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)

This study describes the molecular mechanism by which treatment with 3-AB, a potent inhibitor of PARP, allows human osteosarcoma MG-63 cells to restrict growth and enter differentiation. Our findings show that in MG-63 cells, aberrant gene expression keeps Rb protein constitutively inactivated through hyperphosphorylation and this promotes uncontrolled proliferation of the cells. After 3-AB-treatment, the poly(ADP-ribosyl)ation of nuclear proteins markedly decreases and this results in an increase in both the hypophosphorylated active form of Rb and pRb/E2F complexes. These effects are accompanied by G1 arrest, downregulation of gene products required for proliferation (cyclin D1, beta-catenin, c-Jun, c-Myc and Id2) and upregulation of those implicated in the osteoblastic differentiation (p21/Waf1, osteopontin, osteocalcin, type I collagen, N-cadherins and alkaline phosphatase). Our study suggests that use of PARP inhibitors may induce a remodeling of chromatin with the reprogramming of gene expression and the activation of differentiation.
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PMID:Differentiative pathway activated by 3-aminobenzamide, an inhibitor of PARP, in human osteosarcoma MG-63 cells. 1567 Aug 17

Treatment with epigallocatechin-3-gallate (EGCG), a polyphenolic compound of green tea, results in activation of p53 and induction of apoptosis in prostate cancer LnCaP cells. However, no direct evidence has delineated the role of p53 and p53-dependent pathways in EGCG-mediated apoptosis. To understand the mechanism of negative growth regulation of prostate cancer cells by EGCG we undertook a genetic approach and generated an isogenic pair of prostate carcinoma cells PC3 (p53-/-) by stably introducing a cDNA encoding wild-type p53. Treatment of the resultant cells, PC3-p53, with EGCG led to, as reported earlier in LnCaP cells, an increase in p53 protein, which exacerbated both G1 arrest and apoptosis. This response was accompanied by an increase in the levels of p21 and Bax. The cells lacking p53 continued to cycle and did not undergo apoptosis upon treatment with similar concentrations of EGCG, thus establishing the action of EGCG in a p53-dependent manner. This observation was revalidated in another prostate cancer LNCaP cells harboring wild-type p53. Inactivation of p53 using small interfering RNA (siRNA) rendered these cells resistant to EGCG-mediated apoptosis. Because p53 activation led to increase in p21 and Bax, we investigated whether these two proteins are important in this process. Ablation of p21 protein by siRNA prevented G1 arrest and apoptosis in PC3-p53 cells. The p53-dependent increase in Bax expression altered the Bax/Bcl-2 ratio and paralleled the activation of caspase 9 and 3 and cleavage of PARP. Transfection of cells with Bax siRNA abolished these effects and inhibited apoptosis but did not affect the accumulation of the cells in G1. In summary, using isogenic cell lines and siRNA, we have clearly demonstrated that EGCG activates growth arrest and apoptosis primarily via p53-dependent pathway that involves the function of both p21 and Bax such that down-regulation of either molecule confers a growth advantage to the cells.
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PMID:Ablation of either p21 or Bax prevents p53-dependent apoptosis induced by green tea polyphenol epigallocatechin-3-gallate. 1576 47

Necrosis in glioblastoma is often associated with high levels of Fas (APO-1), HIF-1alpha and PARP expression. The presence of such molecules suggests a regulative element to cell death within this tissue, which may involve p53. We aimed to establish whether p53 and its downstream targets Bax, MDM2 and p21 play a role in perinecrotic cell death in glioblastoma. Following sequencing of the p53 gene in U87 and U373 glioma cell lines, p53 was found to be reactive in the p53 wild-type line U87 in response to hypoxia but not in the p53 mutant line, U373. Although no increase in perinecrotic p53 expression was detected in spheroid cultures derived from these lines, a 60 kDa MDM2 isoform lacking a C-terminal domain showed perinecrotic localization, irrespective of p53 status. Similar findings were observed surrounding regions of necrosis in 80% of glioblastoma biopsies examined. Increasing levels of wild-type p53 did not affect cell death in U87 spheroid cultures but killed all U373 cells 3 days post transfection. Dominant negative p53 did not affect cell death in U373 and U87 spheroid cultures. Although p53 accumulation appeared not to be important for the onset of cell death both in spheroid and biopsy cases, high levels of perinecrotic 60 kDa MDM2 may have implications for glioma cell death susceptibility in both p53 mutant and wild-type tumour cell populations.
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PMID:Discovery of a perinecrotic 60 kDa MDM2 isoform within glioma spheroids and glioblastoma biopsy material. 1577 12

Retinoid-related molecules are important potential agents for the treatment of cancer. In the present study, we test the effect of a novel retinoid-related ligand, AGN193198 (4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-prophenyl] benzoic acid), on pancreatic cancer cell proliferation and survival. AGN193198 treatment reduces BxPC-3 cell proliferation more efficiently than high-affinity retinoid acid receptor (RAR)- or retinoid X receptor (RXR)-selective retinoids. Moreover, AGN193198 does not activate transcription from RAR or RXR response elements and its effects on cell survival are not reversed by treatment with RAR- or RXR receptor-selective antagonists. These results suggest that the AGN193198-dependent inhibition of BxPC-3 cell function is not mediated via activation of the classical retinoid receptors. Cell cycle analysis of AGN193198-treated BxPC-3 cells indicates that AGN193198 causes accumulation of cells in G2/M. This change is associated with a marked reduction in regulators of S (cyclin A, cyclin-dependent kinase (cdk)2), G2/M (cyclin B1, cdk1, cdc25c) and G1 (cyclin D1, cyclin E, cdk2, cdk4) phase, and an increase in p21 and p27 level. Kinases assays reveal that cdk1, cdk2 and cdk4 activity are suppressed in AGN193198-treated cells. In addition, reduced cell proliferation is associated with enhanced procaspase (3, 8 and 9) and PARP cleavage. Z-VAD-FMK, a pancaspase inhibitor, inhibits AGN193198-dependent caspase activation and attenuates cell death. Z-VAD-FMK inhibits PARP cleavage, but does not alter the AGN193198-dependent reduction in cell cycle regulatory protein expression and activity, suggesting that caspase activation and suppression of cell cycle regulatory protein levels are independent processes. AGN193198 produces similar responses in other pancreatic cancer cell lines including AsPC-1 and MIA PaCa-2. These studies suggest that AGN193198 may be useful for the treatment of pancreatic cancer.
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PMID:A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis. 1585 29

Pretreatment of HepG2 and H1299 cells with chloramphenicol rendered the cells resistant to mitomycin-induced apoptosis. Both mitomycin-induced caspase 3 activity and PARP activation were also inhibited. The mitochondrial DNA-encoded Cox I protein, but not nuclear-encoded proteins, was down-regulated in chloramphenicol-treated cells. Cellular levels of the p21(waf1/cip1) protein and p21(waf1/cip1) mRNA were increased through a p53-independent pathway, possibly because of the stabilization of p21(waf1/cip1) mRNA in chloramphenicol-treated cells. The p21(waf1/cip1) was redistributed from the perinuclear region to the cytoplasm and co-localized with mitochondrial marker protein. Several morphological changes and activation of the senescence-associated biomarker, SA beta-galactosidase, were observed in these cells. Both p21(waf1/cip1) antisense and small interfering RNA could restore apoptotic-associated caspase 3 activity, PARP activation, and sensitivity to mitomycin-induced apoptosis. Similar effects were seen with other antibiotics that inhibit mitochondrial translation, including minocycline, doxycycline, and clindamycin. These findings suggested that mitochondrial stress causes resistance to apoptosis through a p21-dependent pathway.
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PMID:Chloramphenicol-induced mitochondrial stress increases p21 expression and prevents cell apoptosis through a p21-dependent pathway. 1590 68

DNA damage signaling is crucial for the maintenance of genome integrity. In higher eukaryotes a NAD+-dependent signal transduction mechanism has evolved to protect cells against the genome destabilizing effects of DNA strand breaks. The mechanism involves 2 nuclear enzymes that sense DNA strand breaks, poly(ADP-ribose) polymerase-1 and -2 (PARP-1 and PARP-2). When activated by DNA breaks, these PARPs use NAD+ to catalyze their automodification with negatively charged, long and branched ADP-ribose polymers. Through recruitment of specific proteins at the site of damage and regulation of their activities, these polymers may either directly participate in the repair process or coordinate repair through chromatin unfolding, cell cycle progression, and cell survival-cell death pathways. A number of proteins, including histones, DNA topoisomerases, DNA methyltransferase-1 as well as DNA damage repair and checkpoint proteins (p23, p21, DNA-PK, NF-kB, XRCC1, and others) can be targeted in this manner; the interaction involves a specific poly(ADP-ribose)-binding sequence motif of 20-26 amino acids in the target domains.
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PMID:The role of poly(ADP-ribose) in the DNA damage signaling network. 1595 61

The present study examines the effects of ionizing radiation in combination with rituximab (RTX), a chimeric human anti-CD20 monoclonal antibody, on proliferation, cell cycle distribution and apoptosis in B-lymphoma RL and Raji cells. Exposure to ionizing radiation (9 Gy) induced cell growth delay and apoptosis in RL cells, whereas Raji cells showed moderate radio-resistance. The simultaneous exposure of lymphoma cells to ionizing radiation and RTX (10 microg/mL) markedly enhanced apoptosis and cell growth delay in RL and Raji cells. Cooperative antiproliferative and apoptotic effects of RTX and radiation were achieved through the inhibition of c-myc and bcl-XL expression. Furthermore, RTX-modulated expression of cell cycle regulating proteins, such as p53, p21/WAF1, p27/KIP1, contributed to the development of radiation-induced cell killing and growth arrest. Each NHL cell line that underwent apoptosis induced by combination treatment revealed enhanced caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage as compared to only irradiated cells. These findings show that rituximab synergistically enhances radiation-induced apoptosis and cell growth delay through the expression of proteins involved in the programmed cell death and cell cycle regulation pathways.
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PMID:Pretreatment with rituximab enhances radiosensitivity of non-Hodgkin's lymphoma cells. 1598 43

Cervical cancer is considered a common yet preventable cause of death in women. In this report, we studied the role of the NF-kappaB gene family in HeLa human cervical cancer cells, using the Xrel3 c-Rel homologue of Xenopus laevis. The expression of Xrel3/c-Rel slowed cell growth 6-fold, consistent with an upregulated expression of the cell cycle inhibitor p21. The activated PARP apoptosis effector was significantly increased (P<0.01). Based on cell viability assays Xrel3 provided an anti-apoptotic effect in 1 microM cisplatin, and this was associated with significantly lower levels of the apoptotic proteins Bax and MDM-2 (P<0.05). Furthermore, there was a 3-fold drop in the level of the tumor suppressor protein p53. In 5 microM cisplatin, expression of HeLa Xrel3 enhanced apoptosis by significantly increasing the expression of the apoptotic proteins Bax and MDM-2 (P<0.05). However, the tumor suppressor protein p53 showed a significant decrease (P<0.05) relative to the control. Thus, c-Rel/NF-kappaB may potentially be of clinical significance, especially in tumors exhibiting resistance to high-level chemotherapy.
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PMID:Apoptosis effects of Xrel3 c-Rel/Nuclear Factor-kappa B homolog in human cervical cancer cells. 1605 60

Diazene N-phenyl-2-(2-pyridinyl)diazenecarboxamide (JK-279) is a newly synthesized compound, cytotoxic for several tumor cell lines and their drug-resistant sublines. In human cervical carcinoma cells (HeLa), this compound reduced intracellular glutathione content and increased sensitivity to cisplatin. The aim of the present study was to elucidate the molecular mechanisms involved in the cytotoxic effect of diazene JK-279 on HeLa cells. Cytotoxicity was determined by the MTT method. Flow cytometry analysis showed that diazene JK-279 induces G(2)/M phase arrest, mediated by the increase in p21 expression, and accompanied by an alteration in the expression of survivin. The highest concentration of JK-279 altered nuclear morphology in intact cells, showing "apoptosis-like" features. No cleavage of procaspase-3, procaspase-9 and PARP, or altered expression of apoptotic proteins Bcl-2 and Bax were detected. At the same time, PS externalization and internucleosomal DNA cleavage were observed. Partial necrosis was detected as well. Our results demonstrate that cytotoxicity of diazene JK-279 is mostly the consequence of caspase-independent cell death, which is in some aspects "apoptosis-like". Taking into account the multiplicity of mechanisms used by cancer cells to prevent apoptosis, the drugs (like diazene JK-279) that would activate alternative cell death pathways could provide a useful tool for new types of cancer therapy.
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PMID:Diazene JK-279 induces apoptosis-like cell death in human cervical carcinoma cells. 1606 52

2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) has been used to treat patients with advanced solid tumours. However, the molecular mechanisms are not well understood. In the present study, we report that SarCNU inhibited proliferation of human HK-1 and CNE-2 nasopharyngeal carcinoma (NPC) in vivo and in vitro. In vitro study showed that wild-type p53 HK-1 cells were 3-fold more sensitive to SarCNU than p53 mutant CNE-2 cells. G2/M arrest, reduction in p21(Cip1/Waf1) and inactivation of cellular cdc-2 activity were seen in both SarCNU-treated HK-1 and CNE-2 cells. Upregulation of p53, phosphorylated p53 at Ser15 and biochemical markers for apoptosis, such as cleaved caspase-3, cleaved caspase-7 and cleaved PARP, were observed in SarCNU-treated HK-1 but not CNE-2 cells. The levels of cyclin B1, Wee1 and phosphorylated cdc-2 but not total cdc-2 in HK-1 cells were significantly reduced by SarCNU treatment. In contrast to HK-1 cells, decrease in total cdc-2 but increase in phosphorylated cdc-2 at Tyr15, cyclin B1 and Wee1 was observed in CNE-2 cells treated with SarCNU. Introduction of mutant p53 into HK-1 cells resulted in growth enhancement in vivo and increased resistance to SarCNU-induced apoptosis in vitro. Furthermore, CNE-2 cells transfected with wild-type p53 became susceptible to SarCNU-induced apoptosis in vitro but not their growth rate in vivo. The data indicate that in NPC cells SarCNU-induced apoptosis was p53-dependent while SarCNU-induced G2/M arrest was mediated by altering the levels of cyclin B1-cdc-2 complex and phosphorylation of cdc-2 at Tyr15 resulting in inactivation of cellular cdc-2 activity. Our data suggest a potential use of SarCNU in the treatment of NPC.
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PMID:2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) exhibits p53-dependent and -independent antiproliferative activity in human nasopharyngeal carcinoma cells in vitro and in vivo. 1614 32


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