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)

The tumor suppressor gene p53 is expressed in the contrasting cell fates apoptosis and proliferation. We examined whether the transactivation of the p53 target genes, waf1 and mdm2, is dependent on the cause of p53 induction in human peripheral blood mononuclear cells (PBMC). Both apoptosis triggered by the purine analog 2-chlorodeoxyadenosine (CdA) and growth stimulation by the mitogen phytohemagglutinin (PHA) induced a comparable level and time course of p53 mRNA expression. Both stimuli led also to an increase of p53 protein levels. The cytotoxic agent, but not the mitogen, led to transactivation of waf1 and mdm2 within 18 h. Transactivation was followed by apoptosis of 89% of the PBMC within 48 h. The c-myc oncogene and poly(ADP-ribose)polymerase (PARP), which also have a dual function in proliferation and apoptosis, showed an early induction by both CdA and PHA. These results add further evidence that growth stimulation and DNA damage-induced apoptosis share early gene activation pathways in normal cells. However, since p53 does selectively translate into transactivation of target genes depending on the cause of induction, this function of p53 seems to be regulated by additional factors, which are closely related to the ultimate fate of the cell.
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PMID:Type of inducing signal regulates transactivation by p53. 936 63

The acridine derivative m-AMCA (methyl-N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), a carbamate analogue of the topoisomerase II poison amsacrine, is distinguished by its high cytotoxicity against non-cycling tumour cells. We compared the response of cultured Lewis lung carcinoma cells to m-AMCA, amsacrine and the topoisomerase I poison camptothecin. The DNA polymerase inhibitor aphidicolin reversed the cytotoxicity of camptothecin fully, that of amsacrine partially, and that of m-AMCA minimally. The ability of m-AMCA to induce the enzyme poly(ADP-ribose)polymerase (PARP) was markedly lower than that of camptothecin or amsacrine. Cell cycle responses to m-AMCA and amsacrine were similar, with slowing of progress through S-phase and arrest in G2-phase. These cell cycle changes were also observed when plateau phase cultures were exposed to drug for 1 h, washed free of drug and cultured in fresh medium, with m-AMCA having a more pronounced effect than amsacrine and camptothecin having no effect. We also examined the role of p53 protein in the response using cultured human H460 cells. Both m-AMCA and amsacrine induced p53 protein expression in proliferating but not in non-proliferating H460 cells, and induced p21WAF1 regardless of proliferation status. Both induced G1-phase cell cycle arrest. It is suggested that two cytotoxicity mechanisms can be distinguished using these drugs. The first is specific for S-phase cells, is reversed by aphidicolin and induces PARP activity. The second is cell cycle non-specific, does not induce PARP and is unaffected by aphidicolin. Camptothecin activates only the first, m-AMCA primarily the second and amsacrine activates both.
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PMID:Cellular responses to methyl-N-[4-9-acridinylamino)-2-methoxyphenyl] carbamate hydrochloride, an analogue of amsacrine active against non-proliferating cells. 938 32

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.
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PMID:Genetic interaction between PARP and DNA-PK in V(D)J recombination and tumorigenesis. 939 55

The purine analogue 2-chlorodeoxyadenosine (CdA) is unique compared with traditional antimetabolite drugs, as it has shown equal activity in dividing and resting lymphocytes. Poly(ADP-ribose)polymerase (PARP) activation and consecutive NAD+ consumption have been associated with the induction of apoptosis in resting cells. The potential of CdA to induce the p53-dependent DNA damage response was assessed in resting and phytohaemagglutinine (PHA)-activated peripheral blood mononuclear cells (PBMCs) and compared with cisplatin (DDP), a cell cycle-dependent and DNA-damaging agent that is mainly used in the treatment of solid tumours. Both drugs induced transactivation of the p53 target genes waf1 and mdm2, NAD+ consumption and apoptotic death. The expression pattern of p53 and waf1 suggests a partly p53-independent induction of waf1. The expression of c-myc and PARP, which both have a dual role in proliferation and apoptosis, was selectively induced by CdA. Cell cycle stimulation increased the cytotoxic activity of both drugs. These data show that DDP is also a potent inducer of apoptosis in resting and proliferating peripheral blood mononuclear cells. Activation of the p53-dependent DNA damage response seems to be an important component of the toxic effect of CdA.
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PMID:Similarity of apoptosis induction by 2-chlorodeoxyadenosine and cisplatin in human mononuclear blood cells. 940 Sep 41

c-Myc is a transcriptional activator implicated in the control of cell proliferation, differentiation and transformation, but is also involved in the regulation of programmed cell death, apoptosis. Despite intensive research, the molecular mechanisms by which c-Myc triggers and executes cell death remain still elusive. Here, we made use of Rat 1A MycER cells expressing a conditionally active c-Myc protein and tested first the hypothesis that ornithine decarboxylase (ODC), which is a transcriptional target of c-Myc, were a mediator of c-Myc-induced apoptosis. However, our results show that the activity of ODC is not required for the c-Myc-mediated apoptosis to occur in these cells. We also found that the expression of p53, p21waf1/cip1, Bcl-2, Bax, Bcl-xL, Bad and cyclins D1, E, A and B did not show any significant changes following c-Myc induction. But, our studies revealed that the c-Myc induced apoptosis is associated with a specific cleavage of poly(ADPribose) polymerase (PARP), suggesting that a cysteine protease of the ICE/CED-3 family is involved. Moreover, we found that the cysteine protease CPP32/Caspase-3, which is known to cleave PARP, is processed from its inactive form to an active protease composed of 17 and 12 kDa subunits; whilst Ich-1/Caspase-2 belonging to another subset of this protease family was not processed/ activated following c-Myc activation. The activation of CPP32 and apoptotic cell death were inhibited by addition of Z-VAD-fmk, a universal inhibitor of ICE-like proteases. Further, a selective inhibitor of CPP32-like proteases (Z-DEVD-fmk) partly inhibited apoptosis. These results provide evidence that the ICE/CED3-family proteases, CPP32 and likely others, play a critical role in the execution of a nuclear proto-oncogene, c-Myc-induced apoptosis.
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PMID:Involvement of CPP32/Caspase-3 in c-Myc-induced apoptosis. 946 64

Ultraviolet light (UV) induced rapid apoptosis of U937 leukemia cells, concurrent with DNA fragmentation and cleavage of poly(ADP-ribose)polymerase (PARP) by activated caspase-3. The in vitro reconstitution of intact HeLa S3 nuclei and apoptotic U937 cytosolic extract (CE) revealed that (i) Ca2+/Mg(2+)-dependent, Zn(2+)-sensitive endonuclease activated in the apoptotic CE induced DNA ladder in HeLa nuclei at pH 6.8-7.4, (ii) activated caspase-3 cleaved PARP in HeLa nuclei, and (iii) when the apoptotic CE was treated with the caspase-3 inhibitor (1 microM Ac-DEVD-CHO) or the caspase-1 inhibitor (10 microM Ac-YVAD-CHO), the former, but not the latter, caused a 50% inhibition of DNA fragmentation and the complete inhibition of PARP cleavage in HeLa nuclei. Similarly, Ac-DEVD-CHO (100 microM) inhibited apoptosis and DNA ladder by 50% and PARP cleavage completely in UV-irradiated U937 cells, but Ac-YVAD-CHO (100 microM) did not. Thus, UV-induced apoptosis of U937 cells involves the Ca2+/Mg(2+)-dependent endonuclease pathway and the caspase-3-PARP cleavage-Ca2+/Mg(2+)-dependent endonuclease pathway. The former pathway produced directly 50% of apoptotic DNA ladder, and the latter involved activated caspase-3 and PARP cleavage, followed by formation of the remaining 50% DNA ladder by the activated endonuclease. In UV-irradiated B-cell lines, further, p53-dependent increase of Bax resulted in a greater caspase-3 activation compared to its absence. However, UV-induced activation of JNK1 and p38 was not affected by the caspase-1 and -3 inhibitors in U937 cells, so that caspases-1 and -3 do not function upstream of JNK1 and p38.
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PMID:Mechanism of UV-induced apoptosis in human leukemia cells: roles of Ca2+/Mg(2+)-dependent endonuclease, caspase-3, and stress-activated protein kinases. 952 59

DNA strand breaks are potential interaction sites for the nuclear enzyme poly(ADP-ribose) polymerase (PARP; E.C. 2.4.2.30) and the tumor suppressor protein p53. Both proteins bind and respond to DNA breaks and both play a role in DNA damage signaling. A temporary colocalization and complex formation between these proteins has been demonstrated in mammalian cells. Here we show that free and poly(ADP-ribose) polymerase-bound ADP-ribose polymers target three domains in p53 protein for strong noncovalent interactions. The polymer binding sites could be mapped to two amino acid sequences in the sequence-specific core DNA binding domain of p53 (amino acid positions 153-178 and 231-253) and another one in the oligomerization domain (amino acids 326-348). In mobility shift experiments, poly(ADP-ribose) effectively prevented and reversed p53 binding to the palindromic p53 consensus sequence. Additionally, poly(ADP-ribose) also interfered with the DNA single strand end binding of p53. The results suggest that ADP-ribose polymers could play a role in regulating the DNA binding properties of p53.
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PMID:Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions. 956 8

Signal transduction pathways involving the c-Raf protein kinase are frequently activated in tumor cells. We have addressed the relevance of this activation by a loss-of-function approach. An anti-sense phosphorothioate oligonucleotide (ODN) specifically targeted against c-raf mRNA (Monia et al., 1996a) was used to block c-Raf protein expression in four different cell lines derived from lung, cervical, prostate and colon carcinomas. Concomitant with the abrogation of c-Raf expression we observed the occurrence of classical apoptotic markers, including chromatin condensation, inter-nucleosomal DNA cleavage, annexin V binding and cleavage of PARP, which was followed by cell death, affecting most of the cell population. This induction of apoptosis occurred independent of the p53 status of the cell. These findings demonstrate that c-Raf can protect tumor cells from undergoing programmed cell death, and suggest that the interference with c-Raf expression or function by ODNs or specific drugs could represent a powerful means for improving the efficacy of anti-cancer therapy.
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PMID:Abrogation of c-Raf expression induces apoptosis in tumor cells. 958 88

Spontaneous and radiation-induced apoptosis in three lung carcinoma cell lines (U-1285, U-1906 and U-1810) with previously characterised intrinsic radiosensitivities (RS) was assessed by TUNEL-staining, detection of DNA laddering and cleavage of poly-(ADP-ribose) polymerase (PARP). Spontaneous apoptosis was detected at a high level in the radiosensitive U-1285, at an intermediate level in U-1906 and not detected in the radioresistant U-1810 cell line. Radiation-induced apoptosis, assessed by TUNEL assay, was present in U-1285 and U-1906 cells but not in U-1810 cells. To explain these findings, expression of Bcl-2, Bax, c-Myc and RB protein and mutations of the p53 gene were analysed. The ratio Bcl-2/Bax was higher in U-1810 cells compared with U-1285 and U-1906 cells. Overexpression of c-Myc and loss of RB was found in U-1285 cells whereas both U-1906 and U-1810 cells expressed RB and showed lower c-Myc expression. Analysis with sequencing of all p53 exons disclosed mutations in all three cell lines. Thus, apoptosis was a p53 independent process in U-1285 and U-1906 cells. RB loss and overexpression of c-Myc may enhance apoptosis in U-1285 cells. Our data suggest that spontaneous apoptosis may correlate with RS in SCLC.
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PMID:Spontaneous and radiation-induced apoptosis in lung carcinoma cells with different intrinsic radiosensitivities. 961 7

Sulfur mustard (SM) induces vesication via poorly understood pathways. The blisters that are formed result primarily from the detachment of the epidermis from the dermis at the level of the basement membrane. In addition, there is toxicity to the basal cells, although no careful study has been performed to determine the precise mode of cell death biochemically. We describe here two potential mechanisms by which SM causes basal cell death and detachment: namely, induction of terminal differentiation and apoptosis. In the presence of 100 microM SM, terminal differentiation was rapidly induced in primary human keratinocytes that included the expression of the differentiation-specific markers K1 and K10 and the cross-linking of the cornified envelope precursor protein involucrin. The expression of the attachment protein, fibronectin, was also reduced in a time- and dose-dependent fashion. Features common to both differentiation and apoptosis were also induced in 100 microM SM, including the rapid induction of p53 and the reduction of Bcl-2. At higher concentrations of SM (i.e., 300 microM), formation of the characteristic nucleosome-sized DNA ladders, TUNEL-positive staining of cells, activation of the cysteine protease caspase-3/apopain, and cleavage of the death substrate poly(ADP-ribose) polymerase, were observed both in vivo and in vitro. Both the differentiation and the apoptotic processes appeared to be calmodulin dependent, because the calmodulin inhibitor W-7 blocked the expression of the differentiation-specific markers, as well as the apoptotic response, in a concentration-dependent fashion. In addition, the intracellular Ca2+ chelator, BAPTA-AM, blocked the differentiation response and attenuated the apoptotic response. These results suggest a strategy for designing inhibitors of SM vesication via the Ca2+-calmodulin or caspase-3/PARP pathway.
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PMID:Sulfur mustard induces markers of terminal differentiation and apoptosis in keratinocytes via a Ca2+-calmodulin and caspase-dependent pathway. 966 88


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