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)

MBP-1, a cellular factor, appears to be involved in multiple functions, including transcriptional modulation, apoptosis and cell growth regulation. In this study, we have investigated the signaling pathway involved in MBP-1 mediated apoptotic cell death. Human carcinoma cells infected with a replication deficient adenovirus expressing MBP-1 (AdMBP-1) induced apoptosis, when compared with cells infected by replication-defective adenovirus (dl312) as a negative control. Transduction of MBP-1 in carcinoma cells releases cytochrome c from mitochondria into the cytosol leading to activation of procaspase-9, procaspase-3 and PARP cleavage. We previously observed that MBP-1 mediated apoptosis can be protected by Bcl-2, although MBP-1 does not share a homology with the BH domain of the Bcl-2 family member of proteins. To further understand the mechanism of MBP-1 mediated apoptosis, we examined whether MBP-1 modulates the Bcl-2 gene family. Our results demonstrated that human breast carcinoma cells infected with AdMBP-1 selectively reduced Bcl-xL mRNA and protein expression when compared with dl312 infected negative control cells. An in vitro transient reporter assay also suggested repression of the Bcl-x promoter activity by MBP-1. Additional studies indicated that MBP-1 modulates Ets family protein function, thereby downregulating Bcl-xL expression. Taken together, our results suggest that MBP-1 selectively represses Bcl-xL expression in MCF-7 cells and induces mitochondrial involvement in the apoptotic process.
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PMID:MBP-1 mediated apoptosis involves cytochrome c release from mitochondria. 1197 36

We asked whether the constitutive level of DNA strand breaks (SBs) in four human squamous carcinoma cell lines is associated with their radiosensitivity, measured by the clonogenic assay. Because impairment in DNA replication and the action of endogenous deoxyribonucleases are two major sources of DNA strand breaks under normal cell metabolism, we also analyzed DNA polymerase and DNA ligase activities as well as the functional status of Poly(ADP-ribose) polymerase (PARP) and nucleolytic degradation of genomic DNA. We showed that the two relatively radioresistant cell lines, UM-SCC-1 and UT-SCC-5, had a statistically significant lower constitutive level of DNA SBs, as measured by DNA precipitation technique, compared with the two relatively radiosensitive cell lines, UM-SCC-14A and UT-SCC-9. We found that cell lines with a higher level of broken DNA tended to have a higher constitutive level of DNA polymerase alpha activity, measured by incorporation of [(3)H]dTTP in DNase I-activated DNA. UM-SCC-1, UT-SCC-5, and UM-SCC-14A did not show any difference in DNA ligase activity when a nicked oligonucleotide was used as substrate. The most radiosensitive cell line, UT-SCC-9, had a significantly lower ligation efficiency compared to the other three cell lines. The functional status of the PARP was the same in the four cell lines. Although none of the four cell lines showed a characteristic apoptotic or necrotic degradation of genomic DNA, when tested with the "plasmid rejoining assay," a significant degradation of the plasmid DNA in UT-SCC-9 was detected. We conclude that the high fraction of DNA SBs for UT-SCC-9, the most radiosensitive cell line, is most likely a consequence of low ligation efficiency combined with a relatively high DNA polymerase alpha activity and the nuclease degradation of DNA.
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PMID:Radiosensitivity of human squamous carcinoma cell lines is associated with amount of spontaneous DNA strand breaks. 1199 85

Apigenin, a common dietary flavonoid abundantly present in fruits and vegetables, may have the potential for prevention and therapy for prostate cancer. Here, we report for the first time that apigenin inhibits the growth of androgen-responsive human prostate carcinoma LNCaP cells and provide molecular understanding of this effect. The cell growth inhibition achieved by apigenin treatment resulted in a significant decrease in AR protein expression along with a decrease in intracellular and secreted forms of PSA. These effects were also observed in DHT-stimulated cells. Further, apigenin treatment of LNCaP cells resulted in G1 arrest in cell cycle progression which was associated with a marked decrease in the protein expression of cyclin D1, D2 and E and their activating partner cdk2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. The induction of WAF1/p21 appears to be transcriptionally upregulated and is p53 dependent. In addition, apigenin inhibited the hyperphosphorylation of the pRb protein in these cells. Apigenin treatment also resulted in induction of apoptosis as determined by DNA fragmentation, PARP cleavage, fluorescence microscopy and flow cytometry. These effects were found to correlate with a shift in Bax/Bcl-2 ratio more towards apoptosis. Apigenin treatment also resulted in down-modulation of the constitutive expression of NF-kappaB/p65. Taken together, these findings suggest that apigenin has strong potential for development as an agent for prevention against prostate cancer.
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PMID:Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. 1203 41

C8-ceramide, a synthetic cell-permeable analog of endogenous ceramides, interfered with cell proliferation, and was cytotoxic to papilloma virus-containing human cervix carcinoma cells, CALO, INBL, and HeLa, that match two clinical stages of tumor progression. C8-ceramide (3 microM) markedly reduced the tumor cell number after 48 h of treatment, an effect that endured even after the removal of C8-ceramide. The carcinoma cells showed morphologic changes, characteristic of necrosis and released lactate dehydrogenase (LDH). A biologically inactive analog C8-dihydro-ceramide had no effect on cell viability in any of the cell lines tested. Seventy-two hours after C8-ceramide treatment none of the biochemical and morphological markers characteristic of apoptosis: (a) nuclear chromatin condensation, (b) DNA fragmentation, (c) proteolysis of the caspase-3 substrate poly-(ADP-ribose)-polymerase (PARP), and (d) appearance of phosphatidylserine on the external cell membrane, were observed. C8-ceramide had no effect on human cervix fibroblasts and induced a mild reduction (30%) in the proliferation of normal human cervix epithelia and HeLa cells (IV-B metastatic stage). The cytotoxicity of C8-ceramide was restricted to CALO (early II-B) and INBL (IV-A non-metastatic) carcinoma cells. The possible application of ceramide in the treatment of early stages of cervical cancer is discussed.
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PMID:Ceramide promotes the death of human cervical tumor cells in the absence of biochemical and morphological markers of apoptosis. 1205 63

beta-Lapachone, a novel anticancer drug, induces various human carcinoma cells to undergo apoptotic cell death. However, we report here that, in human osteocarcinoma (U2-OS) cells, beta-lapachone induces necrosis rather than apoptosis. beta-Lapachone-induced necrotic cell death in U2-OS cells was characterized by propidium iodide uptake, cytochrome c release, a decreased mitochondrial membrane potential, and ATP depletion. The mitochondrial potential transition (MPT), including the reduction of the mitochondrial transmembrane potential and the release of mitochondrial cytochrome c, occurred in beta-lapachone-treated cells; cotreatment of these cells with cyclosporin A, an inhibitor of MPT pore, failed to prevent necrotic cell death. This indicates that the MPT transition does not play a crucial role in this process. Furthermore, beta-lapachone-induced necrosis was independent of oxidative stress and caspase activation. However, excessive poly(ADP-ribose) polymerase (PARP) activation and subsequent depletion of intracellular NAD(+) and ATP were seen in beta-lapachone-treated U2-OS cells. Cotreatment with a PARP inhibitor, 3-aminobenzamide, decreased beta-lapachone-induced PARP activation and provided significant protection from necrosis by preventing depletion of intracellular NAD(+) and ATP. Taken together, our results suggest that PARP plays an important role in the signaling pathway for beta-lapachone-induced necrosis in U2-OS cells.
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PMID:Inhibition of poly(ADP-ribose) polymerase activation attenuates beta-lapachone-induced necrotic cell death in human osteosarcoma cells. 1214 Jan 75

Malignant transformation of cells is associated with changes in gene expression. Gross alterations in chromatin organization may be involved in such gene dysregulation, as well as the involvement of specific transcription factors. Specialized genomic DNA segments that exhibit high affinity to the nuclear matrix in vitro have been designated as matrix/scaffold attachment regions (MARs/SARs). MARs are postulated to anchor chromatin onto the nuclear matrix, thereby organizing genomic DNA into topologically distinct loop domains that are important in replication and transcription. In support of this notion, MARs often colocalize or exist in close proximity to regulatory sequences including enhancers. Base unpairing regions (BURs) are typically 100-150 bp regions within MARs, possess an intrinsic propensity to unwind under negative superhelical strain, and are considered to be hallmark of MARs. To investigate a potential mechanism that could lead to significant alterations in gene expression in cancer cells, this review focuses on a group of chromatin-associated proteins that specifically recognize double stranded BURs. Several important proteins have been identified from cancer cells as BUR-binding proteins, including poly (ADP-ribose) polymerase (PARP-1), Ku autoantigen, SAF-A, HMG-I(Y), nucleolin and p53. Many of these proteins are dramatically upregulated in malignancy of the breast. Increase in the amount of these BUR-binding proteins, some of which are known to interact with each other, may not only provide an architectural core but also recruit functional multi-molecular complexes at the base of chromatin loops to affect multiple distant genes. Experimental strategies by which these proteins can be exploited as carcinoma-specific diagnostic markers and as targets for antineoplastic therapy are discussed.
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PMID:Chromatin (dis)organization and cancer: BUR-binding proteins as biomarkers for cancer. 1218 16

Irinotecan (CPT-11), a recently introduced component of a standard chemotherapy for colorectal cancer, induces in colon cancer cell lines in vitro cell cycle arrest and apoptosis. Since sporadic colon carcinomas exhibit in 50-60% mutations in the p53 gene and in 10-15% an MSI phenotype due in the great majority of the cases to hMLH1 inactivation, we investigated how these lesions influence the cellular effects of CPT-11 by using colorectal carcinoma cell line HCT116 (which has the genotype p53(+/+),hMLH1(-)) and 2 derivative cell lines with the genotypes p53(+/+),hMLH1(+) and p53(-/-),hMLH1(-). CPT-11 treatment induced G2/M arrest in all 3 cell lines within 48 hr. In the p53(+/+),hMLH1(+) cell line, G2/M arrest was maintained for at least 12 days. There was little concomitant apoptosis, but this was enhanced when the hMLH1 protein was absent. This enhanced apoptosis was accompanied by a shorter duration of the G2/M arrest than in the hMLH1(+) cell line. Partial abrogation of G2/M arrest by caffeine enhanced apoptosis in both hMLH1(+) and hMLH1(-) cells. By contrast, in the p53(-/-) cell line, the G2/M arrest was terminated within 4 days. Termination of the G2/M arrest was accompanied by a high level of apoptosis detectable through poly(ADP-ribose)polymerase (PARP) cleavage, DNA fragmentation and by the appearance of cells with a DNA content <2N. The triggering of G2/M arrest was accompanied in the 3 cell lines by a transient phosphorylation of cdc-2, while the maintenance of the arrest in the p53(+/+) cell lines was accompanied by the overexpression of p53 and p21 proteins and, consequently, by the inhibition of cdc-2 kinase activity. These data indicate that: (i) CPT-11 induces long-term arrest in p53(+/+) cells and a short-term arrest followed by apoptosis in p53(-/-) cells; (ii) triggering of the arrest is p53 independent and is associated with a brief increase of phosphorylation of cdc-2, while the p53-dependent maintenance of G2/M arrest is associated with the inhibition of cdc-2 kinase activity by p21; and (iii) lack of hMLH1 protein enhances CPT-11-induced apoptosis. These results may be useful for designing rational therapies dependent on the p53 and mismatch-repair status in the tumor.
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PMID:Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. 1220 84

Sphingolipids have been implicated in apoptosis after various stress inducers. To assess the involvement of the de novo sphingolipid pathway in apoptosis, photodynamic therapy (PDT) with the photosensitizer Pc 4 was used as a novel stress inducer. Here we provide biochemical and genetic evidence of the role of the de novo sphingolipids in apoptosis post-Pc 4-PDT. In Jurkat cells PDT-induced intracellular sphinganine accumulation, DEVDase activation, PARP cleavage, and apoptosis were suppressed by the de novo sphingolipid synthesis inhibitor ISP-1 (Myriocin). Coincubation with sphinganine, sphingosine, or C16-ceramide specifically reversed the antiapoptotic actions of ISP-1 or the singlet oxygen scavenger L-histidine. PDT-induced cytochrome c release from mitochondria into the cytosol was inhibited by L-histidine, but not by ISP-1. Cotreatment with sphinganine did not reverse the inhibitory effect of L-histidine. In addition, PDT-induced sphinganine accumulation and apoptosis were ISP-1-sensitive in A431 human epidermoid and HT29 human carcinoma cells. Furthermore, in LY-B cells, CHO-derived mutants deficient in the de novo sphingolipid synthesis enzyme serine palmitoyltransferase (SPT) activity, DEVDase activation and apoptosis were delayed and suppressed post-PDT. Hence, the data are consistent with the partial involvement of the de novo sphingolipid pathway in apoptosis via DEVDase activation downstream of mitochondrial cytochrome c release post-Pc 4-PDT.
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PMID:A role for the de novo sphingolipids in apoptosis of photosensitized cells. 1221 23

We have previously proposed the horseradish peroxidase (HRP) and the non-toxic plant hormone indole-3-acetic acid (IAA) as a novel system for gene-directed enzyme/prodrug therapy (GDEPT). The cytotoxic potential of HRP/IAA GDEPT and the induction of a bystander effect were demonstrated in vitro under normoxic as well as hypoxic tumour conditions. To date, the chemical agents and the cellular targets involved in HRP/IAA-mediated toxicity have not been identified. In the present work, some of the molecular and morphological features of the cells treated with HRP/IAA gene therapy were analysed. Human T24 bladder carcinoma cells transiently transfected with the HRP cDNA and exposed to the prodrug IAA showed chromatin condensation, formation of apoptotic bodies, DNA fragmentation, and Annexin V binding. Similar effects were observed when the cells were incubated with the apoptotic agent cisplatin. Caspases appeared to be involved as effectors in HRP/IAA-mediated apoptosis, since treatment with a general caspase inhibitor decreased the fraction of cells with micronuclei (MN) by 30%, with fragmented DNA by 50%, and with condensed chromatin by 60%. However, very little degradation of one of the downstream targets of caspase-3, PARP, could be detected, and apoptosis alone did not appear to account for the killing levels measured with a clonogenic assay. The effect of HRP/IAA treatment on cell cycle progression was also investigated, and a rapid cytostatic effect, equally affecting all phases of the division cycle, was observed.
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PMID:Mechanisms of cytotoxicity induced by horseradish peroxidase/indole-3-acetic acid gene therapy. 1224 74

Poly(ADP-ribose) polymerase (PARP) has strong affinity for DNA strand breaks and cycles on and off the DNA ends to allow DNA repair. A DNA-binding domain of PARP (PARP-DBD) acts as a dominant-negative mutant by binding to DNA strand breaks irreversibly and sensitizing mammalian cells to DNA-damaging agents. Therefore, expression of PARP-DBD in prostate carcinoma cells offers a strategy to achieve sensitization to genotoxic treatments. Toward this end, we developed recombinant plasmids expressing the PARP-DBD under the control of the 5'-flanking sequences of the human prostate-specific antigen (PSA) gene. Tissue specificity of PARP-DBD expression in human tumor cells was confirmed using the PSA-producing (LNCaP) and PSA-negative (PC-3) prostate cancer cells, as well as cells of nonprostate origin, Ewing's sarcoma (A4573 cells). LNCaP cells stably transfected with the PSA-regulated cDNA for PARP-DBD exhibit an androgen-dependent induction of PARP-DBD expression as determined by Western blotting, reverse transcription-PCR, and in situ immunofluorescence. Furthermore, we found that PARP-DBD sensitized LNCaP cells to DNA-damaging agents, such as ionizing radiation and etoposide. Androgen (R1881) -dependent stimulation of PARP-DBD expression resulted in a 2-fold growth inhibition in LNCaP cells as compared with controls, and an augmented apoptotic cell death in response to ionizing radiation or etoposide. Taken together, the plasmid vector developed in this study permits the expression of the human PARP-DBD in an androgen-inducible and PSA-dependent fashion, and sensitizes prostatic adenocarcinoma cells to DNA-damaging treatments. These results provide proof-of-principle for a novel therapeutic strategy for the treatment of prostate cancer.
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PMID:Gene therapy for prostate cancer by targeting poly(ADP-ribose) polymerase. 1246 Sep 2


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