Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophages produce reactive oxygen species such as O2-, H2O2 and *OH that contribute to the pathogenesis of diseases such as inflammation and atherosclerosis. The cells have multiple defense systems against those reactive oxygen species, and we describe here such an oxidative stress-inducible defense system. Upon exposure to reactive oxygen species and electrophilic agents, murine peritoneal macrophages induce stress proteins to protect themselves. Using differential screening, we cloned two novel proteins designated MSP23 and A170 that are induced in the cells by low levels of reactive oxygen species, electrophilic agents and other oxidative stress agents. MSP23 is murine peroxiredoxin I having a thioredoxin peroxidase activity and A170 is known as an ubiquitin- and PKC xi-binding protein. In addition to these two proteins, heme oxygenase-1 (HO-1) and cystine transport activity are also induced in the cells under oxidative stress conditions. Using nrf2-deficient macrophages, we found that transcription factor Nrf2, which is known to interact with antioxidant responsive elements (AREs) in the regulatory sequences of the genes, plays an important role in the oxidative stress-inducible response in the cells.
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PMID:Oxidative stress-inducible proteins in macrophages. 1051 40

Peroxiredoxin I (Prx I) is an oxidative stress-inducible antioxidant protein with thioredoxin peroxidase activity. Here we report that the levels of Prx I mRNA and protein are dramatically increased in a murine osteoblast cell line, MC3T3-E1, by treatment with sodium arsenate. We further studied the signaling pathways that control the induction of Prx I expression. The treatment of osteoblasts with arsenate activated ERK1/2, JNK, and p38 MAPK. Pre-treating cells with inhibitors of p38 MAPK abolished the induction of Prx I protein but had minimal effect on the induction of Prx I mRNA, suggesting that p38 MAPK activity was required for post-transcriptional regulation. The inhibition of ERK1 and ERK2 had no effect on the induction of Prx I expression. Furthermore, rottlerin, an inhibitor of protein kinase Cdelta (PKCdelta) and calmodulin kinase III, abrogated the up-regulation at both protein and mRNA levels. Staurosporine and Go6983, inhibitors for PKC, also inhibited the induction of Prx I, suggesting that protein kinase Cdelta is required for the induction by arsenate. PKCdelta was activated by arsenate treatment by in vitro kinase assays. The inhibition of PKCdelta by rottlerin did not affect the activation of p38 MAPK by arsenate. These results suggest that there are two separate signaling pathways involved in the up-regulation of Prx I protein in response to arsenate, PKCdelta required for transcriptional activation and p38 MAPK required for post-transcriptional regulation.
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PMID:Pathways of induction of peroxiredoxin I expression in osteoblasts: roles of p38 mitogen-activated protein kinase and protein kinase C. 1179 22

Evidence from live cell bioassays shows that the flat mucosa from patients with colon cancer exhibits resistance to bile salt-induced apoptosis. Three independent cell lines derived from the colonic epithelial cell line HCT-116 were selected for resistance to bile salt-induced apoptosis. These cell lines were developed as tissue culture models of apoptosis resistance. Selection was carried out for resistance to apoptosis induced by sodium deoxycholate (NaDOC), the bile salt found in highest concentrations in human fecal water. Cultures of HCT-116 cells were serially passaged in the presence of increasing concentrations of NaDOC. The resulting apoptosis resistant cells were able to grow at concentrations of NaDOC (0.5 mM) that cause apoptosis in a few hours in unselected HCT-116 cells. These cells were then analyzed for changes in gene expression. Observations from cDNA microarray, 2-D gel electrophoresis/MALDI-mass spectroscopy, and confocal microscopy of immunofluorescently stained preparations indicated underexpression or overexpression of numerous genes at either the protein or mRNA level. Genes that may play a role in apoptosis and early stage carcinogenesis have been identified as upregulated in these cell lines, including Grp78, Bcl-2, NF-kappaB(p50), NF-kappaB(p65), thioredoxin peroxidase (peroxiredoxin) 2, peroxiredoxin 4, maspin, guanylate cyclase activating protein-1, PKCzeta, EGFR, Ras family members, PKA, PI(4,5)K, TRAF2 and BIRC1 (IAP protein). Under-expressed mRNAs included BNIP3, caspase-6, caspase-3 and serine protease 11. NF-kappaB was constitutively activated in all three resistant cell lines, and was responsible, in part, for the observed apoptosis resistance, determined using antisense oligonucleotide strategies. Molecular and cellular analyses of these resistant cell lines has suggested potential mechanisms by which apoptosis resistance may develop in the colonic epithelium in response to high concentrations of hydrophobic bile acids that are associated with a Western-style diet. These analyses provide the rationale for the development of hypothesis-driven intermediate biomarkers to assess colon cancer risk on an individual basis.
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PMID:Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. 1250 30

The antioxidant protein peroxiredoxin (Prx) I is a thioredoxin peroxidase that is involved in the regulation of proliferation and differentiation of mammalian cells. Here, it is shown that Prx I gene expression was induced transcriptionally by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in cultured rat liver tissue macrophages and RAW264.7 monocytic cells. TPA-dependent induction of Prx I gene expression was mediated by two proximal activator protein-1 sites of the rat Prx I promoter region that were nuclear targets of c-Jun as determined by transfection studies with luciferase reporter gene constructs and electrophoretic mobility shift assays. The transcription factor Nrf2, however, was not involved in the regulation of Prx I promoter activity. Prx I gene induction by TPA was decreased by protein kinase C inhibitors and overexpressed dominant negative forms of Ras and MEKK1, but not Raf-1. The p38 MAPK inhibitor SB202190 and overexpression of dominant negative mutants of MAPK kinase 4 (MKK4), MKK6, and p38 inhibited the TPA-dependent induction of Prx I gene transcription. In contrast, inhibitors of the JNK, SP600125, and the NF-kappaB signaling pathway, caffeic acid phenethyl ester, respectively, as well as overexpressed dominant negative MKK7 and IkappaB, had no effect on the up-regulation of Prx I reporter gene activity by TPA. Cotransfection of wild-type p38alpha and p38beta, but not that of p38gamma and p38delta, increased Prx I promoter activity. The data indicate that a protein kinase C, Ras, MEKK1, p38 MAPK signaling pathway plays a major role for the transcriptional up-regulation of Prx I gene expression.
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PMID:Phorbol ester-dependent activation of peroxiredoxin I gene expression via a protein kinase C, Ras, p38 mitogen-activated protein kinase signaling pathway. 1296 Jan 65

c-Abl and Atm have been implicated in cell responses to DNA damage and oxidative stress. However, the molecular mechanisms by which they regulate oxidative stress response remain unclear. In this report, we show that deficiency of c-Abl and deficiency of ATM differentially altered cell responses to oxidative stress by induction of antioxidant protein peroxiredoxin I (Prx I) via Nrf2 and cell death, both of which required protein kinase C (PKC) delta activation and were mediated by reactive oxygen species. c-abl-/- osteoblasts displayed enhanced Prx I induction, elevated Nrf2 levels, and hypersusceptibility to arsenate, which were reinstated by reconstitution of c-Abl; Atm-/- osteoblasts showed the opposite. These phenotypes correlated with increased PKC delta expression in c-abl-/- osteoblasts and decreased PKC delta expression in Atm-/- cells, respectively. The enhanced responses of c-abl-/- osteoblasts could be mimicked by overexpression of PKC delta in normal cells and impeded by inhibition of PKC delta, and diminished responses of Atm-/- cells could be rescued by PKC delta overexpression, indicating that PKC delta mediated the effects of c-Abl and ATM in oxidative stress response. Hence, our results unveiled a previously unrecognized mechanism by which c-Abl and Atm participate in oxidative stress response.
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PMID:Distinct roles of c-Abl and Atm in oxidative stress response are mediated by protein kinase C delta. 1528 56

ATP has been shown to mediate stress responses in the brain. The present study examined the ATP-stimulated stress protein expression of RBA-2 type-2 astrocytes. Our results revealed that ATP stimulated HSP60 expression in a dose- and time-dependent manner. The stimulation requires a minimal ATP concentration of 500 microM and high concentration of extracellular ATP (1 mM) stimulated a significant increase of HSP60 expression from 2 to 24 h. In addition, the ATP-stimulated HSP60 expressions were inhibited by inhibitors for protein kinase C (PKC) and phospholipase D (PLD), and by antioxidants, resveratrol, and catalase. Furthermore, ATP stimulated the expression of Cu/Zn superoxide dismutase (SOD). In addition, ATP and P2X7 receptor selective agonist BzATP also decreased mitochondria membrane potential measured by flow cytometry. To further examine the proteins involving in ATP-mediated stress responses, we conducted proteomic analysis. We found that RBA-2 astrocytes possess abundant peroxiredoxin II (Prx II), an antioxidant enzyme. ATP and exogenous H2O2 stimulated Prx II shifting from oxidized form to reduced form. Thus, we concluded that ATP potentiated the expression of HSP60 and Cu/Zn SOD, and decreased mitochondria membrane potential. In addition, RBA-2 astrocytes expressed Prx II that might also serve as a protective mechanism to control the concentration of reactive oxygen species.
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PMID:Elucidation of ATP-stimulated stress protein expression of RBA-2 type-2 astrocytes: ATP potentiate HSP60 and Cu/Zn SOD expression and stimulates pI shift of peroxiredoxin II. 1617 11

In a recent study, we described that UV-C irradiation resulted in redox-dependent activation and relocalization of A-SMase (acid sphingomyelinase) to the external surface of raft membrane microdomains, hydrolysis of SM (sphingomyelin) associated with the plasma membrane outer leaflet, ceramide generation and apoptosis. In the present study, we have investigated the influence of PKCzeta (protein kinase Czeta), an atypical form of PKC on this pathway. This study shows that PKCzeta overexpression resulted in the abrogation of UV-C-induced A-SMase translocation and activation into the raft microdomains, lack of ceramide generation and apoptosis inhibition. Moreover, PKCzeta overexpression resulted in a decrease in UV-C-induced ROS (reactive oxygen species) production, which correlated with increased gene expression level of various antioxidant enzymes, including TRx (thioredoxin), TR (thioredoxin reductase) 1, TR2 and peroxiredoxin 1/TPx2 (thioredoxin peroxidase 2). Importantly, enforced TPx2 gene expression inhibited UV-C-induced A-SMase translocation. Finally, PKCzeta inhibition led to a significant reduction in TPx2 protein expression. Altogether, these results suggest that PKCzeta interferes with the UV-activated sphingolipid signalling pathway by regulating the TRx system. These findings may have important consequences for UV-induced carcinogenesis and resistance to phototherapy.
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PMID:PKCzeta protects against UV-C-induced apoptosis by inhibiting acid sphingomyelinase-dependent ceramide production. 1734 42

Prdx6, a unique member of the peroxiredoxin family of antioxidants, is highly expressed in liver and protects cells from oxidative damage by reducing H2O2 and various lipid peroxides. We investigated the transcriptional regulation of Prdx6 in the H2.35 mouse hepatocyte cell line and sought to determine the mechanism of basal and induced expression. We found that Prdx6 expression is down-regulated upon serum deprivation and subsequently induced in a time-dependent manner in response to KGF, TNF-alpha, dexamethasone, and H2O2. Inhibitors of both PKC and MEK largely prevented Prdx6 induction by KGF and, to a lesser extent, TNF-alpha. Interestingly, inhibition of NF-kappaB led to a marked increase in Prdx6 regulation in the absence or presence of inducers, suggesting a normal role for NF-kappaB in Prdx6 suppression. Using reporter constructs from the mouse gene, we found that the first 160 bp of the proximal promoter was sufficient for low levels of expression, and expression increased sixfold with 1200 bp of the proximal promoter. These regions were not, however, sufficient to mediate up-regulation by the known Prdx6 inducers in our system. Together, these data support multiple pathways of Prdx6 regulation and reveal important promoter regions that mediate its transcriptional regulation.
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PMID:Investigating transcriptional regulation of Prdx6 in mouse liver cells. 1738 7

The obligate intracellular parasite Toxoplasma gondii is an important pathogen of humans and animals. The tachyzoite of T. gondii is the main life-cycle stage that is responsible for toxoplasmosis. Study of the antigenicity of soluble tachyzoite antigen (STAg) is important for discovery of protective antigens which will aid in the detection and prevention of toxoplasmosis. At present, no complete proteome map of T. gondii STAg is established, although a large-scale whole proteomic analysis of tachyzoites is underway. In this study, 1227 protein spots of T. gondii soluble tachyzoite antigen (STAg) were fractionated by 2-dimensional electrophoresis (2-DE) at pH range 3-10. By mass spectrometry (MS) analysis, among the separated 1227 protein spots, 426 were identified by searching the Swissport and NCBI nr databases. Two hundred and thirty of these identified spots (230/426, 54%) were demonstrated to be T. gondii protein by MS. Of the 21 Toxoplasma protein spots identified by Western blot with rabbit anti-T. gondii serum, 16 had immunoregulatory functions and five had immune defense functions. Due to multiple spots for a single protein, these 16 spots represented 11 proteins: a putative protein disulfide isomerase (PDI), heat shock protein 60 (Hsp60), a pyruvate kinase (PK), a putative glutamate dehydrogenase (GDH), a coronin, a heat shock protein 70 (Hsp70), a protein kinase C receptor 1 (RACK1), a malate dehydrogenase (MDH), a major surface antigen 1 (SAG1), an uridine phosphorylase (UPase) and a peroxiredoxin (Prx). Among the identified 11 proteins, except that the antigenicity and immunogenicity of the SAG1 has been reported and antigenicity of Hsp70 has been disputed, the remaining antigenic proteins were first identified in this study. In conclusion, we obtained nine novel types of immunogenic proteins that might be potential candidates of vaccine development for toxoplasmosis, which we will confirm in later studies.
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PMID:Toxoplasma gondii: proteomic analysis of antigenicity of soluble tachyzoite antigen. 1954 23

Extracellular proteins secreted/released by protozoan parasites are key mediators of the host-parasite interaction. To characterise the profile of proteins secreted/released by Leishmania (Viannia) braziliensis promastigotes, a proteomic approach combining two-dimensional electrophoresis (2DE), tandem matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF/TOF) mass spectrometry, and data mining was carried out. The 2DE map revealed a set of 270 secreted protein spots from which 42 were confidently identified and classified into 11 categories according to Gene Ontology (GeneDB database) and KEEG Ontology annotation of biological processes. Parasite promastigotes were able to secrete/release proteins involved in immunomodulation, signal transduction, and intracellular survival, such as HSP70, acid phosphatase, activated protein kinase C receptor (LACK), elongation factor 1beta, and tryparedoxin peroxidase. Data mining showed that approximately 5% of identified proteins present a classical secretion signal whereas approximately 57% were secreted following non-classical secretion mechanisms, indicating that protein export in this primitive eukaryote might proceed mainly by unconventional pathways. This study reports a suitable approach to identify secreted proteins in the culture supernatant of L. braziliensis and provides new perspectives for the study of molecules potentially involved in the early stages of infection.
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PMID:Proteomic characterization of the released/secreted proteins of Leishmania (Viannia) braziliensis promastigotes. 1970 3


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