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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis plays an essential role in atherosclerosis. Oxidized low-density lipoproteins (oxLDL) and activated T lymphocytes are present in atherosclerotic lesions, and we have previously reported that oxLDL induce apoptosis of activated T lymphocytes. We now show that this is preceded by an increase of Fas and FasL expression. Fas and FasL overexpression was dependent on reactive oxygen species (ROS) production as well as ERK and JNK activation. In addition, oxLDL triggered an early production of soluble FasL by T lymphocytes. Blocking anti-Fas antibody or Fas-Fc protein, but also antioxidant molecules and inhibitors of ERK and JNK, decreased oxLDL-mediated apoptosis. Moreover, PHA-activated murine lymphocytes lacking a functional Fas receptor were partially resistant to oxLDL. Finally, Jurkat T cells deficient for FADD, an adaptor protein required for Fas signaling, resisted oxLDL-induced apoptosis. OxLDL triggered caspase 8 and 3 activation as well as ceramide production in PHA-activated lymphocytes and in Jurkat cells. Caspase activation was completely impaired in FADD-deficient cells, but ceramide production was not affected. Altogether, our results highlight the putative role of both membrane-bound and soluble FasL in oxLDL-induced Fas and FADD-dependent apoptosis of T lymphocytes and suggest an involvement of ROS, ERK, and JNK in this process.
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PMID:Expression of membrane-bound and soluble FasL in Fas- and FADD-dependent T lymphocyte apoptosis induced by mildly oxidized LDL. 1463 Jul 9

The chemopreventive properties of the isothiocyanates have been attributed to their ability to inhibit phase I enzymes that activate procarcinogens, induce phase II protective enzymes and trigger apoptosis in transformed cells. In this study we provide evidence for a new mechanism of chemoprevention, wherein sublethal doses of phenethyl isothiocyanate (PEITC) sensitize cells to Fas-mediated apoptosis. The phenomenon was observed in the Fas-resistant T24 bladder carcinoma cell line and in Jurkat T cells overexpressing the anti-apoptotic protein Bcl-2. Caspase-3-like activity was increased up to 20-fold of that observed with either PEITC or anti-Fas antibody alone. While PEITC activated ERK, JNK and p38, inhibitors of these MAP kinases did not block apoptosis. PEITC transiently depleted cellular glutathione, providing a putative mechanism for sensitizing the cells to apoptosis. However, lowering glutathione with buthionine sulfoximine did not mimic the effect of PEITC. Instead, we propose that PEITC promotes apoptosis by directly modifying intracellular thiol proteins. The ability of PEITC to sensitize cells to receptor-mediated apoptosis provides an additional mechanism to explain its chemopreventive properties.
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PMID:The chemopreventive agent phenethyl isothiocyanate sensitizes cells to Fas-mediated apoptosis. 1472 92

Most of the commonly used cytotoxic anticancer drugs have been shown to induce apoptosis in susceptible cells. However, the signaling pathway of their apoptotic effects remains undefined. In this study, the cytotoxic effect of emodin on various human hepatoma cell lines was investigated. Results demonstrated that emodin exhibited strongly suppressing effect on HepG2/C3A, PLC/PRF/5, and SK-HEP-1 cells, with the IC(50) value of 42.5, 46.6, and 53.1 microM, respectively. Furthermore, emodin induced apoptosis in HepG2/C3A cells was clearly verified by the appearance of DNA fragmentation and sub-G(1) accumulation. Besides, HepG2/C3A cells were found to be arrested in G(2)/M phase after the cells were treated with 60 microM emodin for 48 h. Moreover, significant increase in the levels of apoptosis-related signals such as p53 (419.3 pg/ml), p21 (437.4 units/ml), Fas (6.6 units/ml), and caspase-3 (35.4 pmol/min) were observed in emodin treated HepG2/C3A cells. Taken together, emodin displays effective inhibitory effects on the growth of various human hepatoma cell lines and stimulates the expression of p53 and p21 that resulted in the cell cycle arrest of HepG2/C3A cells at G(2)/M phase. Results also suggest that emodin-induced apoptosis in HepG2/C3A cells were mediated through the activation of p53, p21, Fas/APO-1, and caspase-3. It implies that emodin could be a useful chemotherapeutical agent for treatment of hepatocellular carcinoma (HCC).
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PMID:Emodin-induced apoptosis through p53-dependent pathway in human hepatoma cells. 1498 52

The hepatocyte growth factor (HGF) receptor, encoded by the MET oncogene, is expressed in approximately 70% of human ovarian carcinomas and overexpressed in 30% of cases. Because HGF is known to protect cells from apoptosis, we investigated whether receptor expression modifies ovarian cancer cell response to chemotherapy. The apoptotic effect of the front-line chemotherapeutic drugs paclitaxel and cisplatin on cells treated with HGF was studied. In ovarian cancer cell lines, pretreatment with HGF surprisingly enhances the apoptotic response to low doses of paclitaxel and cisplatin. HGF empowers specifically the intrinsic apoptotic pathway, whereas it protects cells from extrinsic Fas-induced apoptosis. Chemotherapy sensitization is specific for HGF because another growth factor (e.g., epidermal growth factor) increases ovarian cancer cell survival. In nonovarian cancer cell models, as expected, HGF provides protection from drug-induced apoptosis. These data show that HGF sensitizes ovarian carcinoma cells to low-dose chemotherapeutic agents. This suggests that HGF may be used to improve response to chemotherapy in a set of human ovarian carcinomas molecularly classified based on the MET oncogene expression.
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PMID:Hepatocyte growth factor sensitizes human ovarian carcinoma cell lines to paclitaxel and cisplatin. 1499 35

Arsenic is a well established human carcinogen and is associated with a variety of cancers including those of the skin. Paradoxically, arsenic has also been used, amid at low doses, in the treatment of leukemia for over a century. Here we demonstrate that low to moderate concentrations of arsenite (2-10 microm) that has little or no effect on normal melanocytes may induce apoptosis of human melanomas including highly metastatic ones despite their low surface Fas levels. The two prerequisites that dictate apoptotic response of melanomas upon arsenite treatment are low nuclear NF-kappaB activity and an endogenous expression of tumor necrosis factor alpha. Under these conditions, melanoma cells acquired sensitivity to tumor necrosis factor alpha-mediated killing. On the other hand, signaling pathways including those of phosphatidylinositol 3-kinase-AKT, MEK-ERK, and JNK play a protective role against arsenite-induced oxidative stress and apoptosis in melanoma cells. Suppression of these pathways dramatically accelerates arsenite-induced apoptosis. Taken together, these data could provide potential approaches to sensitize melanomas to the cytotoxic effects of arsenite through modulating the signaling pathways.
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PMID:Arsenite sensitizes human melanomas to apoptosis via tumor necrosis factor alpha-mediated pathway. 1502 28

Synthetic analogs of 1,4-anthraquinone (AQ code number), a compound that mimics the antiproliferative effects of daunorubicin (daunomycin) in the nanomolar range in vitro but has the advantage of blocking nucleoside transport and retaining its efficacy in multidrug-resistant tumor cells, were tested for their ability to induce apoptosis in the HL-60 cell system. AQ10 and, especially, the new lead antiproliferative compounds AQ8 and AQ9 reduce the growth and integrity of wild-type, drug-sensitive, HL-60-S cells more effectively than AQ1, suggesting that various methyl group substituents at C6 may enhance the bioactivity of the parent compound. Internucleosomal DNA fragmentation, a late marker of apoptosis, is similarly induced in a biphasic manner by increasing concentrations of AQ8 and AQ9 at 24 hr. Poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, an early event required for cells committed to apoptosis, is detected within 3-6 hr in HL-60-S cells treated with AQ9. In accord with the fact that the caspases 9 and 3 cascade is responsible for PARP-1 cleavage, the activities of initiator caspase-9 and effector caspase-3 are induced by AQ9 in the same time- and concentration-dependent manners and to the same maximal degrees in both the HL-60-S and multidrug-resistant HL-60-RV cell lines. Interestingly, a 1-hr pulse treatment is sufficient for AQ8 and AQ9 to maximally induce caspase-9 and -3 activities at 6 hr. The release of mitochondrial cytochrome c (Cyt c) is also detected within 3-6hr in HL-60-S cells treated with AQ9, a finding consistent with the fact that Cyt c is the apoptotic trigger that activates caspase-9. Moreover, AQ analogs induce Cyt c release, caspase-9 and -3 activities and PARP-1 cleavage in relation with their abilities to decrease tumor cell growth and integrity, AQ8 and AQ9 being consistently the most effective. Since apical caspases 2 and 8 may both act upstream of mitochondria to promote Cyt c release, it is significant to show that AQ9 maximally induces caspase-2 and -8 activities at 6 and 9 hr, respectively. During AQ8 treatment, the caspase-2 inhibitor benzyloxycarbonyl (z)-Val-Asp-Val-Ala-Asp (VDVAD)-fluoromethyl ketone (fmk) totally blocks caspase-9, -3, and -8 activations, whereas the caspase-8 inhibitor z-Ile-Glu-Thr-Asp-(IETD)-fmk does not prevent caspase-2, -9, and -3 activations, suggesting that AQ-induced caspase-2 activity is an upstream event critical for the activation of the downstream caspases 9 and 3 cascade, including the mitochondrial amplification loop through caspase-8. However, these caspase-2 and -8 inhibitors fail to alter AQ8-induced Cyt c release, suggesting that AQs might also target mitochondria independently from caspase activation. Furthermore, the antagonistic anti-Fas DX2 and ZB4 monoclonal antibodies (mAbs), which block the induction of Cyt c release and caspase-2, -8, and -9 activities by the agonistic anti-Fas CH11 mAb, and the neutralizing anti-Fas ligand (FasL) NOK-1 mAb all fail to inhibit AQ9-induced Cyt c release and caspase-2, -8, and -9 activities, suggesting that the FasL/Fas signaling pathway is not involved in the mechanism by which antiproliferative AQ analogs trigger apoptosis in HL-60 cells.
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PMID:Synthetic 1,4-anthracenedione analogs induce cytochrome c release, caspase-9, -3, and -8 activities, poly(ADP-ribose) polymerase-1 cleavage and internucleosomal DNA fragmentation in HL-60 cells by a mechanism which involves caspase-2 activation but not Fas signaling. 1503 4

Airway epithelial cells are often the sites of targeted adenovirus vector delivery. Activation of the host inflammatory response and modulation of signal transduction pathways by adenovirus vectors have been previously documented, including activation of MAP kinases and phosphatidylinositol 3-kinase (PI3-kinase). The effect of activation of these pathways by adenovirus vectors on cell survival has not been examined. Both the PI3-kinase/Akt and ERK/MAP kinase signaling pathways have been linked to cell survival. Akt has been found to play a role in cell survival and apoptosis through its downstream effects on apoptosis-related proteins. Constitutive activation of either PI3-kinase or Akt blocks apoptosis induced by c-Myc, UV radiation, transforming growth factor-beta, Fas, and respiratory syncytial virus infection. We examined the effect of adenovirus vector infection on activation of these prosurvival pathways and its downstream consequences. Airway epithelial cells were transduced with replication-deficient adenoviral vectors containing a nonspecific transgene, green fluorescent protein driven by the cytomegalovirus promoter, or an empty vector with no transgene. They were then exposed to the proapoptotic stimulus actinomycin D plus TNF-alpha, and evidence of apoptosis was evaluated. Compared with the cells treated with actinomycin/TNF alone, the adenovirus vector-infected cells had a 50% reduction in apoptosis. When we examined induction of the prosurvival pathways, ERK and AKT, in the viral vector-infected cells, we found that there was significant activation of both Akt and ERK.
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PMID:Adenovirus vectors activate survival pathways in lung epithelial cells. 1510 95

Neutrophils represent an important line of innate host defence against invading microorganisms and their functional detriment during HIV infection, including accelerated spontaneous cell death, has been shown to contribute to AIDS development. Neutrophils are susceptible to apoptosis via Fas and an interaction between Fas and FasL was suggested originally as a mechanism to explain constitutive neutrophil apoptosis. We have explored some intracellular pathways leading to PMN apoptosis from 28 HIV-infected patients and 24 healthy volunteers. As previously reported, accelerated spontaneous apoptosis was observed in HIV+ patients, but this did not correlate with viral load. Furthermore, an increase in the level of spontaneous apoptosis was detected in neutrophils from HIV-infected patients following inhibition of ERK, suggesting an impairment of this kinase pathway during the early stages of infection which may contribute to PMN dysfunction. An elevated susceptibility to undergo apoptosis was observed following cross-linking of Fas, which correlated both with viral load and co-expression of Fas/FasL surface molecules. Different mechanisms for spontaneous and Fas-induced apoptosis are proposed which together contribute to the neutropenia and secondary infections observed during the progression to AIDS.
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PMID:Increased Fas-mediated apoptosis in polymorphonuclear cells from HIV-infected patients. 1519 58

The INK4A/ARF locus on chromosome 9 is a tumor suppressor gene frequently mutated in human cancers. In order to study the effects of p14ARF expression in tumor cells, we constructed a recombinant adenovirus containing p14ARF cDNA (Adp14ARF). Adp14ARF infection of U2OS osteosarcoma cells which has wild type p53 and mutant p14ARF revealed high levels of p14 (ARF) expression within 24h. In addition, Adp14ARF-mediated expressing of p14 (ARF) was associated with increased levels of p53, p21, and mdm2 protein. Growth inhibition assays following Adp14ARF infection demonstrated that the growth of U2OS cells was inhibited relative to infection with control virus. Furthermore, TUNEL analysis as well as PARP cleavage assays demonstrated that Adp14ARF infection was associated with increased apoptosis in U2OS cell line and that it was associated with Adp14ARF induced overexpression of Fas and Fas-L. Addition of Fas-L neutralizing antibody NOK-1 decreased Adp14-mediated cell death, indicating that p14 (ARF) induction of the Fas pathway is associated with increased apoptosis. The finding that Adp14ARF infection did not induce Fas expression in U2OS/E6 and MCF/E6 cells suggests that wild type p53 expression may be necessary for Adp14ARF-mediated induction of Fas. The observation that overexpression of p53 by Adp53 infection in MCF-7 does not induce increased Fas protein levels nor apoptotic cell death suggests that p53 overexpression is required but not sufficient enough for apoptosis. These studies suggest there are other mechanisms other than induction of p53 in ARF-mediated apoptosis and gene therapy using Adp14ARF may be a promising treatment option for human cancers containing wild type p53 and mutant or deleted p14 expression.
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PMID:Apoptosis induced by adenovirus-mediated p14ARF expression in U2OS osteosarcoma cells is associated with increased Fas expression. 1520 13

A properly functioning immune system is dependent on programmed cell death/apoptosis at virtually every stage of lymphocyte development and activity. Carbon monoxide (CO), an enzymatic product of heme oxyenase-1, has been shown to possess anti-apoptotic effects in a number of different model systems. The purpose of the present study was to expand on this knowledge to determine the role of CO in the well established model of Fas/CD95-induced apoptosis in Jurkat cells, and to determine the mechanism by which CO can modulate T-cell apoptosis. Exposure of Jurkat cells to CO resulted in augmentation in Fas/CD95-induced apoptosis, which correlated with CO-induced up-regulation of the pro-apoptotic protein FADD as well as activation of caspase-8, -9, and -3 while simultaneously down-regulating the anti-apoptotic protein BCL-2. These effects of CO were lost with overexpression of the small interfering RNA of FADD. CO, as demonstrated previously in endothelial cells, was also anti-apoptotic in Jurkat cells against tumor necrosis factor and etoposide. We further demonstrate that this pro-apoptotic effect of CO was independent of reactive oxygen species production and involved inhibition in Fas/CD95-induced activation of the pro-survival ERK MAPK. We conclude that in contrast to other studies showing the anti-apoptotic effects of CO, Fas/CD95-induced cell death in Jurkat cells is augmented by exposure to CO and that this occurs in part via inhibition in the activation of ERK MAPK. These data begin to elucidate specific differences with regard to the effects of CO and cell death pathways and provide important and valuable insight into potential mechanisms of action.
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PMID:Carbon monoxide promotes Fas/CD95-induced apoptosis in Jurkat cells. 1528 Mar 87


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