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)

The steady-state levels of mRNA for the poly(ADP-ribose)polymerase (PARP), c-myc, p53, and histone H3 genes were investigated in 31 high-grade B-cell lymphomas by northern blot analysis. The panel included 15 nodal large B-cell lymphomas, nine mediastinal large B-cell lymphomas, and seven sporadic Burkitt's lymphomas. The PARP mRNA level was significantly higher in lymphomas than in control tissues and corresponded with the amount of PARP protein, as assessed by immunoblot analysis in six samples. The level of PARP mRNA was positively correlated with that of p53 mRNA. No correlation was found between the mRNA expression levels of PARP and histone H3, suggesting that PARP expression levels are independent of the proliferation rate of neoplastic cells. In this setting, the strong correlation between PARP and p53 suggests that the high expression of PARP may be associated with ongoing DNA damage in high-grade lymphomas.
 ...
PMID:Correlation of poly(ADP-ribose)polymerase and p53 expression levels in high-grade lymphomas. 1044 32

Although histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in malignancy, how they exert their effect on osteosarcoama cells is as yet unclear. This study was undertaken to investigate the underlying mechanism of a HDAC inhibitor Trichostatin A (TSA)-induced apoptosis in a osteosarcoma cell line HOS. We observed that TSA treatment decreased the viability of the cells and prominently increased acetylation of histone H3. Evidence was obtained indicating that TSA induced apoptosis of HOS cells as follows: (1) Generation of DNA fragmentation; (2) activation of procaspase-3; (3) cleavage of PARP; and (4) increase of DNA hypoploidy. The reduction of MMP and the release of cytochrome c to cytosol were also shown, indicating that TSA induces apoptosis in HOS cells in a histone acetylation- and mitochondria-dependent fashions. We also examined whether TSA can sensitize HOS cells to the action of an antitumor agent genistein. The combination therapy of TSA and genistein showed synergistic anticancer effect indicating that TSA can be considered as a novel therapeutic strategy for osteosarcoma not only from its direct apoptosis-inducing activity but also from the possibility of sensitization to other antitumor agents.
 ...
PMID:Mechanism of histone deacetylase inhibitor Trichostatin A induced apoptosis in human osteosarcoma cells. 1531 86

Engagement of integrin cell adhesion receptors in mouse lung endothelial cells induces global sensitivity of DNA to nuclease digestion, reflecting alterations in chromatin structure. These structural changes may contribute to the antigenotoxic effects of integrin engagement in lung endothelium. Because histone acetylation and poly(ADP-ribosyl)ation modulate chromatin structure, we investigated the effects of beta1 integrin engagement with antibody on these post-translational modifications and the presence of histones at discrete DNA sequences in the mouse lung endothelial cell genome using chromatin immunoprecipitation. Integrin engagement increased acetylation of core histone H3. The presence of acetylated histone H3 at intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) promoters, and a nonpromoter sequence was also increased. As with integrin engagement, the histone deacetylase inhibitor trichostatin A caused global hypersensitivity of DNA to nuclease digestion and induced acetylation of histone H3 and its coimmunoprecipitation with VCAM-1 and ICAM-1 promoters and nonpromoter DNA. In contrast to acetyl-histone H3, the association of linker histone H1 with specific DNA sequences was either reduced or unaffected by integrin engagement and trichostatin A. Although integrin engagement and trichostatin A treatment did not affect histone H1 poly(ADP-ribosyl)ation, deletion of poly(ADP-ribose) polymerase-1 increased core histone H3 acetylation and increased its level at the iNOS promoter while decreasing the amount of histone H1. The results suggest that integrin engagement, as well as trichostatin A and PARP-1 deletion, regulate chromatin structure via core histone H3 acetylation and reduced linker histone H1-DNA association.
 ...
PMID:Integrin engagement increases histone H3 acetylation and reduces histone H1 association with DNA in murine lung endothelial cells. 1590 51

Proteasome inhibitors are able to efficiently induce apoptosis in many tumor cells while leaving quiescent, untransformed cells largely unharmed. Here we investigated the further enhancement of proteasome inhibitor-mediated apoptosis induction in Bcr-Abl positive K562 CML cells by simultaneous treatment with different histone deacetylase inhibitors (HDIs). Combining proteasome and HDIs resulted in rapid hyperacetylation of histone H3 and accumulation of polyubiquitinated proteins and the synergistic induction of apoptosis. Apoptosis induction was associated with caspase 8, 3 and 9 activation, Bid processing, destruction of the mitochondrial membrane potential, cleavage of PARP and lamin B and extensive DNA fragmentation. The pan-caspase inhibitor Z-VAD-FMK and the caspase-8 inhibitor Z-IETD-FMK could inhibit K562 cell apoptosis. Apoptosis was also delayed by overexpression of Bcl-xL, as well as by crmA, a known inhibitor of caspases 1 and 8. Caspase 8 activity could still be detected in the presence of ectopic Bcl-xL, but not in crmA transfected cells. The most striking anti-apoptotic effect though was obtained by the translational inhibitor cycloheximide, which abolished caspase 8 processing, blocked Bid cleavage and maintained the mitochondrial transmembrane potential. Apoptosis by the combination treatment occurred independently from CD95/Fas receptor stimulation. These results demonstrated that transcriptional activation by HDIs combined with proteasome inhibitor mediated posttranslational stabilization of protein(s) results in significantly enhanced CML apoptosis which was striktly dependent on uninterrupted protein synthesis.
 ...
PMID:Synergistic apoptosis induction by proteasome and histone deacetylase inhibitors is dependent on protein synthesis. 1613 66

The cell cycle-regulated Aurora-B kinase is a chromosomal passenger protein that is implicated in fundamental mitotic events, including chromosome alignment and segregation and spindle checkpoint function. Aurora-B phosphorylates serine 10 of histone H3, a function that has been associated with mitotic chromatin condensation. We find that activation of poly(ADP-ribose) polymerase (PARP) 1 by DNA damage results in a rapid block of H3 phosphorylation. PARP-1 is a NAD(+)-dependent enzyme that plays a multifunctional role in DNA damage detection and repair and maintenance of genomic stability. Here, we show that Aurora-B physically and specifically associates with the BRCT (BRCA-1 C-terminal) domain of PARP-1. Aurora-B becomes highly poly(ADP-ribosyl)ated in response to DNA damage, a modification that leads to a striking inhibition of its kinase activity. The highly similar Aurora-A kinase is not regulated by PARP-1. We propose that the specific inhibition of Aurora-B kinase activity by PARP-1 contributes to the physiological response to DNA damage.
 ...
PMID:Inhibition of Aurora-B kinase activity by poly(ADP-ribosyl)ation in response to DNA damage. 1617 89

Acetylation of histones and nonhistone proteins is an important post-translational modification involved in the regulation of gene expression in mammalian cells. Dysfunction of histone acetyltransferase (HAT) is often associated with the manifestation of several diseases. In this report, HATs are new targets for the development of therapeutics. Our studies first proved that curcumin induces histone hypoacetylation in brain cancer cells and finally induces apoptotic cell death through a (PARP)- and caspase 3-mediated manner. In addition, curcumin induces recontrolling of neural stem cell fates. It induces effective neurogenesis, synaptogenesis, and migration of neural progenitor cells in vitro in brain-derived adult neural stem cells. We also confirmed the neurogenic effect of curcumin in our in vivo experiments. Curcumin actively suppressed differentiation in astrocytes while promoting differentiation into the neurons associated with decrease of histone H3 and H4 acetylation. We suggest that histone hypoacetylation plays an important role in determine stem cell fate through controlling the simultaneous expression of many genes. Thus, the present finding that curcumin, a nontoxic dietary compound, is a histone acetyltransferase inhibitor would supply a new window to understand further the molecular mechanism of histone acetylase inhibitors (HAI) in cancer and neural stem cells and provide a new target molecule for treating central nervous system disorders.
 ...
PMID:Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells. 1664 63

The effect of synthetic isothiocyanate ethyl-4-isothiocyanatobutanoate (E-4IB) on survival of mismatch repair-proficient TK6 and -deficient MT1 cell lines as well as the influence of proteasomal inhibitor MG132, caspase inhibitor Z-VAD-fmk, and ATM inhibitor caffeine on E-4IB modulation of cell cycle and apoptosis was evaluated. Flow cytometric analyses of DNA double strand breaks (gamma-H2AX), mitotic fraction (phospho-histone H3), cell cycle modulation, apoptosis induction (sub-G(0) fraction and fluorescein diacetate staining), and dissipation of transmembrane mitochondrial potential (JC-1 staining) were performed. Western blotting was used for the evaluation of ERK activation, expression of p53, p21(cip1/waf1) and GADD45alpha proteins, as well as PARP fragmentation. Analysis of mitotic nuclei was performed for chromosomal aberrations assessment. MT1 cells were more resistant to E-4IB treatment then TK6 cells (IC(50) 8 muM vs. 4 muM). In both cell lines E-4IB treatment induced phosphorylation of H2AX, increase of p53 protein level, phospho-histone H3 staining, and G(2)/M arrest. The sub-G(0) fragmentation was accompanied by PARP degradation, decreased mitochondrial transmembrane potential, and diminished p21(cip1/waf1) protein expression in TK6 cells. Caspase inhibitor Z-VAD-fmk decreased E-4IB induced sub-G(0) fragmentation and extent of apoptosis in TK6 cells, while proteasome inhibitor MG132 increased number of apoptotic cells in both cell lines tested. A number of aberrant metaphases and clastogenic effect of high E-4IB concentration was observed. The synthetic isothiocyanate E-4IB induced DNA strand breaks, increased mitotic fraction and apoptosis potentiated by MG132 inhibitor in both mismatch repair-proficient and -deficient cell lines.
 ...
PMID:Apoptotic effect of ethyl-4-isothiocyanatobutanoate is associated with DNA damage, proteasomal activity and induction of p53 and p21cip1/waf1. 1683 Feb 28

Mitotic Aurora kinases are required for accurate chromosome segregation during cell division. Ectopic expression of Aurora-A (Aur-A) kinase results in centrosome amplification, aberrant spindles, and consequent aneuploidy. In the present study, we showed that Aurora kinase inhibitory small molecule VX-680 inhibited histone H3 phosphorylation at Ser10, a known in vivo substrate residue of Aurora kinase, in oral squamous cell carcinoma (OSCC) KB cells. In addition, monopolar spindle structures, typical abnormalities induced by inhibition of Aur-A, were generated in VX-680-treated cells. Inhibition of Aurora kinase led to reduced KB cell growth, as assessed by MTT assay. Western blot analysis revealed that VX-680 caused cleavage of two critical apoptotic associated proteins, PARP and caspase-3. In contrast, expression of cell survival factor Bcl-2 was reduced by VX-680 treatment in a dose-dependent manner. Subsequently, nuclear characteristic of DNA fragmentation, indicative of apoptotic cell death, was clearly observed in these OSCC cells with Aurora kinase inhibitory VX-680. Taken together, we showed that Aurora kinase inhibitory VX-680 led to apoptotic cell death in OSCC cells, suggesting a novel therapeutic target in oral cancer.
 ...
PMID:Aurora kinase small molecule inhibitor destroys mitotic spindle, suppresses cell growth, and induces apoptosis in oral squamous cancer cells. 1799 88

Azidothymidine (AZT) is known to decrease HIV virus replication and is one of the most frequently prescribed antiretroviral drugs used for AIDS treatment. Dose-limiting toxicities are the major curse associated with AZT therapy. Recently, we have reported that tannic acid; a PARG inhibitor prevents cisplatin induced nephrotoxicity. The present work was conceived to study the effect of tannic acid on AZT induced hepatotoxicity and genotoxicity. AZT induces increase in plasma levels of ALT, AST and alkaline phosphatase along with increase in micronucleus (MN) count in peripheral blood. Suggesting, AZT is hepatotoxic and genotoxic to mice. Treatment of tannic acid protects AZT induced hepatotoxicity by decreasing the ALT, AST and alkaline phosphatase levels. It also significantly reduces the oxidative damage by preventing reduction in glutathione and decreasing the level of malondialdehyde in liver of AZT treated mice. In addition, tannic acid decreases the PARG expression, PARP cleavage and histone H3 acetylation in liver of AZT treated mice. Moreover, treatment of tannic acid also decreases MN count in peripheral blood, suggesting its anti-mutagenic effect. In light of these findings we suggest the potential role of tannic acid treatment in preventing AZT induced toxicity.
 ...
PMID:Tannic acid prevents azidothymidine (AZT) induced hepatotoxicity and genotoxicity along with change in expression of PARG and histone H3 acetylation. 1829 3

Combined treatment with quercetin and TRAIL induced cytotoxicity and enhanced annexin V staining and poly (ADP-ribose) polymerase (PARP) cleavage in human prostate cancer cell lines DU-145 and PC-3. These indicators of apoptosis resulted from the activation of caspase-8, -9, and -3. Although the expression levels of FLIPs, cIAP1, cIAP2, and the Bcl-2 family were not changed in quercetin-treated cells, significant downregulation of survivin occurred. Knockdown survivin by siRNA significantly increased TRAIL-induced apoptosis. We hypothesized that quercetin-induced activation of MAPK (ERK, p38, JNK) is responsible for downregulation of survivin gene expression. To test this hypothesis, we selectively inhibited MAPK during treatment with quercetin. Our data demonstrated that inhibitor of ERK (PD98059), but not p38 MAPK (SB203580) or JNK (SP600125), significantly maintained the intracellular level of survivin during treatment with quercetin. Interestingly, PD98059 also prevented quercetin-induced deacetylation of histone H3. Data from survivin promoter activity assay suggest that the Sp1 transcription factor binds to the survivin promoter region and quercetin inhibits its binding activity through deacetylation of histone H3. Quercetin-induced activation of the ERK-MSK1 signal transduction pathway may be responsible for deacetylation of histone H3. Taken together, our findings suggest that quercetin enhances TRAIL induced apoptosis by inhibition of survivin expression, through ERK-MSK1-mediated deacetylation of H3.
 ...
PMID:Quercetin augments TRAIL-induced apoptotic death: involvement of the ERK signal transduction pathway. 1837 72


1 2 3 4 5 6 Next >>