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)

Melanoma is a highly metastatic cancer resistant to current chemotherapeutic and radiotherapeutic approaches. Several studies have shown that interactions between cancer cells and the extracellular matrix (ECM) are critical for the survival and invasion of metastatic cancer cells. In this study, we examine the effects of methylselenol generated from selenomethionine (SeMet) by methioninase (METase) on cell proliferation, adhesion, and expression of integrins in murine melanoma B16F10 cells, which are metastatic in the lungs of syngeneic C57BL/6J mice. Combined treatment with SeMet-METase decreased the expression of integrins alpha(4), beta(1), alpha(nu), and beta(3), and inhibited melanoma-ECM adhesion. Caspase-mediated apoptosis was induced following loss of cell adherence. Phosphorylation of focal adhesion kinase (FAK) and Akt, related to integrin-mediated survival, were decreased upon treatment with SeMet-METase while phosphorylation of p38, PKC-delta, and IkappaBalpha increased. In the presence of specific inhibitors of p38, PKC-delta, and NF-kappaB, expression of integrins and cell adhesion to ECM were maintained and cell apoptosis was prevented in SeMet-METase-treated melanoma cells. Treatment with caspase inhibitors restored cell viability and blocked poly (ADP-ribose) polymerase (PARP) cleavage, but did not restore integrin expression and cell adhesion to ECMs reduced by SeMet-METase. Based on these results, we propose that combined treatment with SeMet-METase induces caspase-mediated apoptosis in melanoma cells by altering integrin expression and adhesion. Furthermore, activation of p38, PKC-delta, and NF-kappaB is a prerequisite for the down-regulation of integrin expression, followed by detachment-mediated apoptosis.
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PMID:Methylselenol generated from selenomethionine by methioninase downregulates integrin expression and induces caspase-mediated apoptosis of B16F10 melanoma cells. 1734 6

In order to improve medical treatment of ischemic injury such as myocardial infarction, it is important to elucidate hypoxia-induced changes to endothelial cells. An in vitro blood vessel model, in which HUVECs are stimulated to form a network of capillary-like tubes, was used to analyze hypoxia-induced morphological and biochemical changes. When exposed to hypoxia, the network of capillary tubes broke down into small clusters. This tube breakdown was accompanied by chromatin condensation and cell nuclear fragmentation, morphological markers of apoptosis, and activation of two apoptotic signals, caspase-3 and p38. We investigated what roles caspase cascade and p38 play in hypoxia-induced apoptosis and tube breakdown by using zVAD-fmk and SB203580, specific inhibitors of these two apoptotic signals, respectively. Chromatin condensation and cell nuclear fragmentation and tube breakdown were effectively inhibited by SB203580, but not by zVAD-fmk. SB203580 caused dephosphorylation of p38, which indicates that p38 was autophosphorylated. Inhibition by zVAD-fmk caused slight MW increase in p17 and emergence of p19, which indicates that the inhibitor caused partial processing of caspase-3. Inhibition of p38 suppressed activation of caspase-3 but not vice versa. In addition, these two inhibitors were shown to differentially inhibit cleavage of so-called caspase substrates. SB203580 inhibited cleavage of PARP and lamin A/C, while zVAD-fmk inhibited cleavage of lamin A/C but not that of PARP. Taken together, these results show that p38 is located upstream of caspase cascade and that, although caspase-3 is activated, a p38-regulated caspase-independent pathway is crucial for the execution of hypoxia-induced apoptosis and tube breakdown.
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PMID:Hypoxia-induced apoptosis and tube breakdown are regulated by p38 MAPK but not by caspase cascade in an in vitro capillary model composed of human endothelial cells. 1737 51

Pathogenesis of the highly pathogenic avian influenza virus A/Hong Kong/483/97 (H5N1/97) remains to be investigated. It was demonstrated recently that H5N1 dysregulation of proinflammatory cytokines in human macrophages is a p38-kinase-dependent process. The results indicated that macrophages may play a role in disease severity. To investigate cellular responses to H5N1 infection further, apoptosis and its related pathways were studied in primary blood macrophages. Here, it is shown that the H5N1/97 virus triggered apoptosis, including caspases and PARP activation, in infected macrophages with a delayed onset compared with H1N1 counterparts. Similar results were also found in human macrophages infected by precursors of the H5N1/97 virus. Thus, these results showed that the delay in apoptosis onset in macrophages infected by H5N1/97 and its related precursor subtypes may be a means for the pathogens to have longer survival in the cells; this may contribute to the pathogenesis of H5N1 disease in humans.
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PMID:Differential onset of apoptosis in influenza A virus H5N1- and H1N1-infected human blood macrophages. 1737 72

Bovine viral diarrhea virus (BVDV), a pestivirus of the Flaviviridae family, is an economically important cattle pathogen with a worldwide distribution. Besides the segregation into two distinct species (BVDV1/BVDV2) two different biotypes, a cytopathic (cp) and a noncytopathic (ncp) biotype, are distinguished based on their behavior in epithelial cell cultures. One of the most serious forms of BVDV infection affecting immunocompetent animals of all ages is severe acute BVD (sa BVD) which is caused by highly virulent ncp BVDV2 strains. Previous studies revealed that these highly virulent ncp viruses cause cell death in a lymphoid cell line (BL3) which is not clearly associated with typical apoptotic changes (e.g. PARP cleavage) observed after infection with cp BVDV. To further characterize the underlying molecular mechanisms, we first analyzed the role of the mitochondria and caspases as key mediators of apoptosis. Compared to infection with cp BVDV2, infection with highly virulent ncp BVDV2 resulted in a delayed and less pronounced disruption of the mitochondrial transmembrane potential (DeltaPsi(m)) and a weaker activation of the caspase cascade. In contrast, infection with low virulence ncp BVDV2 showed no significant differences from the uninfected control cells. Since different pro- and anti-apoptotic cellular signaling pathways may become activated upon virus infection, we compared the effect of different BVDV2 strains on cellular signaling pathways in BL3 cells. Stress-mediated p38 MAPK phosphorylation was detected only in cells infected with cp BVDV2. Interestingly, infection with highly virulent ncp BVDV2 was found to influence the phosphoinositide 3-kinase (PI3K)-Akt pathway. This indicates that BL3 cells respond differently to infection with BVDV depending on virulence and biotype.
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PMID:Activation of cell signaling pathways is dependant on the biotype of bovine viral diarrhea viruses type 2. 1737 55

The cellular functions regulated by 17beta-estradiol (E2) start after the hormone binds to its receptors (i.e., ERalpha and ERbeta). These act as ligand-dependent transcription factor transactivating target genes. In addition, E2 induces non-genomic actions, whose activation is triggered by a fraction of the ERs localized at the plasma membrane. Palmitoylation allows ERalpha to localize at the plasma membrane, to associate with caveolin-1, and, upon E2 stimulation, to activate rapid signals relevant for cell proliferation. The existence of a mechanism, which allows ERbeta localization at the plasma membrane and its putative role in anti-proliferative E2 effects is completely unknown. Here, the susceptibility of ERbeta to undergo palmitoylation and the role played by this process has been analyzed in DLD-1 containing endogenous ERbeta or in HeLa cells transiently transfected with ERbeta or ERalpha expression vectors. As for ERalpha, palmitoylation is necessary for ERbeta localization at the plasma membrane and its association with caveolin-1 but, in contrast to ERalpha, the E2 binding increases ERbeta association with caveolin-1 and the p38 member of MAPK family. Moreover, the palmitoyl acyl transferase (PAT) inhibitor blocks the ability of ERbeta-E2 complex to activate p38 impairing the receptor-dependent activation of downstream proapoptotic cascade (i.e., caspase-3 activation and poly(ADP-ribose)polymerase (PARP) cleavage). Consequently, palmitoylation must be considered to be a molecular device for ERbeta, which allows these receptors to interact with the plasma membrane and to regulate E2-induced non-genomic functions relevant to the anti-proliferative effect of this hormone.
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PMID:Role of ERbeta palmitoylation in the inhibition of human colon cancer cell proliferation. 1739 84

Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho-c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer.
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PMID:Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer. 1743 Nov 20

Dipyrithione (2, 2'-dithiobispyridine-1, 1'-dioxide, PTS2), a pyrithione derivate, is highly bactericidal and fungicidal. In this study we examined its apoptotic effect on HeLa cells. PTS2 induced HeLa cell death in a dose and time dependent manner. ERK1/2 and p38 were markedly activated, but little JNK1/2 activation was detected. Suppression of p38 activation by SB203580 reduced the extent of apoptosis of the HeLa cells and also prevented induction of p21, release of cytochrome c, and cleavage of caspase-3 and PARP. Inhibition of ERK1/2 with PD98059 increased apoptosis, indicating that ERK1/2 activation has an anti-apoptotic effect on PTS2-induced HeLa cell apoptosis. PTS2 also inhibited murine sarcoma 180 and hepatoma 22 tumor growth in an animal tumor model. Our findings indicate that PTS2 possesses anti-tumor activity, that caspase-3 and poly (ADP-ribose) polymerase (PARP) are involved in PTS2-induced HeLa cell apoptosis and that ERK1/2 and p38 have opposing effects on this apoptosis.
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PMID:Opposing effects of ERK and p38 MAP kinases on HeLa cell apoptosis induced by dipyrithione. 1746 9

Beta-sitosterol (SITO) is a potential candidate for cancer chemotherapy, however, little is known about the cellular and molecular mechanisms in cancer cells. We herein identified how SITO induces anti-proliferation and cell death in MCA-102 fibrosarcoma cells. SITO exposure induced-apoptosis and the cell death resulted from a significant loss of the Bcl-2 and the inhibitor of apoptosis protein (IAP) family (XIAP, cIAP-1 and cIAP-2), and increased Bax with an alteration of p53 and p21. SITO-induced cell death significantly also increased caspase activity and poly(ADP-ribose) polymerase (PARP) cleavage, and caspase-3 inhibitor z-DEVD-fmk significantly inhibited SITO-induced cell death. These data suggest that the activation of caspase-3 is associated with SITO-induced-apoptosis. Treatment with SITO also induced phosphorylation of extracellular-signal regulating kinase (ERK) and p38 mitogen-activated protein kinase (MARK), but not c-Jun N-terminal kinase (JNK). A specific ERK inhibitor PD98059 significantly blocks SITO-induced-apoptosis, whereas a JNK inhibitor SP600125 has no affect. A p38 MAPK inhibitor SB203580 very slightly suppressed cell death. The induction of apoptosis was also accompanied by an inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt, and PI3K inhibitor LY29004 significantly increases SITO-induced cell death. These findings provide evidence demonstrating that the proapoptotic effect of SITO is mediated through the activation of ERK and the block of the PI3K/Akt signal pathway in MCA-102 cells. Therefore, SITO has a strong potential as a therapeutic agent for preventing cancers such as fibrosarcoma.
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PMID:Beta-sitosterol-induced-apoptosis is mediated by the activation of ERK and the downregulation of Akt in MCA-102 murine fibrosarcoma cells. 1757 Mar 21

Furanodiene (C15H20O), a pure compound isolated from Traditional Chinese medicine, Curcuma wenyujin, named Ezhu in Chinese, which structure was determined on the basis of NMR, MS and UV spectrum. In this study, we attempted to characterize in detail the signaling cascades resulted from furanodiene-induced apoptosis in human hepatoma HepG2 cells. Furanodiene inhibited HepG2 cell growth by causing cell cycle arrest at G2/M and inducing apoptosis as evidenced by DNA fragmentation assay. We found that furanodiene induced mitochondrial transmembrane depolarization, release of mitochondrial cytochrome c, activation of caspases-3 and the cleavage of PARP. The furanodiene mediated mitochondria-caspase apoptotic pathway also involved activation of p38 and inhibition of ERK mitogen-activated protein kinase (MAPK) signaling. These results for the first time have identified the biological activity of furanodiene against HepG2 cells and provide rationales for further development of essential oil of Ezhu and its ingredients such as furanodiene on treatment of liver diseases.
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PMID:Furanodiene induces G2/M cell cycle arrest and apoptosis through MAPK signaling and mitochondria-caspase pathway in human hepatocellular carcinoma cells. 1761 10

It has become increasingly clear that apoptosis plays a major role in ischaemia/reperfusion (I/R)-induced cell death, but the molecular basis of this process remains to be elucidated. Therefore, the aim of this study was to investigate the role of cPLA(2) in MAPK phosphorylation and apoptosis in simulated ischaemia/reperfusion (SI/R)-induced injury in neonatal cardiomyocytes. Inhibition of cPLA(2) with AACOCF(3) significantly improved cell viability during SI/R (60.17+/-1.77 to 80.17+/-1.97%, p<0.05). The increase in cell viability was associated with a significant inhibition of p38 phosphorylation (135.3+/-4.47% to 87.94+/-10.71%, p<0.001) as well as with a significant decrease in caspase-3- (320.32+/-17.32% to 146.7+/-28.69%, p<0.01) and PARP-(263.9+/-8.15% to 154.7+/-2.24%, p<0.001) cleavage during SI/R. This study provides evidence for a role for cPLA(2) during SI/R-induced injury. It appears that p38 MAPK is a central role player in the signalling pathway involved.
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PMID:Apoptosis is mediated by cytosolic phospholipase A2 during simulated ischaemia/reperfusion-induced injury in neonatal cardiac myocytes. 1764 76


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