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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II) exerts contractile and trophic effects in glomerular mesangial cells (MCs). One potential downstream target of Ang II is the protein kinase Akt/protein kinase B (PKB). We investigated the effect of Ang II on Akt/PKB activity in MCs. Ang II causes rapid activation of Akt/PKB (5-10 min) but delayed activation of phosphoinositide 3-kinase (PI3-K) (30 min). Activation of Akt/PKB by Ang II was not abrogated by the PI3-K inhibitors or by the introduction of a dominant negative PI3-K, indicating that in MCs, PI3-K is not an upstream mediator of Akt/PKB activation by Ang II. Incubation of MCs with phospholipase A2 inhibitors also blocked Akt/PKB activation by Ang II. AA mimicked the effect of Ang II. Inhibitors of cyclooxygenase-, lipoxyogenase-, and cytochrome P450-dependent metabolism did not influence AA-induced Akt/PKB activation. However, the antioxidants N-acetylcysteine and diphenylene iodonium inhibited both AA- and Ang II-induced Akt/PKB activation. Dominant negative mutant of Akt/PKB or antioxidants, but not the dominant negative form of PI3-K, inhibited Ang II-induced protein synthesis and cell hypertrophy. These data provide the first evidence that Ang II induces protein synthesis and hypertrophy in MCs through AA/redox-dependent pathway and Akt/PKB activation independent of PI3-K.
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PMID:Angiotensin II activates Akt/protein kinase B by an arachidonic acid/redox-dependent pathway and independent of phosphoinositide 3-kinase. 1153 71

Ultraviolet radiation (UVR) is known to affect a variety of cellular functions, including gene expression. A number of signaling pathways have been suggested to mediate these effects, including the participation of activator protein-1 (AP-1), activator protein-2 (AP-2) and nuclear factor-kappa B (NF-kappa B). The divergent results from previous studies could be explained, at least in part, by the source of UVR with different spectral characteristics as well as the type of cells employed as targets. In this study we have utilized UVA-340 as an energy source with output which closely matches the spectrum of natural sunlight over the range of 295-350 nm for irradiation of cultured fibroblasts. Combination of electrophoretic mobility shift assays and Northern analyses revealed activation of AP-1 but not NF-kappa B or AP-2. Inhibition studies further suggested the participation of protein kinase-C, but not protein kinase-A, and that an inhibitor of mitogen-activated protein kinase (MEK-1/2) did not alter the AP-1 activation. Free radical quenchers, sodium azide and N-acetylcysteine, did not affect the AP-1 binding activity. Finally, UVA-340 was shown to enhance transcriptional expression of the type-VII collagen gene (COL7A1), which is endogenously expressed in dermal fibroblast in an AP-1 dependent manner. Introduction of a mutation into the AP-1 site of the COL7A1 promoter abolished this activation. Thus, our results obtained by utilizing a novel energy source, UVA-340, mimicking natural sunlight at UVB and lower UVA range indicate a role for AP-1 in mediating the enhanced gene expression by UVR. Collectively, these results suggest that AP-1 is an important mediator of UVR action in fibroblasts.
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PMID:UVA-340 as energy source, mimicking natural sunlight, activates the transcription factor AP-1 in cultured fibroblasts: evidence for involvement of protein kinase-C. 1154 66

The cytotoxic side effects of anti-neoplastic drugs are increased in patients with either type 1 or type 2 diabetes mellitus by a mechanism that is not clearly defined. We report that the circulating glucose metabolite, methylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cdelta (PKCdelta). We found that treatment of myeloma cells with the antioxidant N-acetylcysteine completely blocked cisplatin-dependent intracellular GSH oxidation, reactive oxygen species (ROS) generation, poly(ADP-ribose) polymerase cleavage, and apoptosis. Importantly, co-treatment of cells with the reactive carbonyl MGO and cisplatin increased apoptosis by 90% over the expected additive effect of combined MGO and cisplatin treatment. This same synergism was also observed when ROS generation was examined. MGO and cisplatin increased PKCdelta activity by 4-fold, and this effect was blocked by the PKCdelta inhibitor rottlerin but not by NAC. Furthermore, rottlerin blocked combined MGO and cisplatin-induced ROS generation and apoptosis. Finally, MGO and cisplatin induced c-Abl activation and c-Abl:PKCdelta association. Rottlerin blocked c-Abl activation, but the c-Abl inhibitor STI-571 increased MGO and cisplatin-induced apoptosis by 50%. Taken together these data indicate that MGO synergistically enhances cisplatin-induced apoptosis through activation of PKCdelta and that PKCdelta is critical to both cell death and cell survival pathways. These findings suggest that in the patient with diabetes mellitus heightened oxidative stress can enhance the cytotoxicity of agents that induce DNA damage.
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PMID:Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase Cdelta. 1170 30

Culture of an H-2(s)-restricted, bovine myelin basic protein (BMBP)-specific murine Th1 clone with the adenyl cyclase agonist forskolin (FSK) or isobutylmethylxanthine (IBMX), an inhibitor of cAMP catabolism, before culture with anti-CD3 or BMBP and antigen-presenting cells (APC) suppressed antigen or anti-CD3-induced proliferation and production of interferon-gamma (IFN-gamma). Other H-2(s)-derived or H-2(b)-derived clones specific for BMBP or keyhole limpet hemocyanin (KLH) were similarly affected. FSK did not affect the expression of CD4 or the T cell receptor (TCR) but did diminish levels of the phosphorylated (activated) mitogen-activated protein (MAP) kinases early response kinase-1 (ERK-1) and ERK-2. Immunoblotting of lysates from an FSK-treated Th1 clone with antibodies to a carboxy-terminal epitope of p56(lck), a signal transduction enzyme upstream from ERK-1 and ERK2, did not detect p56(lck) unless the lysates were reduced prior to electrophoresis. Immunoblotting of nonreduced lysates with antibodies to an amino-terminal epitope demonstrated p56(lck) with a lower apparent molecular weight, characteristic of oxidized proteins. Reduction restored the detection of p56(lck) by anticarboxy-terminal p56(lck) and to mobilities indistinguishable from controls detected by the antiamino-terminal p56(lck). N-acetylcysteine or catalase prevented FSK-induced suppression of antigen-induced proliferation and the loss of carboxy-terminal epitopes of p56(lck). An inhibitor of cAMP-dependent protein kinase A (PKA) or nitric oxide synthase (NOS) did not affect FSK-induced inhibition of antigen-induced proliferation. In contrast, inhibitors of PKA or NOS, but not catalase, prevented FSK-induced suppression of IFN-gamma production. Moreover, immunoblots of lysates precipitated with anti-p56(lck), phosphotyrosine, or CD4 demonstrated that in FSK-treated, anti-CD3-stimulated cells, p56(lck) is not associated with CD4 zeta chain, nor is p56(lck) or zeta chain phosphorylated. In vitro kinase assays demonstrated that p56(lck) from FSK-treated cells does not have kinase activity. Taken together, the results suggest that an elevation of intracellular cAMP (in the absence of antigen) creates an oxidative environment that oxidizes and inactivates p56(lck) by an H(2)O(2)-dependent, PKA-independent mechanism and inhibits the production of IFN-gamma by an NO, PKA-dependent mechanism. Thus, antigen-induced proliferation and IFN-gamma production in a Th1 clone are controlled separately by different cAMP-dependent, redox-based mechanisms.
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PMID:Differential regulation of T cell receptor-mediated Th1 cell IFN-gamma production and proliferation by divergent cAMP-mediated redox pathways. 1171 Sep 91

In NIH3T3 cells, sphingosine-1-phosphate (S1P) caused a significant increase of Raf-1 kinase activity as early as 2 min. Interestingly, choline phosphate (ChoP) produced synergistic increase of S1P-stimulated Raf-1 kinase activation in the presence of ATP while showing additive effect in the absence of ATP. However, Raf-1 kinase activation induced by S1P decreased in the presence of ATP when applied alone. The overexpression of N-terminal fragment of Raf-1 (RfI) to inhibit Raf--Ras interaction caused the inhibition of S1P-induced Raf-1 kinase activation. Also, wortmannin, phosphatidylinositol-3-kinase (PI3K) inhibitor, exhibited inhibitory effects on S1P-induced activation of Raf-1 kinase. In addition, we demonstrated that the chemical antioxidant, N-acetylcysteine attenuated Raf-1 activation induced by S1P, suggesting that H(2)O(2) may be required for the signalling pathway leading to Raf-1 activation. This H(2)O(2)-induced Raf-1 kinase activation was also blocked by inhibition of Ras--PI3K signalling pathway using alpha-hydroxyfarnesylphosphonic acid and wortmannin. Taken together, these results indicate that S1P-induced Raf-1 kinase activation is mediated by H(2)O(2) stimulation of Ras--PI3K pathway, and is enhanced by ChoP in the presence of ATP.
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PMID:Choline phosphate potentiates sphingosine-1-phosphate-induced Raf-1 kinase activation dependent of Ras--phosphatidylinositol-3-kinase pathway. 1185 45

An elevated blood level of tumor necrosis factor (TNF)-alpha is a validated marker of vascular inflammation, which can result in the development of vascular disease and atherosclerosis. This study examined the hypothesis that ketosis increases the TNF-alpha secretion, both in a cell culture model using U937 monocytes and in type 1 diabetic patients in vivo. U937 cells were cultured with ketone bodies (acetoacetate [AA] and beta-hydroxybutyrate [BHB]) in the presence or absence of high levels of glucose in medium at 37 degrees C for 24 h. This study demonstrates the following points. First, hyperketonemic diabetic patients have significantly higher levels of TNF-alpha than normoketonemic diabetic patients (P < 0.01) and normal control subjects (P < 0.01). There was a significant correlation (r = 0.36, P < 0.05; n = 34) between ketosis and oxidative stress as well as between oxidative stress and TNF-alpha levels (r = 0.47, P < 0.02; n = 34) in the blood of diabetic patients. Second, ketone body AA treatment increases TNF-alpha secretion, increases oxygen radicals production, and lowers cAMP levels in U937 cells. However, BHB did not have any effect on TNF-alpha secretion or oxygen radicals production in U937 cells. Third, exogenous addition of dibutyryl cAMP, endogenous stimulation of cAMP production by forskolin, and antioxidant N-acetylcysteine (NAC) prevented stimulation of TNF-alpha secretion caused by AA alone or with high glucose. Similarly, NAC prevented the elevation of TNF-alpha secretion and lowering of cAMP levels in H(2)O(2)-treated U937 cells. Fourth, the effect of AA on TNF-alpha secretion was inhibited by specific inhibitors of protein kinase A (H89), p38-mitogen-activated protein kinase (SB203580), and nuclear transcription factor (NF)kappaB (NFkappaB-SN50). This study demonstrates that hyperketonemia increases TNF-alpha secretion in cultured U937 monocytic cells and TNF-alpha levels in the blood of type 1 diabetic patients and is apparently mediated by AA-induced cellular oxidative stress and cAMP deficiency.
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PMID:Hyperketonemia increases tumor necrosis factor-alpha secretion in cultured U937 monocytes and Type 1 diabetic patients and is apparently mediated by oxidative stress and cAMP deficiency. 1208 62

We investigated the expression, activation and autophosphorylation of apoptosis signal-regulating kinase 1 (ASK1) in rat hippocampus after cerebral ischemia. The in vitro kinase assay showed that ASK1 activity gradually increased while the autophosphorylation of ASK1 gradually reduced during 5, 15 and 30 min of cerebral ischemia. At various time points of reperfusion, the activation and autophosphorylation of ASK1 reached a high point at 30 min and reduced to basal level at 6 h and then slightly increased at 3 d compared with sham operation. Both of the increases of ASK1 activation and autophosphorylation were suppressed by N-acetylcysteine, a well-known antioxidant, which was administered to the Sprague-Dawley rat 20 min before cerebral ischemia. Immunoprecipitation and Western blotting assay showed that there was no obvious change in the amount of ASK1 at each time point compared with sham control. Our results suggest that ASK1 protein which is known as an upstream mediator of JNK/p38 mitogen-actived protein kinase (MAPK) activation may play an important role in signal transduction in response to ischemic stress, given the fact that activation of JNK/p38 MAPK and subsequent phosphorylation of c-Jun are involved in the apoptotic pathway in cerebral ischemia.
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PMID:Activation and autophosphorylation of apoptosis signal-regulating kinase 1 (ASK1) following cerebral ischemia in rat hippocampus. 1216 19

In light of the emerging concept of a protective function of the mitogen-activated protein kinase (MAPK) pathway under stress conditions, we investigated the influence of the anthracycline daunorubicin (DNR) on MAPK signaling and its possible contribution to DNR-induced cytotoxicity. We show that DNR increased phosphorylation of extracellular-regulated kinases (ERKs) and stimulated activities of both Raf-1 and extracellular-regulated kinase 1 (ERK1) within 10 to 30 minutes in U937 cells. ERK1 stimulation was completely blocked by either the mitogen-induced extracellular kinase (MEK) inhibitor PD98059 or the Raf-1 inhibitor 8-bromo-cAMP (cyclic adenosine monophosphate). However, only partial inhibition of Raf-1 and ERK1 stimulation was observed with the antioxidant N-acetylcysteine (N-Ac). Moreover, the xanthogenate compound D609 that inhibits DNR-induced phosphatidylcholine (PC) hydrolysis and subsequent diacylglycerol (DAG) production, as well as wortmannin that blocks phosphoinositide-3 kinase (PI3K) stimulation, only partially inhibited Raf-1 and ERK1 stimulation. We also observed that DNR stimulated protein kinase C zeta (PKCzeta), an atypical PKC isoform, and that both D609 and wortmannin significantly inhibited DNR-triggered PKCzeta activation. Finally, we found that the expression of PKCzeta kinase-defective mutant resulted in the abrogation of DNR-induced ERK phosphorylation. Altogether, these results demonstrate that DNR activates the classical Raf-1/MEK/ERK pathway and that Raf-1 activation is mediated through complex signaling pathways that involve at least 2 contributors: PC-derived DAG and PI3K products that converge toward PKCzeta. Moreover, we show that both Raf-1 and MEK inhibitors, as well as PKCzeta inhibition, sensitized cells to DNR-induced cytotoxicity.
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PMID:Protein kinase Czeta mediated Raf-1/extracellular-regulated kinase activation by daunorubicin. 1240 11

Human hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which often results in liver cirrhosis and hepatocellular carcinoma. The HCV RNA genome codes for at least ten proteins. The HCV non-structural protein 5A (NS5A) has generated considerable interest due to its effect on interferon sensitivity via binding and inactivating the cellular protein kinase, PKR. It has been shown that NS5A engages in the endoplasmic reticulum (ER)-nucleus signal transduction pathway. The expression of NS5A in the ER induces an ER stress ultimately leading to the activation of STAT-3 and NF-kappaB. This pathway is sensitive to inhibitors of Ca(2+) uptake in the mitochondria (ruthenium red), Ca(2+) chelators (TMB-8, EGTA-AM), and antioxidants (PDTC, NAC, Mn-SOD). The inhibitory effect of protein tyrosine kinase (PTK) inhibitors indicates the involvement of PTK in NF-kappaB activation by NS5A. This implicates an alternate pathway of NF-kappaB activation by NS5A. The actions of NS5A have also been studied in the context of an HCV subgenomic replicon inducing a similar intracellular event. Thus, activation of NF-kappaB leads to the induction of cellular genes, which are largely antiapoptotic in function. These studies suggest a potential function of NS5A in inducing chronic liver disease and hepatocellular carcinoma associated with HCV infection.
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PMID:Endoplasmic reticulum (ER) stress: hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3. 1241 55

Stress-activated protein kinase/extracellular signal-regulated kinase-1 (SEK1/MKK4) was examined in a rat model of global brain ischemia. Western blot assay showed that SEK1 activation was biphasic in CA1 but not CA3/dentate gyrus. The second activation peak (3 days after ischemia) was prevented by pretreatment with l-naphthyl acetyl spermine (Naspm), a channel blocker of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, or N-acetylcysteine (NAC), a free radical scavenger. Concomitantly, the late activation of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal protein kinase (JNK) was also prevented by Naspm or NAC. Moreover, phospho-SEK1 and phospho-JNK co-immunoprecipitated with ASK1 and the bindings peaked at 3 days of reperfusion. Together with previous results, these findings indicate that Ca(2+)-permeable AMPA receptors are important routes to mediate the late activation of ASK1-SEK1-JNK pathway involving oxidative stress in hippocampal CA1 region after ischemia.
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PMID:Biphasic activation of apoptosis signal-regulating kinase 1-stress-activated protein kinase 1-c-Jun N-terminal protein kinase pathway is selectively mediated by Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors involving oxidative stress following brain ischemia in rat hippocampus. 1252 69


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