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

---

Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribose) polymerase 1 (PARP-1) activity is detected in both neuronal and nonneuronal cells in the CNS, and excessive PARP-1 activity is known to be detrimental to tissue because of the cellular energy loss. Accordingly, PARP-1-deficient (PARP-1(-/-)) mice have been shown to be resistant to cerebral ischemia and several forms of inflammation. Recently, PARP-1 in glial cells has been shown to mediate the expression of proinflammatory genes in response to inflammatory stimuli by, in part, enhancing cognate DNA-binding capacities of transcription factors such as NF-kappaB and activator protein 1. Here, we demonstrate an additional mechanism whereby a significant reduction of proinflammatory gene expression such as IL-1beta, tumor necrosis factor alpha, and inducible nitricoxide synthase in PARP-1(-/-) glial cells is linked to defective inflammatory stimuli-induced p38MAPK-mediated phosphorylation of ATF-2 and cAMP-response element-binding protein and phosphorylation of NF-kappaB p65. Importantly, an inflammatory stimuli-induced p38MAPK activation is impaired in PARP-1(-/-) glial cells in a signaling pathway- and cell/tissue type-specific manner. These findings indicate that PARP-1 is an essential host factor among factors that actively mediate excessive production of proinflammatory molecules in glial cells, which may in turn contribute to the initiation of neuronal injuries.
...
PMID:Defective transcription factor activation for proinflammatory gene expression in poly(ADP-ribose) polymerase 1-deficient glia. 1504 47

Increased expression of proinflammatory and proangiogenic factors are associated with aggressive tumor growth and decreased survival of patients with head and neck squamous cell carcinoma (HNSCC). In as much as genes that are regulated by nuclear factor NF-kappaB suppress apoptosis, induce proliferation, and mediate inflammation, angiogenesis and tumor metastasis, agents that suppress NF-kappaB activation have potential as treatment for various cancers including HNSCC. We demonstrate that all HNSCC cell lines expressed constitutively active NF-kappaB and IkappaBalpha kinase (IKK), which is needed for NF-kappaB activation. Treatment of MDA 686LN cells with curcumin (diferuloylmethane), a pharmacologically safe chemopreventive agent, inhibited NF-kappaB activation through abrogation of IKK. As a result expression of various cell survival and cell proliferative genes including Bcl-2, cyclin D1, IL-6, COX-2 and MMP-9 was suppressed. This, in turn, inhibits proliferation of all HNSCC cell lines, arrests cell cycle in G1/S phase (MDA 686LN) and induces apoptosis as indicated by upstream and downstream caspase activation, PARP cleavage, annexin V staining in MDA 686LN cells. Suppression of NF-kappaB by cell-permeable p65-based peptide and NBD peptide also inhibited the proliferation and induced apoptosis in these cells. Our results indicate that curcumin is a potent inhibitor of cell proliferation and an inducer of apoptosis in HNSCC through suppression of IKK-mediated NF-kappaB activation and of NF-kappaB-regulated gene expression.
...
PMID:Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling. 1525 36

The 1,2,4-thiadiazolidine derivatives have been shown to be involved in several biological responses such as anti-bacterial, anti-fungal, anti-tubercular and local anaesthetic activities. In our study, we have synthesized some new 5-substitutedarylimino-2-N-substitutedphenyl-3-oxo-1,2,4-thiadiazolidine and tested for anti-inflammatory and anti-tumor activities. The 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-Oxo-1,2,4-thiadiazolidine (P(3)-25) showed anti-inflammatory activity as it inhibited different inflammatory inducers mediated nuclear transcription factor kappa B (NF-kappaB), a key transcription factor involved in all forms of inflammation. P(3)-25 inhibited TNF-induced NF-kappaB activation as detected by gel shift assay and dependent reporter gene expression. It inhibited IkappaBalpha degradation, IkappaB kinase activation and p65 nuclear translocation. P(3)-25 inhibited TNF-induced Cox2 expression. It inhibited NF-kappaB activation in human epithelial and T cells. Unlike other substitutary derivatives, P(3)-25 was a potent inducer of apoptosis as it induced cell death, caspase-dependent PARP cleavage, ROI generation and lipid peroxidation. Overall our results suggest that P(3)-25 derivative exerts anti-inflammatory and anti-tumor activities, which may have a role in designing such drugs.
...
PMID:1,2,4-Thiadiazolidine derivative inhibits nuclear transcription factor-kappaB and its dependent genes activation but induces apoptosis. 1538 16

The current study investigated the role of poly(ADP-ribose) polymerase (PARP) in the development of diabetic retinopathy. Activity of PARP was increased in whole retina and in endothelial cells and pericytes of diabetic rats. Administration of PJ-34 (a potent PARP inhibitor) for 9 months to diabetic rats significantly inhibited the diabetes-induced death of retinal microvascular cells and the development of early lesions of diabetic retinopathy, including acellular capillaries and pericyte ghosts. To further investigate how PARP activation leads to cell death in diabetes, we investigated the possibility that PARP acts as a coactivator of nuclear factor-kappaB (NF-kappaB) in the retinal cells. In bovine retinal endothelial cells (BRECs), PARP interacted directly with both subunits of NF-kappaB (p50 and p65). More PARP was complexed to the p50 subunit in elevated glucose concentration (25 mmol/l) than at 5 mmol/l glucose. PJ-34 blocked the hyperglycemia-induced increase in NF-kappaB activation in BRECs. PJ-34 also inhibited diabetes-induced increase expression of intercellular adhesion molecule-1, a product of NF-kappaB-dependent transcription in retina, and subsequent leukostasis. Inhibition of PARP or NF-kappaB inhibited the hyperglycemia (25 mmol/l glucose)-induced cell death in retinal endothelial cells. Thus, PARP activation plays an important role in the diabetes-induced death of retinal capillary cells, at least in part via its regulation of NF-kappaB.
...
PMID:Poly(ADP-ribose) polymerase is involved in the development of diabetic retinopathy via regulation of nuclear factor-kappaB. 1550 77

Infection by herpes simplex virus type 1 (HSV-1) induces a persistent nuclear translocation of NFkappaB. To identify upstream effectors of NFkappaB and their effect on virus replication, we employed mouse embryo fibroblast (MEF)-derived cell lines with deletions of either IKK1 or IKK2, the catalytic subunits of the IkappaB kinase (IKK) complex. Infected MEFs were assayed for virus yield, loss of IkappaBalpha, nuclear translocation of p65, and NFkappaB DNA-binding activity. Absence of either IKK1 or IKK2 resulted in an 86 to 94% loss of virus yield compared to that of normal MEFs, little or no loss of IkappaBalpha, and greatly reduced NFkappaB nuclear translocation. Consistent with reduced virus yield, accumulation of the late proteins VP16 and gC was severely depressed. Infection of normal MEFs, Hep2, or A549 cells with an adenovirus vector expressing a dominant-negative (DN) IkappaBalpha, followed by superinfection with HSV, resulted in a 98% drop in virus yield. These results indicate that the IKK-IkappaB-p65 pathway activates NFkappaB after virus infection. Analysis of NFkappaB activation and virus replication in control and double-stranded RNA-activated protein kinase-null MEFs indicated that this kinase plays no role in the NFkappaB activation pathway. Finally, in cells where NFkappaB was blocked because of DNIkappaB expression, HSV failed to suppress two markers of apoptosis, cell surface Annexin V staining and PARP cleavage. These results support a model in which activation of NFkappaB promotes efficient replication by HSV, at least in part by suppressing a host innate response to virus infection.
...
PMID:Efficient replication by herpes simplex virus type 1 involves activation of the IkappaB kinase-IkappaB-p65 pathway. 1556 69

Asthma is an inflammatory disease of the lungs and the transcription factor NF-kappa B regulates the production of numerous inflammatory mediators that may have a role in the pathogenesis of asthma. Hence, the signalling pathways leading to NF-kappa B activation are considered prime targets for novel anti-inflammatory therapies. The prevention of NF-kappa B activity in mice, through the knockout of IKK beta or p65, causes fatal liver degeneration in utero making it difficult to determine the full implications of inhibiting NF-kappaB activity in tissues physiologically relevant to human diseases. This study used adenovirus delivery of a dominant inhibitor of NF-kappaB (I kappa B alpha delta N) and dominant-negative IKK alpha (IKK alpha(KM)) and IKK beta (IKK beta(KA)) to investigate the role of the individual IKKs in NF-kappa B activation and inflammatory gene transcription by human pulmonary A549 cells. Overexpression of IKK beta(KA) or I kappa B alpha delta N prevented NF-kappa B-dependent transcription and DNA binding. IKK beta(KA) also prevented I kappa B alpha kinase activity. Similarly, IKK beta(KA) and I kappa B alpha delta N overexpression also inhibited IL-1beta- and TNF alpha-dependent increases in ICAM-1, IL-8 and GM-CSF in addition to IL-1beta-mediated increases in cyclooxygenase-2 expression, whereas IKK alpha(KM) overexpression had little effect on these outputs. IKK beta(KA) also reduced cell viability and induced caspase-3 and PARP cleavage regardless of the stimuli, indicating the induction of apoptosis. This effect seemed to be directly related to IKK beta kinase activity since I kappa B alpha delta N only induced PARP cleavage in TNF alpha-treated cells. These results demonstrate that inhibition of IKK beta and NF-kappa B suppresses inflammatory mediator production and reduces A549 cell viability. Thus, novel therapies that target IKK beta could have potent anti-inflammatory effects and may be beneficial in the treatment of certain cancers.
...
PMID:Validation of IKK beta as therapeutic target in airway inflammatory disease by adenoviral-mediated delivery of dominant-negative IKK beta to pulmonary epithelial cells. 1572 90

Human mantle cell lymphoma (MCL), an aggressive B cell non-Hodgkin's lymphoma, is characterized by the overexpression of cyclin D1 which plays an essential role in the survival and proliferation of MCL. Because of MCL's resistance to current chemotherapy, novel approaches are needed. Since MCL cells are known to overexpress NF-kappaB regulated gene products (including cyclin D1), we used curcumin, a pharmacologically safe agent, to target NF-kappaB in a variety of MCL cell lines. All four MCL cell lines examined had overexpression of cyclin D1, constitutive active NF-kappaB and IkappaB kinase and phosphorylated forms of IkappaBalpha and p65. This correlated with expression of TNF, IkappaBalpha, Bcl-2, Bcl-xl, COX-2 and IL-6, all regulated by NF-kappaB. On treatment of cells with curcumin, however, downregulated constitutive active NF-kappaB and inhibited the consitutively active IkappaBalpha kinase (IKK), and phosphorylation of IkappaBalpha and p65. Curcumin also inhibited constitutive activation of Akt, needed for IKK activation. Consequently, the expression of all NF-kappaB-regulated gene products, were downregulated by the polyphenol leading to the suppression of proliferation, cell cycle arrest at the G1/S phase of the cell cycle and induction of apoptosis as indicated by caspase activation, PARP cleavage, and annexin V staining. That NF-kappaB activation is directly linked to the proliferation of cells, is also indicated by the observation that peptide derived from the IKK/NEMO-binding domain and p65 suppressed the constitutive active NF-kappaB complex and inhibited the proliferation of MCL cells. Constitutive NF-kappaB activation was found to be due to TNF, as anti-TNF antibodies inhibited both NF-kappaB activation and proliferation of cells. Overall, our results indicate that curcumin inhibits the constitutive NF-kappaB and IKK leading to suppression of expression of NF-kappaB-regulated gene products that results in the suppression of proliferation, cell cycle arrest, and induction of apoptosis in MCL.
...
PMID:Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. 1602 83

Poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear factor kappaB (NF-kappaB) have both been demonstrated to play a pathophysiological role in a number of inflammatory disorders. We recently presented evidence that PARP-1 can act as a promoter-specific coactivator of NF-kappaB in vivo independent of its enzymatic activity. PARP-1 directly interacts with p300 and both subunits of NF-kappaB (p65 and p50) and synergistically coactivates NF-kappaB-dependent transcription. Here we show that PARP-1 is acetylated in vivo at specific lysine residues by p300/CREB-binding protein upon stimulation. Furthermore, acetylation of PARP-1 at these residues is required for the interaction of PARP-1 with p50 and synergistic coactivation of NF-kappaB by p300 and the Mediator complex in response to inflammatory stimuli. PARP-1 physically interacts with the Mediator. Interestingly, PARP-1 interacts in vivo with histone deacetylases (HDACs) 1-3 but not with HDACs 4-6 and might be deacetylated in vivo by HDACs 1-3. Thus, acetylation of PARP-1 by p300/CREB-binding protein plays an important regulatory role in NF-kappaB-dependent gene activation by enhancing its functional interaction with p300 and the Mediator complex.
...
PMID:Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription. 1620 34

Curcumin, the yellow pigment in the spice turmeric, has potent chemopreventive activities that involve diverse molecular pathways. It is widely believed that curcumin pro-apoptotic properties are mediated by downregulation of NF kappa B (NFkappaB). The p65/RelA subunit of NFkappaB may influence cell death, in part by activation of NFkappaB anti-apoptotic target genes including X-linked inhibitor of apoptosis (XIAP), A20, bcl-xL and inhibition of sustained activation of c-Jun N-terminal kinase (JNK). We have shown previously that curcumin inhibits NFkappaB, activates JNK and promotes apoptosis in HCT116 colorectal cancer cells. Here, we show that forced overexpression of p65 does not affect curcumin-induced JNK activation. Indeed, overexpression of p65 enhanced curcumin-mediated apoptosis as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay and poly(ADP-ribose) polymerase (PARP) cleavage. This potentiating effect of p65 upon curcumin-mediated apoptosis was reversed by transfection of cells with an IkappaB super-repressor (DeltaNIkappaB). Curcumin treatment inhibited expression of NFkappaB anti-apoptotic target genes in mock-transfected and in p65-overexpressing HCT116 cells, although expression levels remained higher in the latter. Taken together, these results show that curcumin-mediated activation of JNK or induction of apoptosis does not require inhibition of p65. Furthermore, curcumin/p65 synergy in promotion of apoptosis cannot be attributed to active repression of NFkappaB anti-apoptotic genes.
...
PMID:Overexpression of p65/RelA potentiates curcumin-induced apoptosis in HCT116 human colon cancer cells. 1649 2

The continuous production of the CXC ligand 1 (CXCL1) chemokine by melanoma cells is a major effector of tumor growth. We have previously shown that the constitutive expression of this chemokine is dependent upon transcription factors nuclear factor-kappa B (NF-kappaB), stimulating protein-1 (SP1), high-mobility group-I/Y (HMGI/Y), CAAT displacement protein (CDP) and poly(ADP-ribose) polymerase-1 (PARP-1). In this study, we demonstrate for the first time the mechanism of transcriptional regulation of CXCL1 through PARP-1 in melanoma cells. In its inactive state, PARP-1 binds to the CXCL1 promoter in a sequence-specific manner and prevents binding of NF-kappaB (p65/p50) to its element. However, activation of the PARP-1 enzymatic activity enhances CXCL1 expression, owing to the loss of PARP-1 binding to the CXCL1 promoter, accompanied by enhanced binding of p65 to the promoter. The delineation of the role of NF-kappaB-interacting factors in the putative CXCL1 enhanceosome will provide key information in developing strategies to block constitutive expression of this and other chemokines in cancer and to develop targeted therapy.
...
PMID:Differential regulation of CXC ligand 1 transcription in melanoma cell lines by poly(ADP-ribose) polymerase-1. 1679 43


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---