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

---

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

The exotoxins of Bordetella pertussis and Vibrio cholera have been used to investigate signal transduction in the human T-cell lymphoma Jurkat. Stimulation of the cells, leading to an increase in cytoplasmic free calcium, could be achieved by the anti-T-cell receptor complex antibody OKT3 and by pertussis holotoxin (PTHT), or its B-subunit (PTB), but not by cholera holotoxin (CTHT) or its B-subunit (CTB). Both holotoxins ADP-ribosylated specifically G-proteins in the plasma membrane of intact cells, while their B-subunits had no ADP-ribosyltransferase activity. Incubation of the cells with CTHT led to a state of unresponsiveness to all stimulants. CTB was without any effect, indicating that the ADP-ribosyltransferase activity of cholera toxin (located in the A-subunit of the holotoxin) was necessary for the inhibition of cellular signalling. The inhibitory effect of cholera toxin on the pertussis toxin action was not due to a blockade of pertussis toxin interaction with the cell surface, because pertussis toxin was still able to ADP-ribosylate membrane proteins in cholera toxin treated intact cells. In addition, the cholera toxin mediated inhibition was not due to elevated levels of cyclic-AMP, as forskolin (a direct activator of the adenylate cyclase) and no inhibitory effect. The stimulating effect of PTHT was independent of its ADP-ribosyltransferase activity, because it could also be obtained by the B-subunit alone. In addition, the increase of cytoplasmic free calcium after stimulation by PTHT clearly preceded the ADP-ribosylation. Pre-treatment with PTHT, PTB or OKT3, led to a long lasting increase in the level of intracellular Ca2+ in Jurkat cells, which could not, therefore, be stimulated further. Inhibition by cholera holotoxin of the stimulation by OKT3 and pertussis toxin (PTHT and PTB) imply that the mitogenic effect of pertussis toxin is perhaps mediated via the T-cell antigen receptor signalling cascade. The presented data do not support the idea that a pertussis toxin-sensitive G-protein is involved in coupling the T-cell antigen receptor to the phospholipase C.
...
PMID:Pertussis toxin B-subunit-induced Ca2(+)-fluxes in Jurkat human lymphoma cells: the action of long-term pre-treatment with cholera and pertussis holotoxins. 216 84

Mono ADP-ribosyltransferases catalyze the transfer of the ADP-ribose moiety of nicotinamide adenine dinucleotide (NAD) to proteins. It was reported by Wang et al (J Immunol 153:4048, 1994) that incubation of mouse cytotoxic T lymphocytes (CTL) with NAD resulted in the ADP-ribosylation of membrane proteins and inhibition of cell proliferation and cytotoxicity. Treatment of CTL with phosphatidylinositol-specific phospholipase C (PI-PLC) before incubation with NAD prevented the inhibitory effects of NAD on the cells, consistent with the removal of a glycosylphosphatidylinositol (GPI)-anchored ADP-ribosyltransferase on the lymphocyte surface. We have identified and cloned a GPI-linked ADP-ribosyltransferase from Yac-1 mouse T-cell lymphoma cells. The deduced amino acid sequence of the Yac-1 transferase was 70% and 41% identical to those of the rabbit skeletal muscle and chicken heterophil, respectively. It contained three noncontiguous sequences similar to those found in several of the bacterial toxin and vertebrate ADP-ribosyltransferases. Based on crystallography of the bacterial toxins, these regions are believed to form, in part, the catalytic site consistent with a common mechanism for the ADP-ribose transfer reaction. In rat mammary adenocarcinoma (NMU) cells transformed with the Yac-1 transferase cDNA, transferase activity was present on the cell surface and was released into the medium by treatment of cells with PI-PLC. Thus, we have cloned a novel gene that has properties identical to the transferase detected in CTL, and may be involved in the NAD-dependent regulation of proliferation and cytotoxicity.
...
PMID:Molecular characterization of a glycosylphosphatidylinositol-linked ADP-ribosyltransferase from lymphocytes. 870 49

A protein mono-ADP-ribosyltransferase (ADPRT), anchored in the cell membrane as a glycosylphosphatidylinositol (GPI)-anchored cell-surface enzyme, was recently described on murine cytotoxic T cells (CTL). Expression of this enzyme was shown to exert regulatory functions on CTL proliferation and cytotoxic activity, presumably by modulating activity of the protein tyrosine kinase p56(lck), which is associated with the CTL co-receptor CD8. Here we report on the molecular cloning and expression of this important regulatory enzyme. The ADPRT coding sequence was derived by making use of ADPRT sequence homologies from different vertebrate species. A cDNA fragment of the enzyme coding sequence was generated by reverse transcription polymerase chain reaction (RT-PCR) from murine T-cell lymphoma SL12, which expresses the cell-surface ADPRT. The cDNA fragment was found to share extensive homology with the corresponding sequences of human and rabbit muscle ADPRT. In Northern blot hybridization, this cDNA fragment generates a strong hybridization signal with RNA from murine heart and skeletal muscle. Weak signals are seen with SL12, thymus, and spleen. Therefore, a murine skeletal muscle cDNA library was used to identify and obtain the coding sequence of the ADPRT gene. It is shown that the nucleic acid open reading frame sequence of the murine skeletal muscle gene shares 80.3% and 76.3% homology with the sequences of the human and rabbit muscle genes, respectively. Semiquantitative RT-PCR with intron-spanning primers shows that the ADPRT mRNA is present in lymphoid organs, cytotoxic T cells, and T-cell lines. Transfection of the ADPRT coding sequence into EL4 cells results in expression of the enzyme as a functional GPI-anchored cell-surface protein, able to ADP-ribosylate the arginine analog agmatine as well as cell-surface molecules.
...
PMID:Molecular cloning of a functional murine arginine-specific mono-ADP-ribosyltransferase and its expression in lymphoid cells. 905 44

Inorganic arsenic is considered a human carcinogen based principally on epidemiological evidence. Unlike most initiating chemicals, arsenic is inactive or extremely weak in its ability to directly induce gene mutations. Arsenite has been shown, however, to enhance mutagenicity when present with other agents such as UV radiation. Synergistic potentiation of chromosomal damage has been shown with co-treatment with DNA-crosslinking agents. Arsenite at low concentrations is known to be highly selective in reacting with closely spaced (vicinal) dithiol groups in proteins. Poly(ADP-ribose) polymerase (PARP) is known to contain such vicinal dithiol groups. Stimulation of PARP is an immediate response of eukaryotic cells to DNA strand breaks and has been implicated in DNA repair. The effect of treatment with sodium arsenite on PARP activity was assessed as follows: Molt-3 cells (a human T-cell lymphoma-derived cell line) in culture were treated for 24 h with concentrations of sodium arsenite ranging from 2.5 up to 25 microM. Speciation of inorganic arsenic and cell viability were determined. Cell cycle kinetics were measured by flow cytometry. Poly(ADP-ribose) synthesis was assayed using a palindromic decameric deoxynucleotide to stimulate enzyme activity. Results show that arsenite decreases PARP activity in a dose-dependent manner with an approximately 50% decrease in enzyme activity at 10 microM arsenite and 80% viability. The percent of cells in S-phase increases with increasing concentration of arsenite. These results provide further indication that arsenite may potentiate genetic damage through reaction with dithiols in DNA repair proteins such as PARP, perhaps resulting in interference with normal repair function.
...
PMID:Inhibition of poly(ADP-ribose) polymerase by arsenite. 921 71

Poly(ADP-ribose) polymerase (PARP) and DNA-dependent protein kinase (DNA-PK) are DNA break-activated molecules, Although mice that lack PARP display no gross phenotype and normal DNA excision repair, they exhibit high levels of sister chromatid exchange, indicative of elevated recombination rates. Mutation of the gene for DNA-PK catalytic subunit (Prkdc) cases defective antigen receptor V(D)J recombination and arrests B- and T-lymphocyte development in severe combined immune-deficiency (SCID) mice. SCID V(D)J recombination can be partly rescued in T-lymphocytes by either DNA-damaging agents (gamma-irradiation and bieomycin) or a null mutation of the p53 gene, possibly because of transiently elevated DNA repair activity in response to DNA damage or to delayed apoptosis in the absence of p53. To determine whether the increased chromosomal recombination observed in PARP-deficient cells affects SCID V(D)J recombination, we generated mice lacking both PARP and DNA-PK. Here, we show that thymocytes of SCID mice express both CD4 and CD8 co-receptors, bypassing the SCID block. Double-mutant T-cells in the periphery express TCR beta, which is attributable to productive TCR beta joints. Double-mutant mice develop a high frequency of T-cell lymphoma. These results demonstrate that increased recombination activity after the loss of PARP anti-recombinogenic function can rescue V(D)J recombination in SCID mice and indicate that PARP and DNA-PK cooperate to minimize genomic damage caused by DNA strand breaks.
...
PMID:Genetic interaction between PARP and DNA-PK in V(D)J recombination and tumorigenesis. 939 55

Cells that lack PARP-1 activity are limited in their ability to repair DNA single strand breaks and respond to DNA damage with a strong accumulation of p53 and enhanced rates of apoptotic cell death. We have generated combinatorial mutant mice that both lack p53 and PARP-1 activity due to the expression of a dominant negative PARP-1 allele targeted to T-cells by the lck promoter. Here we report that these double mutant mice develop T-cell lymphoma at a significantly reduced latency period compared to single p53 null mice that are already cancer prone. We demonstrate that the absence of p53 does not only protect T-cells from lck-PARP-DBD transgenic mice from apoptosis but also abrogates the DNA damage induced cell cycle arrest in the G1 phase. T-cells from double mutant mice continue to proliferate after the induction of DNA strand breaks, are limited in their DNA repair capacity and cannot be eliminated by apoptosis. These results indicate that PARP-1 and p53 cooperate in the suppression of tumorigenesis by maintaining genomic integrity after DNA damage through the activation of a G1/S cell cycle checkpoint the initiation of DNA repair and the induction of cell death.
...
PMID:Inhibition of poly(ADP-ribose) polymerase activity accelerates T-cell lymphomagenesis in p53 deficient mice. 1178 27

The use of chemical modifiers as radiosensitizers in combination with low-dose irradiation may increase the therapeutic effect on cancer by overcoming a high apoptotic threshold. Here, we showed that phytosphingosine treatment in combination with gamma-radiation enhanced apoptotic cell death of radiation-resistant human T-cell lymphoma in a caspase-independent manner. Combination treatment induced an increase in intracellular reactive oxygen species (ROS) level, mitochondrial relocalization of B-cell lymphoma-2(Bcl-2)-associated X protein (Bax), poly-adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) activation, and nuclear translocation of apoptosis-inducing factor (AIF). siRNA targeting of AIF effectively protected cells from the combination treatment-induced cell death. An antioxidant, N-acetyl-L-cysteine (NAC), inhibited Bax relocalization and AIF translocation but not PARP-1 activation. Moreover, transfection of Bax-siRNA significantly inhibited AIF translocation. Pretreatment of PARP-1 inhibitor, DPQ (3,4-dihydro-5-[4-(1-piperidinyl)-butoxy]-1(2H)-isoquinolinone), or PARP-1-siRNA also partially attenuated AIF translocation, whereas the same treatment did not affect intracellular ROS level and Bax redistribution. Taken together, these results demonstrate that enhancement of cell death of radiation-resistant cancer cells by phytosphingosine treatment in combination with gamma-radiation is mediated by nuclear translocation of AIF, which is in turn mediated both by ROS-dependent Bax relocalization and ROS-independent PARP-1 activation. The molecular signaling pathways that we elucidated in this study may provide potential drug targets for radiation sensitization of cancers refractive to radiation therapy.
...
PMID:Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release. 1548 61

This study aims to investigate the role of granzyme B in the apoptosis of nasal-type NK/T-cell lymphoma. Twenty-four nasal-type NK/T-cell lymphomas were examined by TdT-mediated deoxyuridine triphosphate (dUTP)-biotin nick-end labeling (TUNEL) assay and immunohistochemical staining for active caspase 3, poly(ADP-ribose) polymerase (PARP-1/p85)/p85, and Bcl-2. In addition, HANK-1 and NKL cell lines were analyzed using Western blot analysis. Immunoprecipitation was performed to identify the binding of granzyme B and intrinsic serpin proteinase inhibitor 9 (PI-9). To localize granzyme B, immunogold labeling and immunofluorescence staining were performed. The expression level of granzyme B in tumor tissue was correlated with the apoptosis rate (P=0.015), degree of necrosis (P=0.002), and the levels of active caspase 3 (P=0.036) and poly ADP-ribose polymerase (PARP)-1/p85 (P=0.040). The granzyme B-positive HANK-1 cell line showed increased spontaneous cell death compared to the granzyme B-negative NKL cell line. The untreated HANK-1 cells released cytochrome c into the cytosol with cleavage of caspase 3 and PARP-1. Treatment with granzyme B inhibitor and caspase inhibitor decreased the cleavage of PARP-1. By performing immunogold labeling, granzyme B was identified within the cytolytic granules as well as in the cytosol. Confocal microscopy and immunoprecipitation assays confirmed the colocalization of PI-9 and granzyme B, which formed an SDS-resistant complex. These results suggested that granzyme B leakage induces cell death in NK/T-cell lymphomas via both caspase-dependent and -independent mechanisms, and this leads to the extensive necrosis that is commonly seen in NK/T-cell lymphoma.
...
PMID:Granzyme B leakage-induced apoptosis is a crucial mechanism of cell death in nasal-type NK/T-cell lymphoma. 1726 2

Peripheral T-cell lymphomas (PTCL) are a diverse group of rare non-Hodgkin lymphomas (NHL) that carry a poor prognosis and are in need of effective therapies. Alisertib (MLN8237) an investigational agent that inhibits Aurora A Ser/Thr kinase has shown activity in PTCL patients. Here we demonstrate that aurora A and B are highly expressed in T-cell lymphoma cell lines. In PTCL patient samples aurora A was positive in 3 of 24 samples and co-expressed with aurora B. Aurora B was positive in tumor cells in 22 of 32 samples. Of the subtypes of PTCL, aurora B was over-expressed in PTCL (NOS) [73%], T-NHL [100%], ALCL (Alk-Neg) [100%] and AITL [100%]. Treatment with MLN8237 inhibited PTCL cell proliferation in CRL-2396 and TIB-48 cells with an IC50 of 80-100nM. MLN8237 induced endo-reduplication in a dose and time dependent manner in PTCL cell lines leading to apoptosis demonstrated by flow cytometry and PARP-cleavage at concentrations achieved in early phase clinical trials. Moreover, inhibition of HisH3 and aurora A phosphorylation was dose dependent and strongly correlated with endo-reduplication. The data provide a sound rationale for aurora inhibition in PTCL as a therapeutic modality and warrants clinical trial evaluation.
...
PMID:Alisertib (MLN8237) an investigational agent suppresses Aurora A and B activity, inhibits proliferation, promotes endo-reduplication and induces apoptosis in T-NHL cell lines supporting its importance in PTCL treatment. 2315 24

Imatinib, the first-generation tyrosine kinase inhibitor, revolutionized the therapeutic management of chronic myeloid leukemia (CML) and is highly effective in inducing remissions and prolonging the survival of CML patients. However, one-third of patients develop intolerance or resistance to treatment, and CML stem cells remain insensitive to this therapy, leading almost inevitably to relapse upon treatment discontinuation. Imidazoquinoxalines are imiquimod derivatives that induce growth inhibition and induction of caspase-dependent apoptosis in melanoma and T-cell lymphoma cells. We investigated the effects of EAPB0203 and EAPB0503, two novel imidazoquinoxaline derivatives, on human CML cell lines and showed that they induced a dose-dependent and time-dependent cell growth inhibition. EAPB0503 proved more potent and induced a specific cell cycle arrest in mitosis in CML cells and direct activation of apoptosis as evidenced by increased pre-G0 population, breakdown of mitochondrial membrane potential, PARP cleavage, and DNA breakage. Interestingly, EAPB0503 decreased BCR-ABL oncoprotein levels. The combination of EAPB0503 with imatinib synergized to inhibit the proliferation of CML cells, and most importantly, EABP0503 inhibited the proliferation of imatinib-resistant CML cells, offering promising therapeutic modalities that would circumvent resistance to tyrosine kinase inhibitors and improve the prognosis of CML.
...
PMID:EAPB0503, a novel imidazoquinoxaline derivative, inhibits growth and induces apoptosis in chronic myeloid leukemia cells. 2446 83


1 2 Next >>

---