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)

Heme oxygenase-1 (HO), the heat shock/stress cognate of the heat shock protein 32 (HSP32) family of proteins, is postulated to be a component of cellular defense mechanisms against oxidative stress-mediated injury. Nitric oxide (NO) is among the extensive array of stimuli that induce HO-1. The cellular signaling mechanisms that regulate the induction of HO-1 by NO are not understood. In the present study, we have demonstrated that exposure of HeLa cells to the NO donor, sodium nitroprusside (SNP), results in concentration and time-dependent increase in HO-1 mRNA and activation of MAPKs: ERK (ERK1 and ERK2) and p38 pathways, but not SAPK/JNK pathway. Pre-treatment of the cells with PD98059, a selective ERK pathway inhibitor, and SB203580, a p38 MAPK inhibitor, blocked the induction of HO-1 by the NO donor in a dose-dependent manner. In addition, an increase in HO-1 mRNA level that was detected as early as 2 hrs.following SNP treatment preceded c-jun and c-fos induction. These transcription factors are downstream of SAPK/JNK pathway, and their increased expression was detected at 3hr. and 6hr. after SNP treatment. Similarly, AP-1 DNA binding activity was not increased when measured 6 hrs. after SNP treatment. ERK and p38 inhibitors also suppressed induction of HO-1 by SNAP and GSNO. The increase in HO-1 mRNA was inhibited by actinomycin D and cycloheximide, but not by NAC, and was not mimicked by the lipophilic cGMP analogue, 8-bromo-cGMP, suggesting that NO-mediated induction required de novo RNA and protein synthesis and was unrelated to cGMP and redox signaling. Collectively, the findings suggest that MAP kinase ERK and p38 pathways are involved in the NO-mediated induction of HO-1 and that SAPK/JNK pathway and increased DNA binding of AP-1 transcription factor are not involved in HO-1 gene activation by NO. A plausible mechanism by which the NO donors cause HO-1 induction may involve HO-1 gene regulation by its substrate, heme.
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PMID:Nitric oxide induces heme oxygenase-1 via mitogen-activated protein kinases ERK and p38. 1087 47

The chelating and antioxidant effects of pyrrolidine dithiocarbamate (PDTC) have been investigated extensively for preventing cell death induced by different insults. However, the toxic effects of PDTC have been studied only recently and fewer studies on the toxic effects on astrocytes have been reported. In our study, we demonstrated that both PDTC and Cu(2+) alone were rated as only weakly toxic in inducing cell death in cortical astrocytes with IC(50) of 300 microM and 180 microM, respectively. However, PDTC and Cu(2+) in the complex form markedly potentiated with each other by about 1,000-fold with IC(50) of 0.3 microM PDTC plus 10 microM Cu(2+). Other metals at concentrations of 3-10 microM (VO(4)(5+), Cr(6+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Zn(2+), Pb(2+), Bi(2+), Ba(2+), UO(2+), Cs(+), SeO(4)(2-), La(3+)) had no such potentiating effects on PDTC. Changes in morphology (nuclear condensation), apoptotic body formation, and hypodiploidity of DNA suggested that the PDTC-Cu(2+) complex induced cell death through an apoptotic process. Further studies showed that the PDTC-Cu(2+) complex decreased mitochondrial membrane potential, increased hydrogen peroxide production, and depleted GSH contents. After the increased oxidative stress, PDTC-Cu(2+) complex differentially activated JNKs, ERK, p38 and caspase 3, which caused PARP degradation in a time-dependent manner. All these effects were consistent with the increased cellular Cu contents. The nonpermeable copper-specific chelator bathocuproine disulfonate (BCPS), but not the permeable Cu(2+) chelator neocuproine, abolished all the observed effects. Antioxidants (N-acetylcysteine [NAC], vitamin C), catalase, and Cu(2+)-binding proteins (albumin, hemoglobin, and higher serum) reduced the cytotoxic effects of PDTC-Cu(2+) complex. We concluded that the death signaling pathway of PDTC-Cu(2+) complex was mediated by oxidative stress and subsequent JNK activation. These findings imply that PDTC, a widely used pesticide and medicine that is capable of penetrating the blood-brain barrier, may cause neurotoxicity through astrocyte dysfunction.
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PMID:Death signaling pathway induced by pyrrolidine dithiocarbamate-Cu(2+) complex in the cultured rat cortical astrocytes. 1094 Nov 51

Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) hypertrophy, which results in several cardiovascular diseases. Ang II-induced cellular events have been mediated, in part, by reactive oxygen species (ROS) which also involve activation of mitogen-activated protein (MAP) kinases. Although it has been proposed that the therapeutic administration of antioxidants is useful for vascular diseases, the precise mechanisms which regulate ROS-sensitive signaling events have not been well characterized. Thus, we hypothesized that antioxidants may affect ROS-mediated MAP kinases activation induced by Ang II. The present findings showed that Ang II stimulated rapid and significant activation of ERK 1/2, JNK and p38 MAPK in cultured rat aortic smooth muscle cells (RASMC). Ang II-induced ERK 1/2 activation was not affected by all antioxidants examined, whereas JNK was sensitive to all antioxidants. In contrast, p38 MAPK activation was inhibited by DPI and ascorbic acid concentration-dependently, but by NAC only at high concentration. DETC and Trolox C had no effects on p38 MAPK activation by Ang II. We further examined the effects of antioxidants on Ang II-induced increases in oxygen consumption as an index of ROS generation in RASMC. DPI strongly inhibited Ang II-induced increases in oxygen consumption. DETC also inhibited Ang II-induced oxygen consumption, whereas ascorbic acid markedly augmented it. These findings suggest that the inhibitory effects of antioxidants on MAP kinases activation in VSMC are attributable, in part, to their modulating effects on ROS generation by Ang II in VSMC. Thus, inhibition of MAP kinases by antioxidants may imply their usefulness for relief of cardiovascular diseases.
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PMID:Antioxidants inhibit JNK and p38 MAPK activation but not ERK 1/2 activation by angiotensin II in rat aortic smooth muscle cells. 1140 48

In this study, we report the cloning and characterization of a novel human Ste20-related kinase that we designated MST4. The 416 amino acid full-length MST4 contains an amino-terminal kinase domain, which is highly homologous to MST3 and SOK, and a unique carboxy-terminal domain. Northern blot analysis indicated that MST4 is highly expressed in placenta, thymus, and peripheral blood leukocytes. Wild-type but not kinase-dead MST4 can phosphorylate myelin basic protein in an in vitro kinase assay. MST4 specifically activates ERK but not JNK or p38 MAPK in transient transfected cells or in stable cell lines. Overexpression of dominant negative MEK1 or treatment with PD98059 abolishes MST4-induced ERK activity, whereas dominant-negative Ras or c-Raf-1 mutants failed to do so, indicating MST4 activates MEK1/ERK via a Ras/Raf-1 independent pathway. HeLa and Phoenix cell lines overexpressing wild-type, but not kinase-dead, MST4 exhibit increased growth rate and form aggressive soft-agar colonies. These phenotypes can be inhibited by PD98059. These results provide the first evidence that MST4 is biologically active in the activation of MEK/ERK pathway and in mediating cell growth and transformation.
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PMID:MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway. 1164 81

Synucleins are small, highly conserved proteins in vertebrates, especially abundant in neurons and typically enriched in presynaptic terminals. alpha-Synuclein protein and a fragment of it, called NAC, have been found in association with pathological lesions of neurodegenerative diseases. Recently, mutations in a alpha-synuclein gene have been reported in families susceptible to an inherited form of Parkinson's diseases. In addition, alpha-synuclein has been implicated in the pathophysiology of other neurodegenerative diseases, including Alzheimer's disease and multiple system atrophy. Far less is known about other members of the synuclein family, beta- and gamma-synucleins. gamma-synuclein is up-regulated in several types of cancer and may affect the integrity of the neurofilament network, while its bovine ortholog, synoretin, activates the Elk-1 signal transduction pathway. In this paper, we present data about the localization and properties of human and bovine gamma-synuclein in several neuronal and non-neuronal cell cultures derived from ocular tissues. We show that gamma-synuclein is present in the perinuclear area and is localized to centrosomes in several types of human interphase cells and in bovine retinal pigment epithelium. In mitotic cells, gamma-synuclein staining is localized to the poles of the spindle. Further, overexpression of synoretin in retinoblastoma cells up-regulates MAPK and Elk-1. These results support the view that gamma-synuclein is a centrosome protein that may be involved in signal transduction pathways.
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PMID:Gamma synuclein: subcellular localization in neuronal and non-neuronal cells and effect on signal transduction. 1174 66

Lysophosphatidylcholine (lysoPC) acts on vascular smooth muscle cells (VSMCs) to produce a mitogenic response through the activation of extracellular signal-regulated kinases 1/2 (ERK1/2). In the present study, we examined the importance of reactive oxygen species (ROS) in lysoPC-stimulated ERK1/2 activation in cultured rat VSMCs. Treatment with lysoPC for 3 minutes caused a 2-fold increase in intracellular ROS that was blocked by the NADH/NADPH oxidase inhibitor, diphenylene iodonium (DPI). Antioxidants, N-acetyl-L-cysteine, glutathione monoester, or alpha -tocopherol, inhibited ERK1/2 activation by lysoPC. Almost identical results were obtained in the VSMC line A10. Pretreatment of VSMCs with DPI but not allopurinol or potassium cyanide (KCN) abrogated the activation of ERK1/2. The Flag-tagged p47phox expressed in A10 cells was translocated from the cytosol to the membrane after 2 minutes of stimulation with lysoPC. The overexpression of dominant-negative p47phox in A10 cells suppressed lysoPC-induced ERK activation. The ROS-dependent ERK activation by lysoPC seems to involve protein kinase C- and Ras-dependent raf-1 activation. Induction of c-fos expression and enhanced AP-1 binding activity by lysoPC were also inhibited by DPI and NAC. Taken together, these data suggest that ROS generated by NADH/NADPH oxidase contribute to lysoPC-induced activation of ERK1/2 and subsequent growth promotion in VSMCs.
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PMID:Lysophosphatidylcholine activates extracellular signal-regulated kinases 1/2 through reactive oxygen species in rat vascular smooth muscle cells. 1200 86

Previous studies indicated that antigen receptor (TcR) stimulation of mature T cells induced rapid generation of reactive oxygen species (ROS). The goal of the current study was to examine the role(s) of ROS in TcR signal transduction, with a focus upon the redox-sensitive MAPK family. TcR cross-linking of primary human T blasts and Jurkat human T cells rapidly activated the ERK, JNK, p38 and Akt kinases within minutes, and was temporally associated with TcR-stimulated production of hydrogen peroxide (H(2)O(2)). TcR-induced activation of ERK was selectively augmented and sustained in the presence of pharmacologic antioxidants that can quench or inhibit H(2)O(2) production (NAC, MnTBAP and Ebselen, but not DPI), while activation of JNK and Akt were largely unaffected. This was paralleled by concurrent changes in MEK1/2 phosphorylation, suggesting that ROS acted upstream of MEK-ERK activation. Molecular targeting of H(2)O(2) by overexpression of peroxiredoxin II, a thioredoxin dependent peroxidase, also increased and sustained ERK and MEK activation upon TcR cross-linking. Enhancement of ERK phosphorylation by antioxidants correlated with increased and sustained serine phosphorylation of the src-family kinase lck, a known ERK substrate. Thus, the data suggest that TcR-stimulated production of hydrogen peroxide negatively feeds back to dampen antigen-stimulated ERK activation and this redox-dependent regulation may serve to modulate key steps in TcR signaling.
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PMID:T cell receptor-stimulated generation of hydrogen peroxide inhibits MEK-ERK activation and lck serine phosphorylation. 1289 42

Effects of the tyrphostin tyrosine kinase inhibitor adaphostin (NSC 680410) have been examined in human leukemia cells (Jurkat, U937) in relation to mitochondrial events, apoptosis, and perturbations in signaling and cell cycle regulatory events. Exposure of cells to adaphostin concentrations > or =0.75 microM for intervals > or =6 h resulted in a pronounced release of cytochrome c and AIF, activation of caspase-9, -8, and -3, and apoptosis. These events were accompanied by the caspase-independent downregulation of Raf-1, inactivation of MEK1/2, ERK, Akt, p70S6K, dephosphorylation of GSK-3, and activation of c-Jun-N-terminal kinase (JNK) and p38 MAPK. Adaphostin also induced cleavage and dephosphorylation of pRb on CDK2- and CDK4-specific sites, as well as the caspase-dependent downregulation of cyclin D1. Inducible expression of a constitutively active MEK1 construct markedly diminished adaphostin-induced cytochrome c and AIF release, JNK activation, and apoptosis in Jurkat cells. Ectopic expression of Raf-1 or constitutively activated (myristolated) Akt also significantly attenuated adaphostin-induced apoptosis, but protection was less than that conferred by enforced activation of MEK. Lastly, antioxidants (e.g., L-N-acetylcysteine; L-NAC) opposed adaphostin-mediated mitochondrial dysfunction, Raf-1/MEK/ERK downregulation, JNK activation, and apoptosis. However, in contrast to L-NAC, enforced activation of MEK failed to block adaphostin-mediated ROS generation. Together, these findings demonstrate that the tyrphostin adaphostin induces multiple perturbations in signal transduction pathways in human leukemia cells, particularly inactivation of the cytoprotective Raf-1/MEK/ERK and Akt cascades, that culminate in mitochondrial injury, caspase activation, and apoptosis. They also suggest that adaphostin-related oxidative stress acts upstream of perturbations in these signaling pathways to trigger the cell death process.
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PMID:Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process. 1464 18

We have previously observed time- and dose-dependent increases in matrix metalloproteinase 2 (Mmp2) protein levels in rat tubule epithelial cells (NRK52E) after irradiation. However, the mechanism(s) involved remains unclear. In the present study, irradiating NRK52E cells with 0-20 Gy gamma rays was associated with time- and dose-dependent increases in Mmp2 mRNA. Studies using the transcription inhibitor actinomycin D (ActD) added 24 h after irradiation revealed the t(1/2) of Mmp2 mRNA to be approximately 8 h in control cells. In contrast, the increase in Mmp2 mRNA levels in irradiated cells was essentially unchanged after incubation with ActD for up to 12 h. Incubating cells with the antioxidants N-acetylcysteine or ebselen or the MEK pathway inhibitors PD98059 and U0126 prior to irradiation abolished the radiation-induced up-regulation of Mmp2. Irradiating NRK52E cells led to reactive oxygen species-mediated Erk1/2 activation; preincubation with NAC prevented the radiation-induced increase in phosphorylated Erk1/2. Transfecting cells with a dominant-negative ERK mutant completely inhibited radiation-induced Erk phosphorylation and abolished the radiation-induced up-regulation of Mmp2 protein. Thus the radiation-induced up-regulation of Mmp2 mRNA is due in part to increased mRNA stability and is mediated by redox; the ERK MAPK signaling pathway may be involved.
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PMID:Radiation-induced up-regulation of Mmp2 involves increased mRNA stability, redox modulation, and MAPK activation. 1503 70

TGF-beta produced by keratinocytes in response to UVB (290-320 nm) is a potential mediator for effects of acute and chronic solar radiation on skin. This study was designed to determine whether reactive oxygen species (ROS) mediate UVB-induced TGF-beta biosynthesis in keratinocytes and the subsequent activation of the latent TGF-beta complex. UVB irradiation elevated both total (latent plus active) and active TGF-beta in the keratinocyte supernatants, with a greater increase in the active form. UVB irradiation induced up to a 30% increase in ROS, and the ROS were detected up to 90 min after irradiation. NAC and Trolox, cytoplasmic ROS scavengers, abolished the UVB-induced TGF-beta and intracellular ROS, suggesting that UVB-induced ROS are involved in TGF-beta regulation. Inhibitors of NADPH oxidase activity, DPI and apocynin, decreased UVB-induced ROS. The increase in NADPH oxidase activity was mediated by EGFR activation. UVB-induced ROS also activated latent TGF-beta complex by stimulating MMP-2 and -9 activities. In summary, physiological doses of UVB increase intracellular ROS, which upregulate TGF-beta biosynthesis and activation of TGF-beta through increased activity of MMPs.
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PMID:Involvement of UVB-induced reactive oxygen species in TGF-beta biosynthesis and activation in keratinocytes. 1574 85


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