Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear factor kappaB (NF-kappaB) have both been demonstrated to play a pathophysiological role in a number of inflammatory disorders. We recently presented evidence that PARP-1 can act as a promoter-specific coactivator of NF-kappaB in vivo independent of its enzymatic activity. PARP-1 directly interacts with p300 and both subunits of NF-kappaB (p65 and p50) and synergistically coactivates NF-kappaB-dependent transcription. Here we show that PARP-1 is acetylated in vivo at specific lysine residues by p300/CREB-binding protein upon stimulation. Furthermore, acetylation of PARP-1 at these residues is required for the interaction of PARP-1 with p50 and synergistic coactivation of NF-kappaB by p300 and the Mediator complex in response to inflammatory stimuli. PARP-1 physically interacts with the Mediator. Interestingly, PARP-1 interacts in vivo with histone deacetylases (HDACs) 1-3 but not with HDACs 4-6 and might be deacetylated in vivo by HDACs 1-3. Thus, acetylation of PARP-1 by p300/CREB-binding protein plays an important regulatory role in NF-kappaB-dependent gene activation by enhancing its functional interaction with p300 and the Mediator complex.
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PMID:Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription. 1620 34

Defective mitotic spindles or an impaired spindle-kinetochore interaction activates the spindle checkpoint. We have previously shown that BubR1 haplo-insufficiency results in enhanced genomic instability and tumorigenesis in mice. Here we report that BubR1 deficiency also leads to a compromised response to DNA damage. Following treatment with doxorubicin, BubR1(+/-) murine fibroblast cells (MEF) were defective in undergoing G(2)/M arrest. Thus, whereas in the presence of DNA damage BubR1(+/+) MEF cells remained arrested in mitosis, BubR1(+/-) MEFs rapidly exited from mitosis and divided. The impaired mitotic arrest of BubR1(+/-) MEFs was associated with low levels of phospho-histone H2AX, p53, and p21 after DNA damage caused by treatment with both doxorubicin and ultraviolet light (UV). The impaired expression of p53 and p21 was also confirmed in human cell lines with BubR1 knockdown via RNA interference. Affinity pull-down coupled with mass spectrometry identified Poly(ADP-ribose) polymerase 1 (PARP-1) as one of the proteins interacting with BubR1. Reciprocal co-immunoprecipitation analysis confirmed the physical interaction between BubR1 and PARP-1. Our further study revealed that the ability of retaining intact PARP-1 or its cleavage product p89 was compromised in BubR1(+/-) MEFs upon treatment with doxorubicin or UV. Given that PARP-1 mediates DNA damage responses and regulates the activity of p53, our studies suggest that there exists a cross-talk between the spindle checkpoint and the DNA damage checkpoint and that BubR1 may play an important role in mediating the cross-talk.
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PMID:BubR1 is involved in regulation of DNA damage responses. 1644 73

ADP-ribosyltransferases (ARTs) are a family of enzymes that catalyze the covalent transfer of an ADP-ribose moiety, derived from NAD, to an amino acid of an acceptor protein, thereby altering its function. To date, little information is available on the protein target specificity of different ART family members. ART2 is a T-cell-specific transferase, attached to the cell surface by a glycosylphosphatidylinositol (GPI) anchor, and also found in serum. Here we investigated the role of ART2 localization in serum or on the cell surface, or solubilized with detergents or enzymes, on its target protein specificity. We found that detergent solubilization of cell membranes, or release of ART2 by phosphoinositide-specific phospholipase C treatment, altered the ability of ART2 to ADP-ribosylate high or low molecular weight histone proteins. Similarly, soluble recombinant ART2 (lacking the GPI anchor) showed a different histone specificity than did cell-bound ART2. When soluble ART2 was incubated with serum proteins in the presence of [32P]-labeled NAD, several serum proteins were ADP-ribosylated in a thiol-specific manner. Mass spectrometry of labeled proteins identified albumin and transferrin as ADP-ribosylated proteins in serum. Collectively, these studies reveal that the membrane or solution environment of ART2 plays a pivotal role in determining its substrate specificity.
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PMID:Substrate specificity of soluble and membrane-associated ADP-ribosyltransferase ART2.1. 1645 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.
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PMID:Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells. 1664 63

Tumor targeting is an important issue in cancer gene therapy. We have developed a light-specific transduction method, named photochemical internalization (PCI), to enhance gene expression from adenoviral vectors selectively in illuminated areas. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in cancer cells, and the aim of this study was to investigate the potential of PCI to enhance transgene expression from AdhCMV-TRAIL and evaluate its impact on apoptotic induction in the two human colorectal cancer cell lines HCT116 and WiDr. PCI-mediated delivery of AdhCMV-TRAIL enabled an increased expression of TRAIL, induced a synergistic reduction in cell viability compared to the individual action of AdhCMV-TRAIL and photochemical treatment, and enhanced the induction of apoptosis demonstrated by an increase in cytoplasmic histone-associated DNA fragments, caspase-8 and caspase-3 activation, PARP cleavage and a decrease in the mitochondrial membrane potential. The synergistic effect could be related to the enhanced TRAIL expression in PCI-treated samples and a modest sensitization of the cancer cells to TRAIL induced apoptosis due to the photochemical treatment. Furthermore, an increased cleavage of Bid and a cell line dependent reduction in the expression levels of anti-apoptotic Bcl-2 family members were observed and could possibly contribute to the enhanced apoptotic level in samples exposed to the combined treatment. The presented results indicate that photochemically mediated delivery of AdhCMV-TRAIL allows a selective enhancement in cell killing, and suggest that PCI may be relevant and advantageous for therapeutic gene delivery in vivo.
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PMID:Photochemically mediated delivery of AdhCMV-TRAIL augments the TRAIL-induced apoptosis in colorectal cancer cell lines. 1720 62

The histone variant mH2A is believed to be involved in transcriptional repression, but how it exerts its function remains elusive. By using chromatin immunoprecipitation and tandem affinity immunopurification of the mH2A1.1 nucleosome complex, we identified numerous genes with promoters containing mH2A1.1 nucleosomes. In particular, the promoters of the inducible Hsp70.1 and Hsp70.2 genes, but not that of the constitutively expressed Hsp70.8, were highly enriched in mH2A1.1. PARP-1 was identified as a part of the mH2A1.1 nucleosome complex and was found to be associated with the Hsp70.1 promoter. A specific interaction between mH2A1.1 and PARP-1 was demonstrated and found to be associated with inactivation of PARP-1 enzymatic activity. Heat shock released both mH2A1.1 and PARP-1 from the Hsp70.1 promoter and activated PARP-1 automodification activity. The data we present point to a novel mechanism for control of Hsp70.1 gene transcription. mH2A1.1 recruits PARP-1 to the promoter, thereby inactivating it. Upon heat shock, the Hsp70.1 promoter-bound PARP-1 is released to activate transcription through ADP-ribosylation of other Hsp70.1 promoter-bound proteins.
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PMID:The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity. 1715 48

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease and one of the cancer entities with the lowest life expectancy. Beside surgical therapy, no effective therapeutic options are available yet. Here, we show that 4-phenylbutyrate (4-PB), a known and well-tolerable inhibitor of histone deacetylases (HDAC), induces up to 70% apoptosis in all cell lines tested (Panc 1, T4M-4, COLO 357, BxPc3). In contrast, it leads to cell cycle arrest in only half of the cell lines tested. This drug increases gap junction communication between adjacent T3M-4 cells in a concentration-dependent manner and efficiently inhibits cellular export mechanisms in Panc 1, T4M-4, COLO 357 and BxPc3 cells. Consequently, in combination with gemcitabine 4-PB shows an overadditive effect on induction of apoptosis in BxPc3 and T3M-4 cells (up to 4.5-fold compared to single drug treatment) with accompanied activation of Caspase 8, BH3 interacting domain death agonist (Bid) and poly (ADP-ribose) polymerase family, member 1 (PARP) cleavage. Although the inhibition of the mitogen-activated protein kinase-pathway has no influence on fulminant induction of apoptosis, the inhibition of the JNK-pathway by SP600125 completely abolishes the overadditive effect induced by the combined application of both drugs, firstly reported by this study.
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PMID:Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells. 1716 59

Engagement of integrin cell adhesion receptors suppresses bleomycin (BLM)-induced DNA strand breakage in endothelial cells. Previous investigation of cells from poly(ADP-ribose) polymerase (PARP)-1 knockout mice and with an inhibitor of the enzyme indicated that this facilitator of base excision repair (BER) is required for integrin-mediated suppression of DNA strand breakage. Here, small inhibitory RNA (siRNA) was used to assess the requirement for the BER proteins, DNA ligase III (Lig3) alpha, PARP-1, and X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), and for the long-patch BER ligase, DNA ligase I (Lig1), in integrin-mediated protection from BLM-induced DNA breakage. Murine lung endothelial cells (MLECs) were transfected with siRNA, treated with anti-beta1 integrin antibody, and then BLM. 3'-OH in DNA and accumulation of phosphorylated histone H2AX (gammaH2AX), which reflects double-strand breakage, were measured. Integrin antibody inhibited the increases in 3'-OH caused by BLM in MLECs transfected with either control or Lig1 siRNA. However, after knockdown of Lig3alpha, PARP-1, or XRCC1, suppression of DNA breakage by integrin antibody was limited. BLM increased gammaH2AX levels, and integrin treatment inhibited this by 57 to 73% in MLECs transfected with control siRNA. Integrin engagement also inhibited increases in gammaH2AX in BLM-treated cells transfected with Lig1 siRNA. In contrast, Lig3alpha, PARP-1, and XRCC1 siRNAs prevented integrin-mediated inhibition of BLM-induced gammaH2AX levels. The results suggest that the BER proteins, Lig3alpha, PARP-1, and XRCC1, are required for integrin-mediated suppression of BLM-induced DNA breakage.
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PMID:Base excision repair proteins are required for integrin-mediated suppression of bleomycin-induced DNA breakage in murine lung endothelial cells. 1720 2

Interactions between tumor cells and their substratum influence cancer progression by modulating cell proliferation and survival. We now investigated whether signaling responses to UV irradiation differ on adhesion-permissive or restrictive substrates. The latter conditions diminished spreading and proliferation of neo 6.3/C8161 melanoma in which metastasis is suppressed by introduction of neo-tagged chromosome 6, but permitted proliferation of human metastatic C8161 melanoma. Apoptosis-associated PARP cleavage and DNA fragmentation induced by UV irradiation were diminished on the restrictive substrate in C8161 melanoma. Genotoxic responses to UV irradiation like persistent increases in the phosphorylation of histone H2AX, induction of the tumor suppressor p53 protein and greater binding of this protein to its DNA consensus sequence, were all decreased on the restrictive substrate. The latter also promoted a 2 fold increase of DNA condensation in chromatin and enhanced activation of the survival - and invasion-associated MMP-9 gelatinase B, preferentially in metastatic C81261 melanoma. Our data suggest that adaptation to restrictive substrates in metastatic C8161 melanoma decreases UV-induced apoptosis, partly through attenuation of DNA damage signaling responses and changes in genomic organization.
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PMID:Attenuation of genotoxicity under adhesion-restrictive conditions through modulation of p53, gamma H2AX and nuclear DNA organization. 1720 47

PolyADP-ribose polymerases (PARPs) catalyze a posttranslational modification of nuclear proteins by polyADP-ribosylation. The catalytic activity of the abundant nuclear protein PARP-1 is stimulated by DNA strand breaks, and PARP-1 activation is required for initiation of DNA repair. Here we show that PARP-1 also acts within extracellular signal-regulated kinase (ERK) signaling cascade that mediates growth and differentiation. The findings reveal an alternative mode of PARP-1 activation, which does not involve binding to DNA or DNA damage. In a cell-free system, recombinant PARP-1 was intensively activated and thereby polyADP-ribosylated by a direct interaction with phosphorylated ERK2, and the activated PARP-1 dramatically increased ERK2-catalyzed phosphorylation of the transcription factor Elk1. In cortical neurons treated with nerve growth factors and in stimulated cardiomyocytes, PARP-1 activation enhanced ERK-induced Elk1-phosphorylation, core histone acetylation, and transcription of the Elk1-target gene c-fos. These findings constitute evidence for PARP-1 activity within the ERK signal-transduction pathway.
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PMID:DNA-independent PARP-1 activation by phosphorylated ERK2 increases Elk1 activity: a link to histone acetylation. 1724 36


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