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)

Post-irradiation changes in DNA synthesis and ADP-ribosyltransferase (ADPRT) activity in L5178YS and L5178YR, radiation sensitive and resistant murine lymphoma cells are described. DNA synthesis was inhibited to a greater extent in L5178YS than in L5178YR cells. The stimulation of ADPRT activity by irradiation was not significantly different between these two cell lines. These observations contribute to other evidence which has failed to confirm a general association of ADP-ribosylation with the DNA synthesis inhibition response. The contrast between the response of L5178Y cells and the corresponding behaviour of ataxia telangiectasia cells and normal human cells indicate that entirely different mechanisms are involved in determining the differences in radiosensitivity in these two systems.
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PMID:Post-irradiation inhibition of scheduled DNA synthesis and stimulation of ADP-ribosylation in sensitive and resistant L5178Y murine lymphoma cells. 631 90

Arginine-specific ADP-ribosyltransferase activity was detected in chicken spleen membrane fraction and the activity was extracted by phosphatidylinositol-specific phospholipase C but not by 1 M NaCl or 1% Triton X-100. The transferase activity extracted from the spleen membrane was thiol-independent and was not inhibited by 200 mM NaCl. Zymographic analysis of the transferase, under non-reducing conditions, showed two forms of active bands corresponding to a molecular mass of 46 and 42 kDa. Thus, the presence of this novel arginine-specific ADP-ribosyltransferase, anchored to the membrane through glycosylphosphatidylinositol and different from previously cloned chicken transferases, AT1 and AT2, is being given further attention.
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PMID:A newly identified GPI-anchored arginine-specific ADP-ribosyltransferase activity in chicken spleen. 757 41

Two arginine-specific ADP-ribosyltransferase cDNAs (designated AT1 and AT2) were cloned from chicken bone marrow cells. Each cDNA encodes a different peptide of 312 amino acid residues. Homology of deduced amino acid sequences between AT1 and AT2 was 78.3%. We found all six combined peptide sequences of 222 amino acid residues derived from purified chicken heterophil ADP-ribosyltransferase (Mishima, K., Terashima, M., Obara, S., Yamada, K., Imai, K., and Shimoyama, M. (1991) J. Biochem. (Tokyo) 110, 388-394) in the deduced amino acid sequence of AT1, with two amino acid mismatches. Arginine-specific ADP-ribosyltransferase activity was detected in culture medium of COS 7 cells transiently transfected with AT1 cDNA, while activity from the cells transfected with AT2 cDNA was found in both culture medium and cell lysate. AT1 transferase required 2-mercaptoethanol for the activity. The activity was inhibited in the presence of NaCl while AT2 enzyme was activated by either agent. On zymographic in situ gel analysis, estimated molecular masses of the AT1, AT2 and purified chicken heterophil transferases were 32, 34, and 27.5 kDa, respectively. Northern blot analysis with specific probes to AT1 or AT2 cDNAs revealed about a 1.5-kilobase message in chicken bone marrow cells but no signals were observed in heterophils, spleen, and liver of chicken or human HL-60 cells. Highly conserved regions were observed among the deduced amino acid sequences of AT1, AT2, rabbit skeletal muscle transferase, and rodent T-cell surface antigen RT6s.
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PMID:Cloning and expression of cDNA for arginine-specific ADP-ribosyltransferase from chicken bone marrow cells. 796 58

Among a number of tissues and peripheral blood cells in chicken, leukocytes, bone marrow cells, liver and spleen showed high ADP-ribosyltransferase activity, with leukocytes having the highest. Density gradient centrifugation of the leukocytes revealed that the leukocyte ADP-ribosyltransferase originates in the polymorphonuclear cells, so called heterophils. Subcellular distribution of the cells showed the localization of the enzyme in the granule fraction. Based on the obtained amino acid sequences of arginine-specific ADP-ribosyltransferase purified from chicken peripheral heterophils, two arginine-specific ADP-ribosyltransferase cDNAs (designated AT1 and AT2) were obtained from chicken bone marrow cells. Each cDNA encodes a different peptide of 312 amino acid residues. Homology of the deduced amino acid sequences between AT1 and AT2 was 78.3%. Arginine-specific ADP-ribosyltransferase activity was detected in culture medium of COS 7 cells transiently transfected with AT1 cDNA, while activity from the cells transfected with AT2 cDNA was found in both culture medium and cell lysate. AT1 transferase required 2-mercaptoethanol (MSH) for the activity and in the presence of NaCl, the activity was inhibited while the AT2 enzyme was activated by either agent. Highly conserved regions were observed among the deduced amino acid sequences of AT1, AT2, chicken erythroblast and rabbit and human skeletal muscle ADP-ribosyltransferases, and rodent T-cell surface antigen RT6. Two forms of the transferase with much the same properties as AT1 and AT2 proteins, regarding the effect of NaCl and MSH, were detected in bone marrow cells. Based on these results it seems that AT1 and AT2 cDNAs encode the two forms of arginine-specific ADP-ribosyltransferase detected in chicken bone marrow cells.
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PMID:Molecular cloning and characterization of arginine-specific ADP-ribosyltransferases from chicken bone marrow cells. 919 46

Poly(ADP-ribose) polymerase (PARP) is a constitutive factor of the DNA damage surveillance network in dividing cells. Based on its capacity to bind to DNA strand breaks, PARP plays a regulatory role in their resolution in vivo. ATM belongs to a large family of proteins involved in cell cycle progression and checkpoints in response to DNA damage. Both proteins may act as sensors of DNA damage to induce multiple signalling pathways leading to activation of cell cycle checkpoints and DNA repair. To determine a possible relationship between PARP and ATM, we examined the PARP response in an ATM-null background. We demonstrated that ATM deficiency does not affect PARP activity in human cell lines or Atm-deficient mouse tissues, nor does it alter PARP activity induced by oxidative damage or gamma-irradiation. Our results support a model in which PARP and ATM could be involved in distinct pathways, both effectors transducing the damage signal to cell cycle regulators.
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PMID:Poly(ADP-ribose) polymerase activity is not affected in ataxia telangiectasia cells and knockout mice. 993 67

The mechanism(s) of c-Myc transcription factor-induced apoptosis is still obscure. The activation of c-Myc has been found to lead into the processing/activation of caspases (caspase-3), but the significance of this for the cell demise is debatable. Here we report that several targets of caspases (PKCdelta, MDM2, PARP, replication factor C, 70 kDa U1snRNP, fodrin and lamins) are cleaved during c-Myc-induced apoptosis in Rat-1 MycER cells, indicating an important role for caspases in the apoptotic process. We further found that the ATM (ataxia telangiectasia mutated)--protein is a novel key substrate of caspases. In in vitro assays, purified recombinant ATM protein was found to be cleaved by the effector caspases 3 and 7. The functional significance of the ATM cleavage is supported by the finding that ectopic expression of ATM protected in part against apoptosis. We also show that c-Myc-induced apoptosis involves loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria into the cytosol and subsequent processing of caspase-9. The cleavage of caspase-9 is, however, minimal and a much later event than the processing/activation of caspase-3, suggesting that it is not the apical caspase. Evidence is provided that there is, nevertheless, an upstream caspase(s) regulating the functions of caspase-3 and mitochondria. Additionally, it was found that p53 becomes upregulated, together with its transcriptional targets MDM2 and p21, upon c-Myc induction, but this occurs also at a later time than the activation of caspase-3.
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PMID:Caspases and mitochondria in c-Myc-induced apoptosis: identification of ATM as a new target of caspases. 1082 87

The average length of telomere repeats at the ends of chromosomes in most normal human somatic cells has been found to decrease by 50-200 base pairs with each cell division. The loss of telomere repeats has been causally linked to replicative senescence by the demonstration that overexpression of the enzyme telomerase can result in the elongation or maintenance of telomeres and immortalization of somatic cells with a diploid and apparently normal karyotype. Major questions that remain are related to the actual mechanism by which telomere shortening induces replicative senescence and the importance of telomere shortening and replicative senescence in the homeostasis of cells in renewal tissues and aging. This perspective is concerned with the consequences of telomere shortening at individual chromosomes in individual cells. Experimental evidence indicates that short telomeres accumulate prior to senescence and that replicative senescence is not triggered by the first telomere to reach a critical minimal threshold length. These observations are compatible with limited repair of short telomeres by telomerase-dependent or telomerase-independent DNA repair pathways. Deficiencies in telomere repair may result in accelerated senescence and aging as well as genetic instability that facilitates malignant transformation. Examples of molecules that may have a role in the repair of telomeric DNA prior to replicative senescence include ATM, p53, PARP, DNA-PK, Ku70/80, the human hRad50-hMre11-p95 complex, BRCA 1 and 2 and the helicases implicated in Bloom's and Werner's syndrome.
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PMID:Repair of telomeric DNA prior to replicative senescence. 1098 22

Here we found that wortmannin sensitized Chinese hamster V79 cells to hyperthermic treatment at 44.0 degrees C as determined either by colony formation assay or by dye exclusion assay. Wortmannin enhanced heat-induced cell death accompanying cleavage of poly (ADP-ribose) polymerases (PARP). Additionally, the induction of heat shock protein HSP70 was suppressed and delayed in wortmannin-treated cells. Heat sensitizing effect of wortmannin was obvious at more than 5 or 10 microM of final concentrations, while radiosensitization was apparent at 5 microM. Requirement for high concentration of wortmannin, i.e., order of microM, suggests a possible role of certain protein kinases, such as DNA-PK and/or ATM among PI3-kinase family. The sensitization was minimal when wortmannin was added at the end of heat treatment. This was similar to the case of X-ray. Since heat-induced cell death and PARP cleavage preceded HSP70 induction phenomenon, the sensitization to the hyperthermic treatment was considered mainly caused by enhanced apoptotic cell death rather than secondary to suppression or delay by wortmannin of HSP70 induction. Further, in the present system radiosensitization by wortmannin was also at least partly mediated through enhancement of apoptotic cell death.
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PMID:Sensitization by wortmannin of heat- or X-ray induced cell death in cultured Chinese hamster V79 cells. 1103 77

PARP-1 and ATM are both involved in the response to DNA strand breaks, resulting in induction of a signaling network responsible for DNA surveillance, cellular recovery, and cell survival. ATM interacts with double-strand break repair pathways and induces signals resulting in the control of the cell cycle-coupled checkpoints. PARP-1 acts as a DNA break sensor in the base excision repair pathway of DNA. Mice with mutations inactivating either protein show radiosensitivity and high radiation-induced chromosomal aberration frequencies. Embryos carrying double mutations of both PARP-1 and Atm genes were generated. These mutant embryos show apoptosis in the embryo but not in extraembryonic tissues and die at embryonic day 8.0, although extraembryonic tissues appear normal for up to 10.5 days of gestation. These results reveal a functional synergy between PARP-1 and ATM during a period of embryogenesis when cell cycle checkpoints are not active and the embryo is particularly sensitive to DNA damage. These results suggest that ATM and PARP-1 have synergistic phenotypes due to the effects of these proteins on signaling DNA damage and/or on distinct pathways of DNA repair.
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PMID:Early embryonic lethality in PARP-1 Atm double-mutant mice suggests a functional synergy in cell proliferation during development. 1123 19

The methylation status of seven cancer-related genes was investigated in a series of 58 colorectal cancers, 18 of which showed the microsatellite instability (MSI+) phenotype. Methylation of the hMLH1, p16 and MDR1 genes was found in 23, 29 and 28% of tumors, respectively. None of the tumors showed methylation of the TS, ATM, PARP or p21 genes. Methylation of the hMLH1, p16 and MDR1 genes was more frequent and more concordant in MSI+ compared to MSI- tumors (P<0.001) and was also strongly associated with poor histological differentiation (P<0.001). There were trends for associations between methylation at one or more of these loci and proximal tumor location, advanced Dukes' stage and the presence of wild-type p53 (P=0.06 for each).
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PMID:Methylation of the hMLH1, p16, and MDR1 genes in colorectal carcinoma: associations with clinicopathological features. 1132 3


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