Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00369 (ROS)
 19,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interstitial collagenases participate in the remodeling of skeletal matrix and are regulated by fibroblast growth factor (FGF). A 0.2-kb fragment of the proximal human interstitial collagenase [matrix metalloproteinase (MMP1)] promoter conveys 4- to 8-fold induction of a luciferase reporter in response to FGF2 in MC3T3-E1 osteoblasts. By 5'-deletion, this response maps to nucleotides -100 to -50 relative to the transcription initiation site. The 63- bp MMP1 promoter fragment -123 to -61 confers this FGF2 response on the rous sarcoma virus minimal promoter. Intact Ets and AP1 cognates in this element are both required for responsiveness. The AP1 site supports basal and FGF-inducible promoter activity. The intact Ets cognate represses basal transcriptional activity in both heterologous and native promoter contexts and is also required for FGF activation. FGF2 up-regulates a DNA-binding activity that recognizes the MMP1 AP1 cognate and contains immunoreactive Fra1 and c-Jun. Both constitutive and FGF-inducible DNA-binding activities are present in MC3T3-E1 cells that recognize the MMP1 Ets cognate; prototypic Ets transcriptional activators are not present in these complexes. Inhibitors of protein kinase C, phosphatidyl inositol 3-OH kinase, and calmodulin-dependent protein kinase do not attenuate MMP1 promoter activation. FGF2 activates ERK1/ERK2 signaling in osteoblasts; however, 25 microM MAPK-ERK kinase (MEK) inhibitor PD98059 (inhibits by > 85% the phosphorylation of ERK1/ERK2) has no effect on MMP1 promoter activation by FGF2. Ligand-activated and constitutively active FGF receptors initiate MMP1 induction. Dominant negative Ras abrogates MMP1 induction by constitutively active FGFR2-ROS, but dominant negative Rho and Rac do not inhibit induction. The mitogen-activated protein kinase (MAPK) phosphatase MKP2 [inactivates extracellular regulated kinase (ERK) = Jun N-terminal kinase (JNK) > p38 MAPK] completely abrogates MMP1 activation, whereas PAC1 (inactivates ERK = p38 > JNK) attenuates but does not completely prevent induction. Thus, a Ras- and MKP2-regulated MAPK pathway, independent of ERK1/ERK2 MAPK activity, mediates FGF2 transcriptional activation of MMP1 in MC3T3-E1 osteoblasts, converging upon the bipartite Ets-AP1 element. The DNA-protein interactions and signal cascades mediating FGF induction of the MMP1 promoter are distinct from two other recently described FGF response elements: the MMP1 promoter (-123 to -61) represents a third FGF-activated transcriptional unit.
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PMID:Fibroblast growth factor receptor signaling activates the human interstitial collagenase promoter via the bipartite Ets-AP1 element. 921 60

Nuclear factor-kappaB (NF-kappaB) activity affects cell survival in ROS 17/2.8 osteoblasts. Preventing NF-kappaB transcription activity with a potent NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), results in apoptosis. Thus, we explored the effect of pyrrolidine dithiocarbamate (PDTC), which potently blocks the activation of nuclear factor-kappaB (NF-kappaB) in serum-exposed condition, on the activation of mitogen activated protein kinase (MAPK), especially, JNK/SAPK and p38 MAPK induction. PDTC transiently increased the phosphotransferase activity of c-Jun N-terminal Kinase1 (JNK1), which might in turn activates transcriptional activity of activating protein-1 (AP-1). The activation of JNK was completely decreased in dominant negative JNK1 transfected cells and the PDTC-induced cell death was attenuated in these cells. In addition, AP-1 activation was decreased in the JNK1 transfected cells, compared with vector-transfected cells. The NF-kappaB inhibitor also transiently activates p38 MAPK but SB203580, a specific p38 MAPK inhibitor, does not have any regulatory effect on PDTC-induced cell death, suggesting that the cell death is mediated by JNK not by p38 MAPK. Thus, overall, these results show that PDTC induces apoptosis and suggest that JNK/SAPK and subsequent AP-1 activation may be involved in the apoptotic pathway in ROS 17/2.8 osteoblasts.
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PMID:Pyrrolidine dithiocarbamate inhibits serum-induced NF-kappaB activation and induces apoptosis in ROS 17/2.8 osteoblasts. 1136 Sep 27

A previous study has shown that UV activates the PI3K/AKT cell survival pathway while inducing cell death in human skin in vivo and cultured human keratinocytes in vitro, and yet the upstream pathway leading to the activation of AKT has not been thoroughly investigated. In this study we found that UV-induced phosphorylation of p38 and AKT in a time-dependent manner. The phosphorylation of p38 started at 5 min post UV irradiation, peaked at about 30 min, and remained elevated up to 2 h. The phosphorylation of AKT started at 15 min post UV treatment, peaked at about 1 h, and remained elevated up to 2 h. We also found that H2O2 induced phosphorylation of p38 and AKT in a time- dependent manner. Pretreatment with NAC abolished UV-induced AKT phosphorylation, suggesting the involvement of reactive oxygen species in AKT activation. Interestingly, SB203085, a known p38 inhibitor, had partially inhibited UV-induced AKT phosphorylation. Further studies showed that cytokines such as TNF-alpha and IL-1beta induced AKT phosphorylation in a time-dependent manner. Pretreatment with SB203085 inhibited IL-1beta-induced p38 and AKT phosphorylation. Collectively, our data suggest that UV activation of PI 3-kinase/AKT pathway is initiated by ROS and prolonged by feedback activation of p38 induced by released cytokines in response to UV irradiation in cultured human keratinocytes.
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PMID:Cytokine-induced p38 activation feedback regulates the prolonged activation of AKT cell survival pathway initiated by reactive oxygen species in response to UV irradiation in human keratinocytes. 1160 9

Redox and ROS regulation of MAPK-mediated TNF-alpha biosynthesis is not well characterized. It was hypothesized that the involvement of the MAPK pathway in regulating LPS-mediated TNF-alpha secretion is redox-dependent, NF-kappaB-sensitive and attenuated by N-acetyl-L-cysteine (NAC) and other antioxidants. In alveolar epithelial cells, LPS induced a time- and dose-dependent phosphorylation of MAPK(p38). This was associated with the activation of MAPK-activated protein kinase, which phosphorylated the small heat-shock protein, Hsp27. MAPK(p38) inhibition (SB-203580) abrogated LPS-induced TNF-alpha production. MAPK(ERK) blockade (PD-98059) attenuated TNF-alpha secretion, an effect synergistically amplified in the presence of SB-203580. Regulation of NF-kappaB by selective inhibitors revealed that this pathway is partially involved in regulating LPS-mediated TNF-alpha secretion. Whereas the proteasome inhibitor, MG-132, had no effect on LPS-mediated TNF-alpha production, CAPE, sulfasalazine and SN-50, a cell-permeant NF-kappaB inhibitor, attenuated but did not abrogate TNF-alpha biosynthesis. LPS up-regulated ROS, an effect abrogated by 4'-hydroxy-3'-methoxy-acetophenone and NAC, which reduced TNF-alpha secretion, induced the accumulation of GSH, reduced the concentration of GSSG, and blockaded the phosphorylation/activation of MAPK(p38) pathway. ROS induced MAPK(p38) phosphorylation and selective antioxidants, including the permeant GSH precursor, gamma-GCE, reduced ROS-dependent MAPK(p38) phosphorylation. These results indicate that the MAPK pathway and MAPK-mediated regulation of TNF-alpha production is redox-dependent, GSH-mediated and requires, at least in part, a NF-kappaB/ROS-sensitive mechanism.
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PMID:Redox/ROS regulation of lipopolysaccharide-induced mitogen-activated protein kinase (MAPK) activation and MAPK-mediated TNF-alpha biosynthesis. 1181 88

The present study investigated the differential requirement of ROS in UV-induced activation of these pathways. Exposure of the mouse epidermal C141 cells to UV radiation led to generation of ROS as measured by electron spin resonance (ESR) and by H2O2 and O2. fluorescence staining assay. Treatment of cells with UV radiation or H2O2 also markedly activated Erks, JNKs, p38 kinase and led to increases in phosphorylation of Akt and p70(S6k) in mouse epidermal JB6 cells. The scavenging of UV-generated H2O2 by N-acety-L-cyteine (NAC, a general antioxidant) or catalase (a specific H2O2 inhibitor) inhibited UV-induced activation of JNKs, p38 kinase, Akt and p70(S6k), while it did not show any inhibitory effects on Erks activation. Further, pretreatment of cells with sodium formate (an .OH radical scavenger) or superoxide dismutase (O2-. radical scavenger) did not inhibit any of these pathways. These results demonstrate that H2O2 generation is required for UV-induced phosphorylation of Akt and p70(S6k), and involved in activation of JNKs and p38 kinase, but not Erks.
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PMID:Differential role of hydrogen peroxide in UV-induced signal transduction. 1216 63

Extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK/SAPK), and p38 mitogen-activated protein kinase (MAPK) were all rapidly activated in a ROS-dependent manner during 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ)-mediated oxidative stress and oncotic cell death in renal proximal tubule epithelial cells (LLC-PK1). TGHQ-induced phosphorylation of ERK1/2 and JNK MAPKs required epidermal growth factor receptor (EGFR) activation, whereas p38 MAPK activation was EGFR independent. In contrast to their established roles in cell survival, TGHQ-activated ERK1/2 and p38 MAPK (but not JNK) appear to contribute to cell death, since inhibition of ERK1/2 or p38 MAPKs with PD098059 or SB202190 respectively, attenuated TGHQ-mediated cell death. TGHQ increased AP-1 and NFkappaB DNA-binding activity, but whereas pharmacological inhibition of ERK1/2 or p38 MAPKs attenuated AP-1 DNA binding activity, it potentiated TGHQ-mediated NFkappaB activation. Consistent with a role for NFkappaB activation in the cytoprotective response to ROS in renal epithelial cells, an anti-NFkappaB peptide SN50 suppressed the protective effects of ERK inhibition (PD098059 treatment). The data provide evidence that the activation of MAPKs by ROS in renal epithelial cells plays an important role in oncotic cell death, and NF-kB is involved in the cytoprotective effects of PD098059.
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PMID:Mitogen-activated protein kinases contribute to reactive oxygen species-induced cell death in renal proximal tubule epithelial cells. 1248 47

Trichothecene mycotoxins cause immunosuppression by inducing apoptosis in lymphoid tissue. Trichothecene-induced leukocyte apoptosis can be augmented by bacterial lipopolysaccharide (LPS) but the mechanisms involved in this potentiating effect are not completely understood. The objective of this study was to test the hypothesis that the trichothecene deoxynivalenol (DON, vomitoxin) can interact with LPS directly and other mediators or agonists associated with immune/inflammatory responses to induce apoptosis in primary murine leukocyte cultures. Primary leukocyte suspensions were prepared from murine thymus (TH), spleen (SP), bone marrow (BM) and Peyer's patches (PP) and then cultured with DON in the absence or presence of LPS, prostaglandin E2 (PGE2), anti-immunoglobulin (as antigen mimic), dexamethasone, Fas ligand, or TNF-alpha. Cytotoxicity and apoptosis were evaluated by MTT assay and morphologic assays, respectively. DON was found to inhibit LPS-induced proliferation and dexamethasone-induced apoptosis in SP cultures. In contrast, potentiation of DON-induced apoptosis and cytotoxicity was observed in BM cultures treated with anti-Fas and in TH cultures treated with TNF-alpha. When potentiation of DON-induced apoptosis by TNF-alpha was assessed using pharmacological inhibitors, generation of ROS, intracellular Ca2+, p38/SAPK, and caspase-3 activation were found to play roles. Taken together, these data demonstrate that LPS and its downstream mediators can interact with trichothecenes to modulate proliferative, cytotoxic and apoptotic outcomes in leukocytes in a tissue-specific manner.
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PMID:Potentiation of trichothecene-induced leukocyte cytotoxicity and apoptosis by TNF-alpha and Fas activation. 1459 25

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

A large number of studies have demonstrated the role of angiotensin II in cardiac preconditioning against ischemic reperfusion injury. Generally, angiotensin II is a detrimental factor for the heart, and its inhibition with an ACE inhibitor provides cardioprotection. This review provides an explanation for such paradoxical behavior of angiotensin II. Angiotensin II can potentiate the induction of the expression of a variety of redox-sensitive factors including p38 MAPK, JNK and Akt, IGF-IR, EGF-R, and HO-1 as well as redox-regulated genes and transcription factors such as NFkappaB. It becomes increasingly apparent that during the earlier phase, the heart attempts to adapt itself against the detrimental effects of angiotensin II by upregulating several cardioprotective genes and proteins. These genes and proteins are redox-regulated and the antioxidants or ROS scavengers block their expressions. Interestingly, an identical pattern of cardioprotective proteins and genes are expressed in the preconditioned heart, which are also inhibited with ROS scavengers. It is tempting to speculate that the induction of the expression of the redox-sensitive cardioprotective proteins is the results of adaptation of the heart against the oxidative stress resulting from angiotensin II; and preconditioning is the net result of harnessing its own protection during ischemic and/or oxidative stress through its ability to trigger redox signaling.
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PMID:Redox regulation of angiotensin II signaling in the heart. 1509 Feb 71

Tetrandrine, which is isolated from Chinese herb Stephania tetrandrae, possesses anti-inflammatory, immunosuppressive, and cytoprotective properties. Though it was previously shown that tetrandrine causes a G1 blockade and apoptosis in various cell types, however, the mechanism by which tetrandrine initiates apoptosis remains poorly understood. In present study, we investigated the mechanisms of apoptosis induced by tetrandrine in U937 leukemia cells. Tetrandrine inhibited U937 cell growth by inducing apoptosis. After treatment of U937 cells with tetrandrine (10microM) for 24h, alteration of cell morphology, chromatin fragmentation, cytochrome c release, and caspase activation were observed. Tetrandrine also induced early oxidative stress, which resulted in activation of JNK, but not ERK and p38 MAPK. A broad-spectrum caspase inhibitor and antioxidants significantly blocked tetrandrine-induced caspase-3 activation. However, inhibition of the JNK activity with SP600125 did not block tetrandrine-induced apoptosis. Tetrandrine-induced apoptosis of U937 cells also required activity of PKC-delta, because pretreatment with a specific PKC-delta inhibitor greatly blocked tetrandrine-induced caspase-3 activation. In addition, the apoptotic response to tetrandrine was significantly attenuated in dominant-negative PKC-delta transfected MCF-7 cells, suggesting that PKC-delta plays an important role in tetrandrine-induced apoptosis and can induce caspase activation. These results suggest that tetrandrine induces oxidative stress, JNK activation, and caspase activation. However, JNK activation by ROS is not involved in the tetrandrine-induced apoptosis. In addition, tetrandrine induces caspase-dependent generation of a catalytically active fragment of PKC-delta, and this fragment also appears to play a role in the activation of caspases.
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PMID:Tetrandrine-induced apoptosis is mediated by activation of caspases and PKC-delta in U937 cells. 1513 Jul 59


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