animal models, and 3) whether an anti-inflammatory treatment improves their condition. Intracerebroventricular administration of LPS induced higher amounts of microglial activation in the FA mouse model vs controls. We also observed an increase in oxidative damage in the form of 8-oxoguanine (8-oxo-G) and the DNA repair proteins MUTYH and PARP-1 in cerebellar microglia of FA mutant mice. We hypothesized that frataxin deficiency increases DNA damage and DNA repair genes specifically in microglia, activating them. siRNA-mediated frataxin knockdown in microglial BV2 cells clearly elevated DNA damage and the expression of DNA repair genes MUTYH and PARP-1. Frataxin knockdown also induced a higher level of PARP-1 in MEF cells, and this was suppressed in MUTYH-/- knockout cells. Administration of the PARP-1 inhibitor PJ34 attenuated the microglial activation induced by intracerebroventricular injection of LPS. The combined administration of LPS and angiotensin II provoke an even stronger activation of microglia and neurobehavioral impairment. PJ34 treatment attenuated the neurobehavioral impairments in FA mice. These results suggest that the DNA repair proteins MUTYH and PARP-1 may form a pathway regulating microglial activation initiated by DNA damage, and inhibition of microglial PARP-1 induction could be an important therapeutic target in Friedreich's ataxia.
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PMID:Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34. 2695 31

Though lambertianic acid (LA) is reported to have hypolipidemic activity in liver, its underlying anticancer mechanism is poorly understood so far. Thus, in the present study, apoptotic mechanism of LA was elucidated in HepG2 and SK-Hep1 hepatocellular carcinoma (HCC) cells. Here LA increased cytotoxicity, sub-G1 population and Annexin V/PI positive cells in two HCC cells. Also, LA cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP), activated phosphorylation of liver kinase B1 (LKB1)/AMP activated protein kinase (AMPK)/ acetyl-CoA carboxylase (ACC) pathway and also suppressed antiapoptotic proteins such as phosphorylation of Akt/ mammalian target of rapamycin (mTOR) and the expression of B cell lymphoma-2 (Bcl-2)/ B-cell lymphoma-extra large (Bcl-xL) and cyclooxygenase-2 (COX-2) in two HCC cells. Furthermore, LA generated reactive oxygen species (ROS) in HepG2 cells and AMPK inhibitor compound C or ROS inhibitor N-acetyl-L-cysteine (NAC) blocked the apoptotic ability of LA to cleave PARP or increase sub G1 population in HepG2 cells. Consistently, cleavages of PARP and caspase-3 were induced by LA only in AMPK+/+ MEF cells, but not in AMPK-/- MEF cells. Also, immunoprecipitation (IP) revealed that phosphorylation of LKB1/AMPK through their binding was enhanced in LA treated HepG2 cells. Overall, these findings suggest that ROS dependent phosphorylation of LKB1/AMPK/ACC signaling is critically involved in LA induced apoptosis in HCCs.
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PMID:Reactive oxygen species dependent phosphorylation of the liver kinase B1/AMP activated protein kinase/ acetyl-CoA carboxylase signaling is critically involved in apoptotic effect of lambertianic acid in hepatocellular carcinoma cells. 2905 Feb 65

Saturated fatty acid (SFA)-induced lipotoxicity is caused by the accumulation of reactive oxygen species (ROS), which is associated with damaged mitochondria. Moreover, lipotoxicity is crucial for the progression of nonalcoholic steatohepatitis (NASH). Autophagy is required for the clearance of protein aggregates or damaged mitochondria to maintain cellular metabolic homeostasis. The NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2)-KEAP1 (kelch like ECH associated protein 1) pathway is essential for the elimination of ROS. ULK1 (unc-51 like autophagy activating kinase 1; yeast Atg1) is involved in the initiation of autophagy; however, its role in lipotoxicity-induced cell death in hepatocytes and mouse liver has not been elucidated. We now show that ULK1 potentiates the interaction between KEAP1 and the autophagy adaptor protein SQSTM1/p62, thereby mediating NFE2L2 activation in a manner requiring SQSTM1-dependent autophagic KEAP1 degradation. Furthermore, ULK1 is required for the autophagic removal of damaged mitochondria and to enhance binding between SQSTM1 and PINK1 (PTEN induced kinase 1). This study demonstrates the molecular mechanisms underlying the cytoprotective role of ULK1 against lipotoxicity. Thus, ULK1 could represent a potential therapeutic target for the treatment of NASH.Abbreviations: ACTB: actin beta; CM-H2DCFDA:5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; GSTA1: glutathione S-transferase A1; HA: hemagglutinin; Hepa1c1c7: mouse hepatoma cells; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch like ECH associated protein 1; LPS: lipopolysaccharides; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK8/JNK: mitogen-activated protein kinase 8; MEF: mouse embryonic fibroblast; MFN1: mitofusin 1; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NASH: nonalcoholic steatohepatitis; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PA: palmitic acid; PARP: poly (ADP-ribose) polymerase 1; PINK1: PTEN induced kinase 1; PRKAA1/2: protein kinase AMP-activated catalytic subunits alpha1/2; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; PRKC/PKC: protein kinase C; RBX1: ring-box 1; ROS: reactive oxygen species; SFA: saturated fatty acid; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUBA: tubulin alpha; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; ULK1: unc-51 like autophagy activating kinase 1.
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PMID:Dual roles of ULK1 (unc-51 like autophagy activating kinase 1) in cytoprotection against lipotoxicity. 3090 26


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