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)

S-Adenosylmethionine decarboxylase (SAMDC) is a key enzyme for the biosynthesis of spermidine. SAMDC-suppressed HL-60 cells overproduced intracellular reactive oxygen species (ROS), which led to cell growth defect and partial cell death. ROS overproduction was caused by a decrease of the total glutathione (GSH) and the ratio of reduced to oxidized GSH, and by an increase of the intracellular iron uptake. When analyzed by real-time polymerase chain reaction, the transcripts of the genes involved in the GSH synthesis (gamma-glutamyl cysteine synthetase, GSH synthetase), as well as the gene of the GSH-reducing enzyme (NADP+-dependent isocitrate dehydrogenase), were decreased dramatically in these cells. DNA-repairing genes (ATM, PARP, RAD51 and MSH2) also were not activated transcriptionally. In these situations, excessive ROS induced severe DNA damage, which could not be repaired, and ultimately led the cells to a spontaneous cell death or an early senescence state. For such cells, gamma-radiation and cisplatin, which are direct DNA-damaging agents, were very effective for promoting cell death.
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PMID:S-Adenosylmethionine decarboxylase partially regulates cell growth of HL-60 cells by controlling the intracellular ROS level: Early senescence and sensitization to gamma-radiation. 1706 47

We demonstrated here for the first time that zerumbone (ZER), a natural cyclic sesquiterpene, significantly suppressed the proliferation of promyelocytic leukemia NB4 cells among several leukemia cell lines, but not human umbilical vein endothelial cells (HUVECs), by inducing G2/M cell cycle arrest followed by apoptosis with 10 microM of IC50. Treatment of NB4 cells with growth-suppressive concentrations of ZER resulted in G2/M cell cycle arrest that was associated with a decline of Cyclin B1 protein, but with the phosphorylation of ATM/ Chk1/Chk2. In addition, ZER induced the phosphorylation of Cdc25C at the Thr48 residue and Cdc2 at the Thr14/Tyr15 residues. Furthermore, ZER-induced apoptosis in NB4 cells was initiated by the expression of Fas (CD95)/Fas Ligand (CD95L), concomitant with the activation of caspase-8. ZER was also found to induce the cleavage of Bid, a mediator that is known to connect the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. ZER also induced the cleavage of Bax and Mcl-1 proteins, but not Bcl-2 or Bcl-XL. ZER-induced apoptosis took place in association with a loss of the mitochondrial transmembrane potential as well as the activation of caspase-3 and -9, resulting in the degradation of the proteolytic poly (ADP-ribose) polymerase (PARP). ZER also triggered a release of cytochrome c into the cytoplasm. Both antagonistic anti-Fas antibody ZB4 and pan-caspase inhibitor Z-VAD inhibited ZER-induced apoptosis in NB4 cells. Taken together, ZER is an inducer of apoptosis in leukemic cells that specifically triggers the Fas/CD95- and mitochondria-mediated apoptotic signaling pathway.
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PMID:Zerumbone, a bioactive sesquiterpene, induces G2/M cell cycle arrest and apoptosis in leukemia cells via a Fas- and mitochondria-mediated pathway. 1712 59

ATM and PARP-1 are two of the most important players in the cell's response to DNA damage. PARP-1 and ATM recognize and bound to both single and double strand DNA breaks in response to different triggers. Here we report that ATM and PARP-1 form a molecular complex in vivo in undamaged cells and this association increases after gamma-irradiation. ATM is also modified by PARP-1 during DNA damage. We have also evaluated the impact of PARP-1 absence or inhibition on ATM-kinase activity and have found that while PARP-1 deficient cells display a defective ATM-kinase activity and reduced gamma-H2AX foci formation in response to gamma-irradiation, PARP inhibition on itself is able to activate ATM-kinase. PARP inhibition induced gamma H2AX foci accumulation, in an ATM-dependent manner. Inhibition of PARP also induces DNA double strand breaks which were dependent on the presence of ATM. As consequence ATM deficient cells display an increased sensitivity to PARP inhibition. In summary our results show that while PARP-1 is needed in the response of ATM to gamma irradiation, the inhibition of PARP induces DNA double strand breaks (which are resolved in and ATM-dependent pathway) and activates ATM kinase.
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PMID:Interaction between ATM and PARP-1 in response to DNA damage and sensitization of ATM deficient cells through PARP inhibition. 1745 51

T cell-based therapies have much promise in cancer treatment. This approach may be enhanced if used in combination with radiotherapy provided that tumor-specific T cells can be protected against the effects of radiotherapy. Previously, we demonstrated that administration of TLR9 ligand into mice decreased activation- and serum deprivation-induced cell death in T cells. We hypothesized that TLR9 engagement on T lymphocytes decreased apoptosis after cellular stress. We show that TLR9 engagement on murine CD4 T cells reduces gamma-radiation-induced apoptosis as judged by decreased annexin-V/PI staining, caspase-3 activation, and PARP cleavage. TLR9-stimulated cells show heightened accumulation at the G2 cell-cycle phase and increased DNA repair rates. Irradiated, TLR9-engaged cells showed higher levels of phosphorylated Chk1 and Chk2. While the levels of activated ATM in response to IR did not differ between TLR9-stimulated and unstimulated cells, inhibition of ATM/ATR and Chk1/Chk2 kinases abolished the radioprotective effects in TLR9-stimulated cells. In vivo, TLR9-stimulated cells displayed higher radio resistance than TLR9-stimulated MyD88(-/-) T cells and responded to antigenic stimulation after total body irradiation. These findings show, for the first time, that TLR9 engagement on CD4 T cells reduces IR-induced apoptosis by influencing cell-cycle checkpoint activity, potentially allowing for combinatorial immunotherapy and radiotherapy.
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PMID:TLR9 engagement on CD4 T lymphocytes represses gamma-radiation-induced apoptosis through activation of checkpoint kinase response elements. 1808 70

DNA double-strand breaks (DSBs) are critical lesions that can result in cell death or a wide variety of genetic alterations including large- or small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining (NHEJ) and homologous recombination (HR), and defects in these pathways cause genome instability and promote tumorigenesis. DSBs arise from endogenous sources including reactive oxygen species generated during cellular metabolism, collapsed replication forks, and nucleases, and from exogenous sources including ionizing radiation and chemicals that directly or indirectly damage DNA and are commonly used in cancer therapy. The DSB repair pathways appear to compete for DSBs, but the balance between them differs widely among species, between different cell types of a single species, and during different cell cycle phases of a single cell type. Here we review the regulatory factors that regulate DSB repair by NHEJ and HR in yeast and higher eukaryotes. These factors include regulated expression and phosphorylation of repair proteins, chromatin modulation of repair factor accessibility, and the availability of homologous repair templates. While most DSB repair proteins appear to function exclusively in NHEJ or HR, a number of proteins influence both pathways, including the MRE11/RAD50/NBS1(XRS2) complex, BRCA1, histone H2AX, PARP-1, RAD18, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and ATM. DNA-PKcs plays a role in mammalian NHEJ, but it also influences HR through a complex regulatory network that may involve crosstalk with ATM, and the regulation of at least 12 proteins involved in HR that are phosphorylated by DNA-PKcs and/or ATM.
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PMID:Regulation of DNA double-strand break repair pathway choice. 1815 61

Many predictive factors of tumor radiosensitivity have been described. Number of clonogenic cells, proliferation rate, hypoxia and intrinsic radiosensitivity are usually considered as the main parameters of tumor control. Intrinsic radiosensitivity is correlated in a first approach to the ability of the cell to detect and repair DNA damages, and so integrity of the different pathways involved in this function: PARP-1, XRCC1, ATM, p53, MRN complex or BRCA1... Genetic polymorphisms of some of these genes, found in normal lymphocytes, have been correlated to late toxicity of normal tissues. But, in tumors, because of the difficulty to obtain samplings and heterogeneity, accurate molecular analysis is not possible in many cases, and no valuable test of radiosensitivity exist at this moment. For example, TP53 gene has been evaluated in many studies and results regarding its potential as a predictive factor of tumor sensitivity are conflicting. Surviving fraction at 2Gy (SF2) allowed a global evaluation of sensitivity, but the obtention of this parameter often takes a long time and failed in 20 to 40%. Evaluation of double-strand break repair capacity by immunochemistry quantification of phosphorylated forms of ATM, H2AX or MRE11 is an interesting topic. However, discovery of tumor stem cells in a number of epithelial tumors could revolutionize the understanding of radiosensitivity. Combination of genomic and functional techniques are probably essential to better predict this parameter.
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PMID:[Determinants and predictive factors of tumour radiosensitivity]. 1818 56

Benzo[a]pyrene (BaP) is a potentially genotoxic and cytotoxic environmental pollutant. Previous studies showed that exposure of HepG(2) cells to BaP causes necrotic cell death [Lin, T., Yang, M.S., 2007b. Cell death induced by benzo[a]pyrene in the HepG(2) cells is dependent on PARP-1 activation and NAD depletion. Toxicology 245, 147-153]. In the present study, the signaling pathways associated with this response was studied. BaP induced accumulation and activation of p53 in HepG(2) cells, which occurred as early as 12h after exposure. Activation of p53 was evidenced by its phosphorylation at serine 15 (Ser15) and acetylation at lysine 382 (Lys382). Chemical inhibition and siRNA-mediated knockdown of p53 expression suppressed its phosphorylation as well as cell death. BaP also activated p38 MAPK and ERK, but not JNK, at 6h after exposure. SB203580 and PD98059, specific inhibitors of p38 MAPK and ERK, respectively, suppressed phosphorylation of p53 at Ser15, but the accumulation of p53 was only moderately reduced. Acetylation of p53 at Lys 382 was not affected by these inhibitors, suggesting that acetylation stabilizes p53 in response to DNA damage. SB203580 and PD98059 prevented downstream energy failure and BaP-induced cell death. Similar results were obtained with siRNA against two isoforms of p38 MAPK, p38alpha and p38beta. Wortmannin, selective inhibitor of DNA-PK and ATM/ATR, abolished p53 phosphorylation, indicating an involvement of multiple pathways of p53 phosphorylation upon exposure to BaP. In summary, the current study demonstrated that both MAPK and p53 activation are required for BaP-induced necrotic cell death. The results also provide a novel model for studying the regulation between p53 and p38 MAPK in the progression of cellular necrosis.
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PMID:MAPK regulate p53-dependent cell death induced by benzo[a]pyrene: involvement of p53 phosphorylation and acetylation. 1840 7

Hereditary breast cancer accounts for up to 5-10% of all breast carcinomas. Recent studies have demonstrated that mutations in two high-penetrance genes, namely BRCA1 and BRCA2, are responsible for about 16% of the familial risk of breast cancer. Even though subsequent studies have failed to find another high-penetrance breast cancer susceptibility gene, several genes that confer a moderate to low risk of breast cancer development have been identified; moreover, hereditary breast cancer can be part of multiple cancer syndromes. In this review we will focus on the hereditary breast carcinomas caused by mutations in BRCA1, BRCA2, Fanconi anaemia (FANC) genes, CHK2 and ATM tumour suppressor genes. We describe the hallmark histological features of these carcinomas compared with non-hereditary breast cancers and show how an accurate histopathological diagnosis may help improve the identification of patients to be screened for mutations. Finally, novel therapeutic approaches to treat patients with BRCA1 and BRCA2 germ line mutations, including cross-linking agents and PARP inhibitors, are discussed.
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PMID:Hereditary breast cancer: from molecular pathology to tailored therapies. 1868 20

Mammalian cells are frequently at risk of DNA damage from multiple sources. Accordingly, cells have evolved the DNA damage response (DDR) pathways to monitor the integrity of their genome. Conceptually, DDR pathways contain three major components (some with overlapping functions): sensors, signal transducers, and effectors. At the level of sensors, ATM (ataxia telangiectasia mutated) and ATR (ATM-Rad3-related) are proximal kinases that act as the core sensors of and are central to the entire DDR. These two kinases function to detect various forms of damaged DNA and trigger DNA damage response cascades. If cells harbor DDR defects and fail to repair the damaged DNA, it would cause genomic instability and, as a result, lead to cellular transformation. Indeed, deficiencies of DDR frequently occur in human cancers. Interestingly, this property of cancer also provides a great opportunity for cancer therapy. For example, by using a synthetic lethality model to search for the effective drugs, ChK1 inhibitors have been shown to selectively target the tumor cells with p53 mutations. In addition, the inhibitors of poly(ADP-ribose) polymerase (PARP-1) showed selectively killing effects on the cells with defects of homologous recombination (HR), particularly in the context of BRCA1/2 mutations. Since Brit1 is a key regulator in DDR and HR repair, we believe that we can develop a similar strategy to target cancers with Brit1 deficiency. Currently, we are conducting a high-throughput screening to identify novel compounds that specifically target the Brit1-deficient cancer which will lead to development of effective personalized drugs to cure cancer in clinic.
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PMID:DNA damage response pathways in tumor suppression and cancer treatment. 1903 64

The impact of DNA damage-induced replication blockage for early activation of stress kinases [stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)] is largely unknown. Here, we show that induction of dual phosphorylation of SAPK/JNK by the DNA polymerase inhibitor aphidicolin was not ameliorated by additional exposure to ultraviolet (UV) light, indicating that overlapping mechanisms participate in signaling to SAPK/JNK triggered by both agents. UV-induced DNA replication blockage, cyclobutane pyrimidine dimer formation and DNA strand break induction coincided with SAPK/JNK phosphorylation at early (< or =30 min) but not late (> or =2 h) time points after exposure. Genotoxin-stimulated SAPK/JNK activation was attenuated in nonproliferating cells, indicating that S phase-dependent mechanisms are involved in signaling to SAPK/JNK. Correspondingly, UV-induced phosphorylation of SAPK/JNK was higher in S-phase cells as compared with G(1)-phase cells. Activation of SAPK/JNK by genotoxins was below detection limit in nonproliferating human peripheral blood lymphocytes, whereas peripheral blood lymphocytes stimulated to proliferation displayed clear SAPK/JNK activation. UV-induced phosphorylation of SAPK/JNK was attenuated in XPC-defective cells, ameliorated in BRCA2 mutated cells and not changed in cells lacking ATM, DNA-PK, CSB, XPA, p53, ERCC1 or PARP as compared with the corresponding wild types. Based on these data, we suggest that DNA replication blockage caused by genotoxin-induced DNA damage contributes to early activation of SAPK/JNK.
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PMID:DNA replication arrest in response to genotoxic stress provokes early activation of stress-activated protein kinases (SAPK/JNK). 1910 74


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