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:3.4.11.18 (MAP)
7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the cellular stress pathways (c-Jun N-terminal kinase [JNK] and p38 mitogen-activated protein [MAP] kinase) is linked to apoptosis. However, whether both pathways are required for apoptosis remains unresolved. Hepatitis B virus X protein (pX) activates p38 MAP kinase and JNK pathways and, in response to weak apoptotic signals, sensitizes hepatocytes to apoptosis. Employing hepatocyte cell lines expressing pX, which was regulated by tetracycline, we investigated the mechanism of apoptosis by p38 MAP kinase and JNK pathway activation. Inhibition of the p38 MAP kinase pathway rescues by 80% the initiation of pX-mediated apoptosis, whereas subsequent apoptotic events involve both pathways. pX-mediated activation of p38 MAP kinase and JNK pathways is sustained, inducing the transcription of the death receptor family genes encoding Fas/FasL and tumor necrosis factor receptor 1 (TNFR1)/TNF-alpha and the p53-regulated Bax and Noxa genes. The pX-dependent expression of Fas/FasL and TNFR1/TNF-alpha mediates caspase 8 activation, resulting in Bid cleavage. In turn, activated Bid, acting with pX-induced Bax and Noxa, mediates the mitochondrial release of cytochrome c, resulting in the activation of caspase 9 and apoptosis. Combined antibody neutralization of FasL and TNF-alpha reduces by 70% the initiation of pX-mediated apoptosis. These results support the importance of the pX-dependent activation of both the p38 MAP kinase and JNK pathways in pX-mediated apoptosis and suggest that this mechanism of apoptosis occurs in vivo in response to weak apoptotic signals.
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PMID:Sustained activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase pathways by hepatitis B virus X protein mediates apoptosis via induction of Fas/FasL and tumor necrosis factor (TNF) receptor 1/TNF-alpha expression. 1554 43

Rheumatoid arthritis is characterised by the interaction of multiple mediators, among the most important of which are cytokines. In recent years, extensive data demonstrates a pivotal role for one cytokine, macrophage migration inhibitory factor (MIF), in fundamental events in innate and adaptive immunity. MIF has now been demonstrated to be involved in the pathogenesis of many diseases, but in the case of RA the evidence for a role of MIF is very strong. MIF is abundantly expressed in the serum of RA patients, and in RA synovial tissue where it correlates with disease activity. MIF induces synoviocyte expression of key proinflammatory genes including TNF, IL-1, IL-6, IL-8, cPLA2, COX2 and MMPs. MIF also regulates the function of endothelial cells and B cells. Moreover, MIF is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumor suppressor protein p53. In multiple rat and mouse models of RA, anti-MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease. MIF -/- mice further demonstrate increases in synovial apoptosis. That the human Mif gene is encoded by different functional alleles in subjects with inflammatory disease also provides evidence for the role of MIF in RA. The mechanism of action of MIF is becoming better understood. MIF appears to interact with cell surface CD74, with consequent activation of MAP kinases but possibly not NFkappaB intracellular signal transduction. This apparent selectivity may be implicated in the ability of MIF to antagonise the effects of glucocorticoids. As MIF expression is induced by glucocorticoids, inhibition of its antagonistic effects may permit enhanced therapeutic effect of glucocorticoids, or "steroid sparing". To date there are no clinical trials of MIF antagonism in any disease, but exploitation of antibody, soluble receptor, or small molecule approaches enabled by the unique crystal structure of MIF, may soon lead to the ability to test in the clinic the importance of this cytokine in human RA.
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PMID:Macrophage migration inhibitory factor in rheumatoid arthritis. 1557 36

ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 10(9) plaque forming units (PFU)/dose (total dose of 5 x 10(9) PFU/cycle) to 10(10) PFU/dose (total dose of 5 x 10(10) PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral DNA in post treatment tumor specimens by ISH and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR, up to 7 days after the last viral dose provide evidence for adenoviral replication. There was evidence of antitumor activity in one out of six patients. Further investigation of this approach in patients with recurrent sarcomas is warranted.
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PMID:Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. 1564 67

The tumor suppressor gene p53 plays an essential role in cell proliferation and apoptosis. Due to its relevance to cancer therapy, most studies have focused on the cellular consequences of p53 activation in relation to cytotoxic drugs. 5-aza-2'-deoxycytidine (5-aza-CdR) is widely used as an anti-cancer drug for the treatment of leukemia and solid tumors. However, the mechanism by which 5-aza-CdR exerts its anti-neoplastic activity remains unclear. Here, we address the role of p53 in regulating cellular responses to 5-aza-CdR treatment in human prostate cancer cells. We found that 5-aza-CdR induces p53 and p21Waf1/Cip1 expression associated with inhibition of cell proliferation in LNCaP cells (p53 wild-type), but not in DU145 cells (p53 mutant). By using pifithrin-alpha, a chemical inhibitor of p53, we confirmed that the increase in p21Waf1/Cip1 expression and inhibition of cell proliferation in LNCaP cells by 5-aza-CdR is p53-dependent. Also, the activation of p53 and p21Waf1/Cip1 pathway by 5-aza-CdR modified multiple gene expressions including apoptotic target genes and MAP kinases in LNCaP cells. 5-aza-CdR-induced apoptosis in LNCaP cells is assessed by DNA fragmentation analysis. Furthermore, knockdown of p53 by pU6-p53 siRNA vector suggests the involvement of MAP kinases in the process of 5-aza-CdR-mediated activation of p53 pathway to inhibit cell proliferation and induce apoptosis. Finally, the comet or SCGE assay and methylation-sensitive restriction analysis demonstrated that 5-aza-CdR induced p53 and p21Waf1/Cip1 expression as a consequence of DNA damage and independent of DNA demethylation. Our findings suggest that 5-aza-CdR induces anti-neoplastic activity primarily through the activation of p53 pathway in response to DNA damage and subsequently leads to inhibition of cell proliferation as well as induction of apoptosis. Therefore, our data indicate that p53 status in tumor cells may be critical for the clinical efficacy and toxicity of 5-aza-CdR.
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PMID:Activation of p53/p21Waf1/Cip1 pathway by 5-aza-2'-deoxycytidine inhibits cell proliferation, induces pro-apoptotic genes and mitogen-activated protein kinases in human prostate cancer cells. 1575 79

The biological activities of the polysaccharide have attracted more and more attention in the biochemical and medical areas due to their anti-cancer effects. To estimate the anti-tumor mechanism of MAP, a novel polysaccharide from the loach, Misgurnus anguillicaudatus, the apoptosis effects of the polysaccharide on the human hepatocellular carcinoma cells (SMMC-7721 cells) were studied. The present studies showed that MAP could induce cell apoptosis which was closely accompanied with an increase of intracellular-free calcium concentration ([Ca2+]i), the enhancement of reactive oxygen species (ROS) level, dissipation of mitochondria membrane potential (MMP), up-regulation of p53 mRNA, increase expression of Bax mRNA, and decrease expression of Bcl-2 mRNA. These results suggested that cell apoptosis induced by MAP mainly was mediated by mitochondrial pathways, not involved death receptors (DRs) pathways. The mechanism possibly is that MAP acts on mitochondria and boosts ROS, ROS mediates a release of Ca2+ from the intracellular Ca2+ pool, increasing [Ca2+]i targets the cells a start-up of the apoptosis program. However, further research on the molecular mechanisms of MAP effecting on the cells' mitochondria is necessary.
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PMID:Mechanism of apoptosis induced by a polysaccharide, from the loach Misgurnus anguillicaudatus (MAP) in human hepatocellular carcinoma cells. 1593 90

Spore-extracted toxins of the indoor mold Stachybotrys chartarum (SC) caused cytotoxicity (release of lactate dehydrogenase), inhibition of cell proliferation, and cell death in murine alveolar macrophage cell line MH-S in a dose- and time-dependent manner. Apoptotic cell death, confirmed based on morphological changes, DNA ladder formation, and caspase 3/7 activation, was detectable as early as at 3 h during treatment with a toxin concentration of 1 spore equivalent/macrophage and was preceded by DNA damage beginning at 15 min, as evidenced by DNA comet formation in single cell gel electrophoresis assay. The apoptotic dose of SC toxins did not induce detectable nitric oxide and pro-inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) but showed exacerbated cytotoxicity in presence of a non-apoptotic dose of the known pro-inflammatory agent LPS (10 ng/ml). Intracellular reduced glutathione (GSH) level showed a significant decrease beginning at 9 h of the toxin treatment whereas oxidized glutathione (GSSG) showed a corresponding significant increase, indicating a delayed onset of oxidative stress in the apoptosis process. The toxin-treated macrophages accumulated p53, an indicator of DNA damage response, and showed activation of the stress-inducible MAP kinases, JNK, and p38, in a time-dependent manner. Chemical blocking of either p38 or p53 inhibited in part the SC toxin-induced apoptosis whereas blocking of JNK did not show any such effect. This study constitutes the first report on induction of DNA damage and associated p53 activation by SC toxins, and demonstrates the involvement of p38- and p53-mediated signaling events in SC toxin-induced apoptosis of alveolar macrophages.
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PMID:DNA damage, redox changes, and associated stress-inducible signaling events underlying the apoptosis and cytotoxicity in murine alveolar macrophage cell line MH-S by methanol-extracted Stachybotrys chartarum toxins. 1647 59

The Cdc25C phosphatase is a key regulator of mitotic entry which activity is tightly regulated by phosphorylation. In response to DNA damage, phosphorylation at serine 216 induces the cytosolic retention of Cdc25C through 14-3-3 binding. We previously reported the ability of the p14ARF tumor suppressor to induce the accumulation of inactive phospho-Cdc25C(Ser216) protein as well as a decrease of Cdc25C steady state level and correlated these events with a p53-independent G2 arrest. The aim of this study was to investigate the cellular signaling pathways involved in this process. By using specific pharmacological inhibitors, we demonstrate that activation of the ERK1/2 MAP kinases pathway is involved in the p53-independent G2 checkpoint induced by p14ARF Moreover, we show that activated P-ERK1/2 bind and phosphorylate Cdc25C on its ser216 residue following p14ARF expression, thereby identifying Cdc25C as a new ERK1/2 target. Importantly, we further show that phosphorylation at Ser216 by phospho-ERK1/2 promotes Cdc25C ubiquitination and proteasomal degradation, suggesting that Cdc25C proteolysis is required for a sustained G2 arrest in response to p14ARF. Taken together, these results demonstrate that the MAPK ERK signaling pathway contributes to the p53-independent antiproliferative functions of p14ARF. Furthermore, they identify a new mechanism by which phosphorylation at serine 216 participates to Cdc25C inactivation.
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PMID:p14ARF triggers G2 arrest through ERK-mediated Cdc25C phosphorylation, ubiquitination and proteasomal degradation. 1658 26

The initiation, growth, and development of new blood vessels through angiogenesis are essential for tumor growth. Tumor masses require access to blood vessels for a sufficient supply of oxygen and nutrients to maintain growth and metastasis. Inhibiting tumor blood vessel formation as proposed by Judah Folkman in the early 1970s, therefore, offers promising therapeutic approaches for treating tumor afflicted patients. The blood vessel growth in normal tissues is regulated though a delicate and complex balance between the collective action of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) and the collective action of angiogenic inhibitors (e.g., thrombospondin-1). In pathological angiogenesis, the angiogenic switch is shifted toward the proangiogenic factors, and if the imbalance continues, irregular tumor vessel growth is the result. Despite intense research, the mechanism of the angiogenic switch is not fully understood. Many factors, however, have been shown to be involved in regulating the equilibrium between angiogenic stimulants and inhibitors. VEGFR tyrosine kinase, methionine aminopeptidase-2 (MetAP-2), p53, tubulin, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) all directly and/or indirectly influence the angiogenic switch. This review will describe some of the advances in inhibitor design and the mechanisms of action for the aforementioned factors (targets) involved in angiogenesis regulation. Our discussion reveals that a diaryl group separated by various connecting modules is one of the most common features for antiangiogenesis drug design. This idea has been a working pharmacophore hypothesis for our own antiangiogenic drug design endeavors over the years. The recent advances of combination therapy (angiogenesis inhibitors with other chemotherapy/radiation) are also discussed.
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PMID:Antiangiogenesis drug design: multiple pathways targeting tumor vasculature. 1661 Oct 71

Doxorubicin (Dox) is a chemotherapeutic agent that causes significant cardiotoxicity. We showed previously that Dox activates p53 and induces apoptosis in mouse hearts. This study was designed to elucidate the molecular events that lead to p53 stabilization, to examine the pathways involved in Dox-induced apoptosis, and to evaluate the effectiveness of pifithrin-alpha (PFT-alpha), a p53 inhibitor, in blocking apoptosis of rat H9c2 myoblasts. H9c2 cells that were exposed to 5 muM Dox had elevated levels of p53 and phosphorylated p53 at Ser15. Dox also triggered a transient activation of p38, p42/p44ERK, and p46/p54JNK MAP kinases. Caspase activity assays and Western blot analysis showed that H9c2 cells treated with Dox for 16 h had marked increase in the levels of caspases-2, -3, -8, -9, -12, Fas, and cleaved poly(ADP ribose) polymerase (PARP). There was a concomitant increase in p53 binding activity, cytochrome c release, and apoptosis. These results suggest that Dox can trigger intrinsic, extrinsic, and endoplasmic reticulum-associated apoptotic pathways. Pretreatment of cells with PFT-alpha followed by Dox administration attenuated Dox-induced increases in p53 levels and p53 binding activity and partially blocked the activation of p46/p54JNK and p42/p44ERK. PFT-alpha also led to decreased levels of caspases-2, -3, -8, -9, -12, Fas, PARP, cytochrome c release, and apoptosis. Our results suggest that p53 stabilization is a focal point of Dox-induced apoptosis and that PFT-alpha interferes with multiple steps of Dox-induced apoptosis.
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PMID:Multiple actions of pifithrin-alpha on doxorubicin-induced apoptosis in rat myoblastic H9c2 cells. 1668 11

The 14-3-3sigma gene is a direct target of the p53 tumor suppressor and its product inhibits cell cycle progression. Recently, a proteomic analysis revealed that 14-3-3sigma regulates additional cellular processes relevant to carcinogenesis, as migration and MAP-kinase signalling. The expression of 14-3-3sigma is down-regulated by CpG methylation in several types of human cancer, among them prostate, lung, breast and several types of skin cancer. The epigenetic inactivation of 14-3-3sigma occurs at an early stage of tumor development and may allow evasion from senescence and promote genomic instability. In the future the detection of CpG methylation of 14-3-3sigma may be used for diagnostic and prognostic purposes.
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PMID:Epigenetic silencing of 14-3-3sigma in cancer. 1669 81


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