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 MDM2 oncogene product is a regulator of the p53 tumor suppressor. MDM2 is cleaved by Caspase 3 (CPP32) during apoptosis after aspartic acid-361, generating a 60 kd fragment. Here we report that human tumor cell lines often express high levels of a 60 kd MDM2 isoform (p60) in the absence of apoptosis. We demonstrate that p60 is a product of caspase cleavage of full length MDM2 after residue 361. The protease that cleaves MDM2 in non-apoptotic cells appears to be distinct from the apoptosis-specific Caspase 3, since Caspase 3 substrate poly(ADP-ribose) polymerase (PARP) is not cleaved in cells producing p60. The p60 form of MDM2 is a significant fraction of the p53-bound MDM2 protein in certain tumor cells, suggesting that it functions in the regulation of p53. p60 is also detected in breast tumors overexpressing MDM2. These observations suggest that MDM2 is regulated by caspase processing in non-apoptotic cells, and may account for the MDM2 proteins of similar mobility seen in tumors and other cell lines.
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PMID:A 60 kd MDM2 isoform is produced by caspase cleavage in non-apoptotic tumor cells. 984 Sep 26

Ceramide, a product of sphingomyelin metabolism, is a novel lipid second messenger that mediates diverse cellular functions. The present study demonstrates the activation of caspase-3/CPP-32beta, during apoptosis induced by cell permeable exogenous ceramides, in AK-5 tumor, a spontaneously regressing rat histiocytoma. The apoptotic events were suppressed by the caspase-3 specific tetrapeptide inhibitor DEVD-CHO but not by the caspase-1 inhibitor YVAD-CMK. In cells overexpressing Bcl-2, a significant decrease in cell death was observed after exogenous addition of ceramides. Furthermore the processing of caspase-3 to its active form upon apoptotic stimulus, and the subsequent cleavage of the substrate PARP, suggested a central role for caspase-3 in the ceramide mediated apoptosis in AK-5 tumor cells.
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PMID:Selective involvement of caspase-3 in ceramide induced apoptosis in AK-5 tumor cells. 984 82

Bcl-2, Bax and p53 gene products have been linked to programmed cell death pathways. p21WAF1 has been shown to mediate p53-induced cell cycle arrest and to inhibit cyclin-dependent kinase activity. We have analysed the expression of these genes and apoptosis induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in several human breast cancer cell line. We found up-regulation of p21WAF1 and Bax expressions, however, the expressions of p53 and Bcl-2 genes remained unchanged in TPA-treated cells. Furthermore, DNA ladder formation and PARP cleavage were observed after treatment for 24 h, indicating apoptotic cell death. Flow cytometry with 7-amino actinomycin D staining showed that the number of apoptotic cells increased with longer treatment of TPA. From these results, we conclude that TPA is not only a tumor promoter, but also induces apoptosis in breast cancer cells. TPA-induced apoptosis appears to be mediated through a p53-independent pathway, and the up-regulation of p21WAF1 and Bax may be the molecular mechanisms by which TPA induces apoptosis.
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PMID:Induction of apoptosis in breast cancer cells by TPA. 987 97

The interaction between poly(ADP-ribose) polymerase (PARP) and the product of the tumor suppressor gene p53 has been described previously. Here, we have investigated whether PARP deficiency may affect the expression and regulation of wild-type (wt) p53. For this purpose, we have used immortalized cells derived from wt and PARP knockout mice. We have found a clearly reduced basal level of PAb421 immunoreactive wt p53 protein in PARP-deficient cells. The monoclonal antibody PAb421 is known to recognize an epitope in the COOH terminus of normally spliced p53 protein. Under indirect immunofluorescence, this antibody stained nuclei in normal but not in PARP-deficient cells. Despite marked reduction of wt p53 protein in PARP knockout cells, no significant difference of the p53 transcription rate was observed between wt and PARP-deficient cells. Interestingly, in both cell types, an additional p53 transcript representing the alternatively spliced (AS) p53 form was detected. Because of its reactivity with different specific anti-p53 antibodies, we have determined that the p53 protein present in PARP knockout mouse cells possesses characteristic features of AS p53. Our results clearly show that PARP-deficient cells constitutively express the AS form of wt p53 and indicate that the regularly spliced p53 is extremely unstable in the absence of PARP. Moreover, PARP-/- cells fail to transactivate p53-responsive genes. Treatment of PARP-/- cells with genotoxic agents primarily leads to the activation of AS p53 protein.
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PMID:Reduced stability of regularly spliced but not alternatively spliced p53 protein in PARP-deficient mouse fibroblasts. 989 79

Apoptosis is a mechanism of cell death that occurs in normal development and on the regulation of vertebrate tissues and organ cellularity. Neurons undergo p53-dependent and p53-independent apoptosis, depending upon the stimulus that triggers DNA fragmentation. Many neurons in the developing nervous system suffer apoptosis, with the cyclin D1 being an essential mediator of neuronal cell death. Other characteristics of apoptosis are: condensation of the nucleus, fragmentation of chromatin at nucleosome linkage sites, membrane blebbing, and the formation of apoptotic bodies. Among the possible molecular mechanisms are: (a) activation of proteases, as ICE (Il-1 beta converting enzyme); (b) calpain is activated in several cells, with PARP (Poly-ADP-ribose polymerase) and a small U1 Ribonucleoprotein, being substrates for ICE and its homologs such as ICH and others proteins. The p53 gene encodes a transcription factor that contributes to several different cellular activities, including apoptosis, the cellular response to radiation, and the activation of proteins such as GADD, Bcl-2 (represses to apoptosis) and Bax. P53 exerts a role as inductor of apoptosis by transactivating expression of the Bax gene. The p53 gene tumor suppressor limits cellular proliferation by including either the arrest of cell cycle in G1, or apoptosis, depending on the cellular context. The p21 is an inhibitor of cyclin-dependent kinase, which is transactivated by p53. During apoptosis, there is an activation of both, c-myc, and the transcription factor NF-kB, which is a important regulator of apoptosis. As an example of signalization of apoptosis we have selected to illustrate the problem related to the system Fas/APO in thymocytes.
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PMID:[Molecular bases of the programmed cell death process: implications of tumor suppressor protein p53 and other proteins in the control of cell cycle. Mechanisms of apoptotic action. Review]. 992 5

Photodynamic therapy (PDT) is a cancer treatment modality utilizing a photosensitizer, light and oxygen. Photodynamic therapy with Photofrin has been approved by the U.S. Food and Drug Administration for treatment of advanced esophageal and early lung cancer. Because of certain drawbacks associated with the use of Photofrin, there is a need to identify new photosensitizers for human use. The photosensitizer Pc 4 (HOSiPc-OSi[CH3]2[CH2]3N[CH3]2) has yielded promising PDT effects in many in vitro and in vivo systems. The aim of this study was to assess the usefulness of Pc 4 as a PDT photosensitizer for a human tumor grown as a xenograft in athymic nude mice. The ovarian epithelial carcinoma (OVCAR-3) was heterotransplanted subcutaneously in athymic nude mice. Sixty mice bearing OVCAR-3 tumors (approximately 80-130 mm3) were divided into six groups of 10 animals each, three for controls and three for treatment. The Pc 4 was given by tail vein injection, and 48 h later a 1 cm area encompassing the tumor was irradiated with light from a diode laser coupled to a fiberoptic terminating in a microlens (lambda = 672 nm, 150 J/cm2, 150 mW/cm2). Tumors of control animals receiving no treatment, light alone or Pc 4 alone continued to grow. Of animals receiving 0.4 mg/kg Pc 4 and light, one (10%) had a complete response and was cured (no regrowth up to 90 days post-PDT), while all others (90%) had a partial response and were delayed in regrowth. Of animals receiving 0.6 mg/kg Pc 4 and light, eight (80%) had a complete response, and two of these were cured. Of animals receiving 1.0 mg/kg Pc 4 and light, six (60%) had a complete response, and two of these were cured. In additional experiments, tumors from animals treated with Pc 4 (1 mg/kg) and light were removed 15, 30, 60 and 180 min post-PDT, and from these tumors DNA and protein were extracted. Agarose gel electrophoresis revealed the presence of apoptotic DNA fragmentation as early as 15 min post-PDT. Western blotting showed the cleavage of the 116 kDa native poly(ADP-ribose) polymerase (PARP) into fragments of approximately 90 kDa, another indication of apoptosis, and the presence of p21/WAF1/CIP1 (p21) in all PDT-treated tumors. These changes did not occur in control tumors. Pc 4 appears to be an effective photosensitizer for PDT of human tumors grown as xenografts in nude mice. Early apoptosis, as revealed by PARP cleavage, DNA fragmentation and p21 overexpression, may be responsible for the excellent Pc 4-PDT response. Clinical trials of Pc 4-PDT are warranted.
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PMID:Phthalocyanine 4 (Pc 4) photodynamic therapy of human OVCAR-3 tumor xenografts. 1004 16

Killing of target cells by cytotoxic T cells is mediated by induction of apoptosis requiring functional death pathways. Kill is mediated either by the CD95 or the perforin/granzyme pathway. We found that SH-EP neuroblastoma cells are preferentially killed via CD95, while in the T leukemia cell line CEM CD95 and perforin/granzyme are involved. In both types of cell lines, cells resistant to CD95- and drug-induced apoptosis are crossresistant to cytotoxic T cell kill. Resistant cells show decreased apoptosis and deficient activation of caspases indicated by decreased cleavage of the prototype caspase substrate PARP. Preincubation with the caspase inhibitor zVAD-fmk strongly decreased LAK cell kill in sensitive cells. Although parental CEM cells could be sensitized for LAK kill by preincubation with doxorubicin, resistance could not be reverted in doxorubicin or CD95 resistant CEM cells. These data demonstrate the crossresistance in induction of apoptosis by different cytotoxic regimens in tumor cells and may have implications for the immunotherapy of tumors in which apoptosis resistance was induced by previous chemotherapy.
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PMID:Decreased sensitivity of drug-resistant cells towards T cell cytotoxicity. 1008 32

Though p53-induced apoptosis plays an important role in tumor suppression, the mechanism(s) by which p53 induces apoptosis is still unclear. To elucidate the p53-induced apoptotic pathway, we examined the role of p53 transactivation activity and caspase in J138V5C cells carrying a human temperature-sensitive (ts) p53 mutant (138Ala-->Val). The results showed that p53-induced apoptosis was not blocked by cycloheximide, which effectively prevented the expression of p53 target genes, indicating that transactivation was not essential for p53-induced apoptosis in this system. Western blot analysis showed that PARP, CPP32 and ICH-1 precursors were cleaved during apoptosis. The CPP32-preferential tetrapeptide inhibitor Ac-DEVD-CHO blocked the cleavage of ICH-1 and PARP precursors, suggesting that CPP32 or some other DEVD-sensitive caspase(s) is the upstream activator of ICH-1. We also examined the role of the Fas pathway by using Fas and Fas ligand-neutralizing antibodies. Both antibodies failed to block p53-induced apoptosis, suggesting that the Fas pathway was not essential for p53-induced apoptosis in this system. Taken together, our results indicate that p53-induced, transactivation-independent apoptosis in Jurkat cells involves sequential activation of CPP32 or some other DEVD-sensitive caspase(s) and ICH-1, via a Fas-independent pathway.
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PMID:Activation of caspases in p53-induced transactivation-independent apoptosis. 1018 88

Tumor necrosis factor (TNF) signal transduction is a complex process involving activation of receptor-linked and stress-sensitive signaling cascades that stimulate apoptosis in some tumor cell lines. Initial studies suggested that these signaling events cooperatively induced TNF responses, but recent studies suggest that some of these signals antagonize the apoptotic response or play no discernible role in cell death. As TNF induces cellular stress and activates several stress-sensitive cascades that may play a role in apoptosis, TNF-induced stress signaling was examined in MCF-7 cells and compared with a variant MCF-7 cell line resistant to TNF-mediated apoptosis (MCF-7/3E9). TNF rapidly stimulated both NF-kappaB and JNK activation in MCF-7 and MCF-7/3E9 cells, but JNK activation was significantly reduced (threefold) in apoptotically resistant cells. TNF also stimulated p53, p21WAF1, and Bax accumulation with subsequent PARP cleavage and nucleosomal DNA laddering in MCF-7 cells but did not stimulate these processes in MCF-7/3E9 cells. Importantly, 3E9 cells retained wild-type p53 function, induced p21WAF1 in response to DNA damage, and expressed almost equal sensitivity to other stress stimuli (gamma-radiation, chemotherapeutic agents) as parental MCF-7 cells. These results suggest that selective defects in TNF-activated stress cascades are associated with reduced sensitivity to TNF but not other cell death stimuli. Loss of potent TNF-mediated activation of JNK and p53 cascades may permit tumor cells to evade receptor-mediated apoptosis but have only limited influence on cellular sensitivity to other agents that effectively engage these stress pathways.
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PMID:JNK and p53 stress signaling cascades are altered in MCF-7 cells resistant to tumor necrosis factor-mediated apoptosis. 1021 65

Adhesion of tumor cells to host cell layers and subsequent migration are pivotal steps in cancer invasion and metastasis. The small GTP-binding protein RhoA controls cell adhesion and motility through organization of the actin cytoskeleton and regulation of actomyosin contractility. Cultured rat MM1 hepatoma cells migrate through a mesothelial cell monolayer in vitro in a serum-dependent, RhoA-mediated manner (K. Yoshioka et al., J. Biol. Chem., 273: 5146-5154, 1998). Furthermore, the ROCK family of RhoA-associated serine-threonine protein kinases is involved in this migration, and an inhibitor for these kinases effectively inhibits the invasion of MM1 cells in vitro and in vivo (K. Itoh et al., Nat. Med., 5: 221-225, 1999). Although there have been no reports of genetic alterations directly affecting RhoA in human cancer, the expression level of RhoA in tumors has been several times higher than that of surrounding normal tissue; RhoA was especially highly expressed in the metastatic region. To determine whether RhoA is activated by its overexpression, we made stable transfectants of MM1 cells expressing various levels of wild-type human RhoA. These transfectants showed promoted invasive ability in vitro in the absence and presence of 1-oleoyl-lysophosphatidic acid, marked adherence to the plastic culture dish with scattered shape, elevated phosphorylation of Mr 20,000 myosin light chain, and translocation of RhoA protein from the cytosol to the membrane. All of these phenotypes were similar to those of active RhoA transfectants, correlated with the expression level of RhoA and reversed by the treatment of the cells with Clostridium botulinum exoenzyme C3 ADP-ribosyltransferase. In addition, overexpression of wild-type RhoA in MM1 cells also conferred invasive ability in vivo after the cells were transplanted into the syngeneic rats. Thus, high expression of RhoA in the cell facilitates the translocation of this protein to the membrane, where it is activated, resulting in the stimulation of the RhoA-ROCK-actomyosin system, leading to invasion.
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PMID:Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells. 1021 13


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