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)

Mitogen-activated protein kinases (MAPK) play a crucial role in signal transduction that regulates gene expression through transcriptional factor activity. The purpose of this study was to investigate the temporal expression and topographic distribution of the activated MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK following traumatic brain injury (TBI) in the cortex of the rat brain. Adult male Sprague-Dawley rats (300-400 g) were subjected to lateral fluid percussion injury of moderate severity (3.5-4.0 atm) using the Dragonfly device model (no. HPD-1700). Phosphorylated-MAPK protein levels were quantified using Western blot analysis. Topographic distribution of immunoreactivity for phosphorylated-MAPK was examined using immunohistochemistry. Our findings showed that TBI significantly increased the phosphorylated-ERK (p-ERK) and -JNK (p-JNK) levels, but not the -p38 (p-p38) protein levels in the cortex surrounding the injury site. The immunoreactivity for p-ERK and p-JNK immediately after TBI were localized in neurons. The immunoreactivity for p-JNK was uniformly but only transiently induced and returned to control levels 1 h after TBI. The immunoreactivity for p-ERK was confirmed up until 30 min after TBI in the superficial neuronal layers. Double immunostaining using a glial-specific marker demonstrated that p-ERK was prominent in astrocytes 6 h after TBI. The current results suggest that the ERK and JNK pathways, but not the p38 MAPK pathways are involved in signal transduction in the cortex following TBI.
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PMID:Temporal and spatial profile of phosphorylated mitogen-activated protein kinase pathways after lateral fluid percussion injury in the cortex of the rat brain. 1254 59

The zeta isotype of protein kinase C (PKCzeta) is a member of the atypical PKC subfamily and has been widely implicated in the regulation of cellular functions. Increasing evidence from studies using in vitro and in vivo systems points to PKCzeta as a key regulator of critical intracellular signaling pathways induced by various extracellular stimuli. The major activation pathway of PKCzeta depends on phosphatidylinositol (PI)-3,4,5-trisphosphate (PIP(3)), which is mainly produced by PI-3 kinase. 3'-PI-dependent protein kinase 1, which binds with high affinity to PIP(3), phosphorylates and activates PKCzeta. Many studies demonstrated the involvement of PKCzeta in the mitogen-activated protein kinase cascade, transcriptional factor NFkappaB activation, ribosomal S6-protein kinase signaling, and cell polarity. An important molecular event in a cell is the association of PKCzeta with other signaling molecules, as well as scaffold proteins, to form large complexes that regulate their pathways. The understanding of the mechanisms underlying PKCzeta-mediated control of intracellular signaling is beginning to provide important insights into the roles of PKCzeta in various cells.
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PMID:Protein kinase Czeta (PKCzeta): activation mechanisms and cellular functions. 1276 Nov 92

The molecular mechanism of hypoxia-induced apoptosis has not been clearly elucidated. In this study, we investigated the involvement of extracellular signal-regulated protein kinase (ERK 1/2) in hypoxia-induced apoptosis using cobalt chloride in HeLa human cervical cancer cells. The cobalt chloride was used for the induction of hypoxia, and its IC(50) was 471.4 microM. We demonstrated the DNA fragmentation after incubation with concentrations more than 50 microM cobalt chloride for 24 h, and also evidenced the morphological changes of the cells undergoing apoptosis with electron microscopy. Next, we examined the signaling pathway of cobalt chloride-induced apoptosis in HeLa cells. ERK1/2 activation occurred 6 and 9 h after treatment with 600 microM cobalt chloride. Meanwhile, the pretreatment of the MEK 1 inhibitor (PD98059) completely blocked the cobalt chloride-induced ERK 1/2 activation. At the same time, the activated ERK 1/2 translocated into the nucleus and phosphorylated its transcriptional factor, c-Jun. In addition, the pretreatment of PD98059 inhibited the cobalt chloride-induced DNA fragmentation and apoptotic cell death. These results suggest that cobalt chloride is able to induce apoptotic activity in HeLa cells, and its apoptotic mechanism may be associated with signal transduction via ERK 1/2.
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PMID:Cobalt chloride-induced apoptosis and extracellular signal-regulated protein kinase activation in human cervical cancer HeLa cells. 1453 30

The sequestration of neutrophils in the lung and the release of proinflammatory mediators, including neutrophil elastase, are responsible for sepsis-induced microvascular permeability and alveolar epithelial cell damage. To assess the underlying mechanism, human neutrophil elastase (0.01-0.5 microg/ml) was added to cultured A549 epithelial cells in the presence or absence of inhibitors. IL-8 was analyzed by ELISA or by RT-PCR to measure the IL-8 synthesis capacity. Mitogen-activated protein kinase (MAPK) activity was detected by Western blot analysis. Neutrophil elastase dose-dependently increased IL-8 release from cultured A549 epithelial cells. Pretreatment with a specific elastase inhibitor, elastase inhibitor II (at 0.5, 5, and 50 microg/ml), dose-dependently inhibited neutrophil elastase-induced IL-8 release. The activities of MAPK, p38, and extracellular signal-regulated kinase (ERK) were upregulated by neutrophil elastase. Nuclear transcriptional factor-kappa B (NF-kappaB) and activator protein 1 (AP-1) were also activated. These responses were significantly inhibited by elastase inhibitor II. A specific inhibitor of p38 MAPK (SB203580) and an NF-kappaB inhibitor (pyrrolidine dithiocarbamate), but not an ERK inhibitor (PD 98059), significantly inhibited neutrophil elastase-induced IL-8 release and mRNA expression. The specific tyrosine kinase inhibitor, genistein, and the protein kinase C (PKC) inhibitor, Ro 31-8220, also inhibited IL-8 release and mRNA expression as well as p38 and NF-kappaB activation. There was no significant effect by the protein kinase A inhibitor, H-89, on neutrophil elastase-induced IL-8 synthesis or p38 MAPK activation. Our results indicate that neutrophil elastase activates p38 MAPK which upregulates NF-kappaB and AP-1 activities, thus inducing IL-8 mRNA expression and protein synthesis. Tyrosine kinase and PKC are implicated in neutrophil elastase activation of the MAPK pathway.
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PMID:Neutrophil elastase induces IL-8 synthesis by lung epithelial cells via the mitogen-activated protein kinase pathway. 1473 Feb 9

Prenatal exposure to cocaine has been shown to induce an increase in the myocardial expression and activation of the cAMP response binding protein (CREB), a transcriptional factor that has been shown to regulate gene expression. Several different kinases, including protein kinase A, calcium calmodulin kinase II, and mitogen-activated protein kinase can induce phosphorylation of CREB at serine 133, a necessary step for CREB activation. We examined whether the mitogen-activated protein kinase-extracellular receptor kinase (ERK) pathway may be involved in mediating the serine 133 CREB phosphorylation in cardiac nuclei after perinatal cocaine exposure. Pregnant rats were treated daily with saline or cocaine at 60 mg/kg (C60) by intragastric administration during the entire gestational period, and treatment was continued in the nursing dams after delivery until the time of the study. Nuclear extracts were isolated from hearts of 1-d- and 7-d-old neonatal rats. We performed immunoblotting experiments using an antibody that recognized CREB with phosphorylation specifically at the serine 133 site and an antibody that recognized both the phosphorylated and the unphosphorylated forms of CREB, as well as antibodies for total ERK, phospho-ERK, total ribosomal S6 kinase 1 (RSK1), RSK2, and phospho-RSK. We assessed the interaction of RSK with CREB or CREB-binding protein by performing co-immunoprecipitation experiments. We found that perinatal cocaine exposure increased both phospho-ERK and phospho-RSK expression, indicative of an increased activity of these two enzymes. Furthermore, we demonstrated that phospho-RSK was immunoprecipitated with CREB in all neonatal cardiac nuclei and that the greatest interaction was found in day 7 hearts after perinatal cocaine exposure. Our results thus illustrate that the ERK-RSK pathway was active in the postnatal rat heart at 1 and 7 d of age and that this pathway may mediate the increase in myocardial CREB activation after perinatal cocaine exposure in the day 7 hearts.
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PMID:Extracellular receptor kinase and cAMP response element binding protein activation in the neonatal rat heart after perinatal cocaine exposure. 1547 Jan 97

The genomes of representatives of three bacterial phyla have been compared with the list of 347 eukaryotic signature proteins (ESPs) derived by Hartman and Fedorov [Proc. Natl. Acad. Sci. USA 99 (2002) 1420]. The species included Prosthecobacter dejongeii of the Verrucomicrobia phylum, Gemmata sp. Wa-1 of the Planctomycetes phylum and Caulobacter crescentus of the Proteobacteria. The protist Trypanosoma brucei was used as a eukaryotic control. P. dejongeii had unique ERGO blast matches to alpha-, beta-, and gamma-tubulin, to Set2, a transcriptional factor associated with eukaryotic DNA, and to LAMMER protein kinase for a total of 10 high-scoring ESP matches altogether. Gemmata sp. Wa-1 shared four of its 17 high-scoring ESP matches with P. dejongeii, and that information coupled with other genomic data provides strong support that these two phyla are related to one another. If the ESP list is an accurate listing of unique eukaryotic proteins, then the low number of high-scoring matches between the proteins of these two bacteria with the list raises doubts about these phyla being direct ancestors of the Eucarya. However, this does not rule out the possibility that ancestral members of either the Verrucomicrobia or Planctomycetes may have played an important role in the evolution of a proto-eukaryotic organism.
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PMID:Eukaryotic signature proteins of Prosthecobacter dejongeii and Gemmata sp. Wa-1 as revealed by in silico analysis. 1566 94

Chromosomal translocation t(11; 22)(q24; q12) is detected in approximately 90% of Ewing's family tumors (EFTs) including Ewing's sarcoma and primitive neuroectodermal tumor. This results in the formation of the EWS-Fli1 fusion gene, which produces EWS-Fli1 fusion protein. This chimerical gene product acts as an aberrant transcriptional activator, which may be responsible for the tumorigenesis of EFTs. We have previously reported that cyclin E expression was upregulated in EFT cells and in EWS-Fli1 transformed fibroblastic cells. However, the mechanism of the overexpression of cyclin E by EWS-Fli1 is still unknown. In our study, we investigated the mechanism of transactivation of the cyclin E gene in EFT cells. We found that EWS-Fli1 enhanced the activity of the cyclin E gene promoter partially through E2F binding sites in the promoter. In addition, the basic transcriptional factor, Sp1, might also be involved in the transactivation of the cyclin E gene by EWS-Fli1. To study the biological significance of cyclin E overexpression in EFT cells, we used flavopiridol, a pan-cyclin-dependent kinase (CDK) inhibitor and found that flavopiridol efficiently suppressed the growth of EFT cells in vitro and in vivo by the inhibition of cyclinE/CDK2 kinase activity and the induction of apoptosis. These results suggest that targeting of the cyclin/CDK complex may provide new insight into treatment of EFTs.
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PMID:Transactivation of cyclin E gene by EWS-Fli1 and antitumor effects of cyclin dependent kinase inhibitor on Ewing's family tumor cells. 1581 98

Proteasome inhibitors represent novel anti-cancer drugs which interact with the proteasome-ubiquitin pathway. The 26S proteasome is a multicatalytic threonine protease with three distinct catalytic activities. It is responsible for intracellular protein turnover in eukaryotic cells, including the processing and degradation of short- and some long-living proteins required for regulation of various cellular functions. Subsequently, the inhibition of the proteasomal function results in stabilization and accumulation of its substrates, which notably include cyclins, cyclin-dependent kinase inhibitors, transcriptional factors, tumor suppressor proteins and proto-oncogenes. This results in confounding signals in the cell inducing cell cycle arrest and activation of apoptotic programs. Acting on transcriptional factor NF-kappaB, which is upregulated in some tumors undergoing chemotherapy or irradiation and downregulated by proteasome inhibition, a significant chemosensitization and consequently synergistic effects concerning the anti-tumor activity could be achieved. Bortezomib is the first proteasome inhibitor that has entered clinical trials. In multiple myeloma, both the US Food and Drug Administration and European Medicine Evaluation Agency granted approval for the use of bortezomib (Velcade) for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. At present, other trials examine the activity in a variety of solid tumors and hematological malignancies. This paper reviews preclinical and clinical results.
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PMID:Proteasome: an emerging target for cancer therapy. 1584 12

The human transcriptional factor T-complex protein 10 like (TCP10L) gene is expressed exclusively in the liver and testis. However, the function of TCP10L in the testis remains unknown. We examined the expression of TCP10L in human testis and found that TCP10L was expressed specifically in the nucleus of spermatogenic cells during spermatogenesis. In addition, we identified death associated protein kinase 3 (DAPK-3/ZIP kinase) as a binding partner for TCP10L by yeast two-hybrid screening, followed with immunoprecipitation and subcellular localization experiments. Mutagenesis study revealed that this interaction was dependant on the leucine zipper motif-containing region. The specific expression pattern of TCP10L and interaction with DAPK-3 implies that TCP10L might play crucially important roles in spermatogenesis through its interaction with DAPK-3.
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PMID:TCP10L is expressed specifically in spermatogenic cells and binds to death associated protein kinase-3. 1591 May 42

The zeta isotype of protein kinase C (PKCzeta) is a member of the atypical PKC subfamily and has been widely implicated in the regulation of cellular functions. PKCzeta, as an important message molecular, is involved in many intracellular signaling pathways, such as the mitogen-avtivated protein kinase (MAPK) cascade, transcriptional factor NF-kappaB activation, ribosomal S6-protein kinase signaling and so on. Increasing evidence from studies support the concept that the activation mechanisms of PKCzeta are tissue/cell specific. The understanding of the mechanisms underlying PKCzeta-mediated control of intracellular signaling is beginning to provide important insightsinto the roles of PKCzeta in various cells.
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PMID:[Activation mechanisms of protein kinase Czeta and its cellular function]. 1640 68


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