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)

Recently a new member of the human tumor necrosis factor (TNF) family named as VEGI was reported. However, very little is known about the biological activities displayed by this cytokine. In this report, we show that in myeloid cells VEGI activated the transcription factor kappa B (NF-kappa B) as determined by the electrophoretic mobility shift assay, induced degradation of I kappa B alpha, and nuclear translocation of p65 subunit of NF-kappa B. VEGI also activated NF-kappa B-dependent reporter gene expression. In addition, VEGI activated c-Jun N-terminal kinase. When examined for growth modulatory effects, VEGI inhibited the proliferation of breast carcinoma (MCF-7), epithelial (HeLa), and myeloid (U-937 and ML-1a) tumor cells; and activated caspase-3 leading to PARP cleavage. VEGI-induced cytotoxicity was potentiated by inhibitors of protein synthesis. VEGI also induced proliferation of normal human foreskin fibroblast cells. The activity of VEGI could neither be neutralized by antibodies against TNF, nor could it compete with TNF binding, indicating that the activity of VEGI is not due to TNF and it binds to a distinct receptor. These results suggest that VEGI, a new member of the TNF family, has a signaling pathway similar to TNF and is most likely a multifunctional cytokine.
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PMID:VEGI, a new member of the TNF family activates nuclear factor-kappa B and c-Jun N-terminal kinase and modulates cell growth. 1059 52

The DNA-binding activity of NF-kappaB in nuclear extracts of poly(ADP-ribose) polymerase (PARP)-defective mutant L1210 cell clones was markedly increased and was inversely correlated with the PARP content in these cells. The DNA-binding activity of NF-kappaB in a clone with the lowest PARP content (Cl-3527, contained 6% of PARP of wild type cells) was about 35-fold of that of the wild-type cells, whereas the change in the DNA-binding activity of AP-1 and SP-1 in the mutant was relatively small or not so significant. Transfection of a PARP-expressing plasmid to the mutant cells decreased the abnormally high levels of NF-kappaB complexes, especially p50/p65(Rel A) complex, to near the normal level. Moreover, poly(ADP-ribosyl)ation of nuclear extracts in vitro suppressed the ability of NF-kappaB to form a complex with its specific DNA probe by approx. 80%. Further analysis with purified recombinant NF-kappaB proteins revealed that both rp50 and rMBP-p65 (Rel A) proteins, but not rGST-IkappaB, could be poly(ADP-ribosyl)ated in vitro and that the modification resulted in a marked decrease in the DNA-binding activity of rMBP-p65, whereas a slight activation was observed in rp50. Poly(ADP-ribosyl)ated p65/NF-kappaB was detected in the cytosol of wild type L1210 cells by immunoblotting with anti-poly(ADP-ribose) and anti-p65 antibodies. Taken together, these results strongly suggest that PARP is involved in the regulation of NF-kappaB through the protein modification.
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PMID:Evidence for regulation of NF-kappaB by poly(ADP-ribose) polymerase. 1069 90

African swine fever (ASF) is an asymptomatic infection of warthogs and bushpigs, which has become an emergent disease of domestic pigs, characterized by hemorrhage, lymphopenia, and disseminated intravascular coagulation. It is caused by a large icosohedral double-stranded DNA virus, African swine fever virus (ASFV), with infection of macrophages well characterized in vitro and in vivo. This study shows that virulent isolates of ASFV also infect primary cultures of porcine aortic endothelial cells and bushpig endothelial cells (BPECs) in vitro. Kinetics of early and late gene expression, viral factory formation, replication, and secretion were similar in endothelial cells and macrophages. However, ASFV-infected endothelial cells died by apoptosis, detected morphologically by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and nuclear condensation and biochemically by poly(ADP-ribose) polymerase (PARP) cleavage at 4 h postinfection (hpi). Immediate-early proinflammatory responses were inhibited, characterized by a lack of E-selectin surface expression and interleukin 6 (IL-6) and IL-8 mRNA synthesis. Moreover, ASFV actively downregulated interferon-induced major histocompatibility complex class I surface expression, a strategy by which viruses evade the immune system. Significantly, Western blot analysis showed that the 65-kDa subunit of the transcription factor NF-kappaB, a central regulator of the early response to viral infection, decreased by 8 hpi and disappeared by 18 hpi. Both disappearance of NF-kappaB p65 and cleavage of PARP were reversed by the caspase inhibitor z-VAD-fmk. Interestingly, surface expression and mRNA transcription of tissue factor, an important initiator of the coagulation cascade, increased 4 h after ASFV infection. These data suggest a central role for vascular endothelial cells in the hemorrhagic pathogenesis of the disease. Since BPECs infected with ASFV also undergo apoptosis, resistance of the natural host must involve complex pathological factors other than viral tropism.
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PMID:African swine fever virus infection of porcine aortic endothelial cells leads to inhibition of inflammatory responses, activation of the thrombotic state, and apoptosis. 1158 5

Tyrosine kinase oncogenes such as p210BCR-ABL activate multiple signal pathways. As a result, it is difficult to infer the functional relevance of a pathway acting alone or in cooperation with another. One or 2 second-tier kinases represented in the p21ras and phosphatidylinositol-3-kinase (PI-3-kinase) pathways (activated RafCAAX and gag-akt, respectively) were expressed in parental H7 interleukin-3 (IL-3)-dependent myeloid cells. IL-3-dependent cells served, independently, as recipients of p210BCR-ABL, which activated p21ras and PI-3-kinase pathways, including raf/erk and akt, respectively, en route to transformation. By contrast, neither RafCAAX nor gag-akt when expressed in parental cells in isolation produced factor-independent cells. On the other hand, H7 cells expressing both RafCAAX and gag-akt (H7gag-akt/RafCAAX) were transformed. Such transformation in H7gag-akt/RafCAAX was accomplished in the absence of active versions of Shc or cbl, and there was no evidence of Stat activity and only modest amounts of bcl-xL, a Stat5 transcriptional target protein, all of which characterized the cells transformed by BCR-ABL. However, H7gag-akt/RafCAAX cells and H7BCR-ABL cells cultured in the absence of IL-3 shared strikingly increased p65 nuclear factor kappaB (NFkappaB) activity. Treatment of cells with a specific NFkappaB inhibitor, parthenolide, led to loss of NFkappaB activity and down-regulation of antiapoptotic c-IAP2. In cells with only gag-akt/RafCAAX, this was sufficient to allow polyADP ribosyltransferase (PARP)-degradative apoptosis, but in cells with p210BCR-ABL, apoptosis was blocked, possibly by a Stat5/bcl-xL-dependent mechanism. Therefore, one hematopoietic antiapoptotic program, among others, available to certain tyrosine kinase oncogenes involves a cooperative response between raf/erk and akt, unambiguous components of p21ras and PI-3-kinase pathways, to induce p65 NFkappaB and c-IAP2.
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PMID:Transformation of interleukin-3-dependent cells without participation of Stat5/bcl-xL: cooperation of akt with raf/erk leads to p65 nuclear factor kappaB-mediated antiapoptosis involving c-IAP2. 1158 49

Poly(ADP-ribose) polymerase 1 (PARP-1)-deficient mice are protected against septic shock, diabetes type I, stroke, and inflammation. We report that primary cells from PARP-1(-/-) animals are impaired in kappa B-dependent transcriptional activation induced by different stimuli involved in inflammatory and genotoxic stress signaling. PARP-1 was also required for p65-mediated transcriptional activation. PARP-1 enzymatic inhibitors did not inhibit the transcriptional activation of a kappa B-dependent reporter gene in wild type cells. Remarkably, neither the enzymatic activity nor the DNA binding activity of PARP-1 was required for kappa B-dependent transcriptional activation in PARP-1(-/-) cells complemented with different PARP-1 mutants. However, PARP-1 interacted in vitro directly with both subunits of NF-kappa B (p50 and p65), and mapping of the interaction domains revealed that both subunits bind to different PARP-1 domains. Furthermore, a PARP-1 mutant lacking the enzymatic and DNA binding activity interacted comparably to the wild type PARP-1 with p65 or p50. Finally, we showed that PARP-1 is activating the natural inducible nitric-oxide synthase and P-selectin promoter in a kappa B-dependent manner upon stimulation of the cells with inflammatory stimuli or cotransfection of p65. Our results provide evidence that neither the DNA binding nor the enzymatic activity of PARP-1 but its direct protein-protein interaction with both subunits of NF-kappa B is required for its coactivator function, thus expanding the role of PARP-1 as an essential and novel classical transcriptional coactivator for kappa B-dependent gene expression in vivo.
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PMID:The enzymatic and DNA binding activity of PARP-1 are not required for NF-kappa B coactivator function. 1159 Jan 48

Tumor necrosis factor (TNF) is one of the most potent activators of nuclear transcription factor NF-kappaB, c-Jun N-terminal protein kinase (JNK), and apoptosis in a wide variety of cells. The biological effects of TNF are mediated through sequential interactions of various cytoplasmic proteins with intracellular domains of TNF receptors. Whether signal transducer and activator of transcription-1 (STAT1), which mediates interferon (IFN) signaling, also plays any role in the TNF-mediated activation of NF-kappaB, JNK, and apoptosis has not been established. Here, we report our investigation of the role of STAT1 in TNF signaling using STAT1-deficient U3A and STAT1-stably transfected U3A-PSG91 cells. IFNalpha inhibited the proliferation of STAT1-expressing U3A-PSG91 cells but had no effect on STAT1-negative U3A cells. TNF alone, even up to 10 nM, had no effect on the proliferation of either U3A-PSG91 or U3A cells. Irrespective of STAT1 status, TNF induced cytotoxic effects in the presence of cycloheximide (CHX) in both cell types. Additionally, TNF-induced caspase-3 and caspase-8 activation and TNF-induced PARP cleavage were unaffected by the presence or absence of STAT1. TNF activated NF-kappaB, consisting of p50 and p65, in both U3A and U3A-pSG91 cells in a dose- and time-dependent manner, but the degree and rate of activation were slightly lower in U3A cells, as were IkappaBalpha degradation and NF-kappaB-dependent reporter gene expression. STAT1 was, however, required for IFNalpha-mediated downregulation of TNF-induced NF-kappaB activation. TNF activated JNK in both cell types, but dose and time of exposure required for optimum activation differed slightly. Thus, overall our results indicate that STAT1 plays a minimal role in TNF-mediated cellular responses.
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PMID:Lack of requirement of STAT1 for activation of nuclear factor-kappaB, c-Jun NH2-terminal protein kinase, and apoptosis by tumor necrosis factor-alpha. 1183 5

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

Silibinin, the flavonoid found in the milk thistle, has been shown to suppress cell growth and exhibit anti-cancer effects. Some flavonoids were reported to inhibit angiogenesis which is essential for tumor growth and metastasis. In this study, to clarify the underlying mechanisms for the anti-cancer effect of silibinin, we examined the effects of silibinin on human endothelial ECV304 cells. Silibinin was found to suppress the growth and induce the apoptosis of ECV304 cells. The induction of apoptosis by silibinin was confirmed by ladder-patterned DNA fragmentation, cleaved and condensed nuclear chromatin and DNA hypoploidy. Silibinin could effectively inhibit constitutive NF-kappaB activation as revealed by electrophoretic mobility shift assay and NF-kappaB-dependent luciferase reporter study. Consistent with this, silibinin treatment resulted in a significant decrease in the nuclear level of p65 subunit of NF-kappaB. In addition, silibinin treatment caused a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. Silibinin also induced the cytochrome c release, activation of caspase-3 and caspase-9 and cleavage of PARP. These results suggest that silibinin may exert, at least partly, its anti-cancer effect by inhibiting angiogenesis through induction of endothelial apoptosis via modulation of NF-kappaB, Bcl-2 family and caspases.
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PMID:Involvement of NF-kappaB and caspases in silibinin-induced apoptosis of endothelial cells. 1465 75

Green tea constituent (-) epigallocatechin-3-gallate (EGCG) has shown remarkable cancer-preventive and some cancer-therapeutic effects. This is partially because of its ability to induce apoptosis in cancer cells without affecting normal cells. Previous studies from our laboratory have shown the involvement of NF-kappa B pathway in EGCG-mediated cell-cycle deregulation and apoptosis of human epidermoid carcinoma A431 cells. Here we show the essential role of caspases in EGCG-mediated inhibition of NF-kappa B and its subsequent apoptosis. Treatment of A431 cells with EGCG (10-40 microg/ml) resulted in dose-dependent inhibition of NF-kappa B/p65, induction of DNA breaks, cleavage of poly(ADP-ribose) polymerase (PARP) and morphological changes consistent with apoptosis. EGCG treatment of cells also resulted in significant activation of caspases, as shown by the dose- and time-dependent increase in DEVDase activity, and protein expression of caspase-3, -8 and -9. EGCG-mediated caspase activation induces proteolytic cleavage of NF-kappa B/p65 subunit, leading to the loss of transactivation domains, and driving the cells towards apoptosis. EGCG-mediated induction of apoptosis was significantly blocked by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-FMK), and moderately blocked by the specific caspase-3 inhibitor Z-DEVD-FMK. Further, pretreatment of cells with Z-VAD-FMK was found to suppress the cleavage of NF-kappa B/p65 subunit, thereby increasing nuclear translocation, DNA binding and transcriptional activity, thus protecting the cells from EGCG-induced apoptosis. Taken together, these studies for the first time demonstrate that EGCG-mediated activation of caspases is critical, at least in part, for inhibition of NF-kappa B and subsequent apoptosis.
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PMID:Essential role of caspases in epigallocatechin-3-gallate-mediated inhibition of nuclear factor kappa B and induction of apoptosis. 1467 29

Development of effective agents for treatment of hormone-refractory prostate cancer has become a national medical priority. We have reported recently that apigenin (4',5,7-trihydroxyflavone), found in many common fruits and vegetables, has shown remarkable effects in inhibiting cell growth and inducing apoptosis in many human prostate carcinoma cells. Here we demonstrate the molecular mechanism of inhibitory action of apigenin on androgen-refractory human prostate carcinoma DU145 cells that have mutations in the tumor suppressor gene p53 and pRb. Treatment of cells with apigenin resulted in a dose- and time-dependent inhibition of growth, colony formation, and G1 phase arrest of the cell cycle. This effect was associated with a marked decrease in the protein expression of cyclin D1, D2, and E and their activating partner, cyclin-dependent kinase (cdk)2, 4, and 6, with concomitant upregulation of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18. The induction of WAF1/p21 and its growth inhibitory effects by apigenin appears to be independent of p53 and pRb status of these cells. Apigenin treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome c and induction of apoptotic protease-activating factor-1 (Apaf-1). This effect was found to result in a significant increase in cleaved fragments of caspase-9, -3, and poly(ADP-ribose) polymerase (PARP). Further, apigenin treatment resulted in downmodulation of the constitutive expression of nuclear factor-kappaB (NF-kappaB)/p65 and NF-kappaB/p50 in the nuclear fraction that correlated with an increase in the expression of IkappaB-alpha (IkappaBalpha) in the cytosol. Taken together, we concluded that molecular mechanisms during apigenin-mediated growth inhibition and induction of apoptosis in DU145 cells was due to (1) modulation in cell-cycle machinery, (2) disruption of mitochondrial function, and (3) NF-kappaB inhibition.
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PMID:Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. 1475 Feb 16


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