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)

Histamine H1 receptor (H1R) levels vary under various pathological conditions, and these changes may be responsible for some pathogenesis such as in allergic rhinitis. Several stimulants, including histamine, muscarinic agonists and platelet-activating factor, have now been shown to regulate H1R levels and may have roles in regulating the H1R level in physiological and pathological conditions. Results for beta2-adrenoceptor (beta2AR) stimulation are conflicting, however.beta2AR up-regulated H1R in bovine tracheal smooth muscle, but down-regulated human H1R expressed in Chinese hamster ovary (CHO) cells. It is possible that this discrepancy comes from the differences in the preparations used for each study: the former cell expressed bovine H1R and the latter cell expressed human H1R. Moreover, CHO cells have been shown to be inadequate for studying the effects on H1R gene expression, because the cells express non-endogenous stably transfected H1R under the control of the SV40 promoter. Therefore, in this study, we have investigated the role of beta2AR stimulation in H1R gene regulation using human U373 astrocytoma cells that express endogenous H1R and transfected beta2AR. Stimulation of beta2AR significantly reduced H1R promoter activity and H1R mRNA levels. H1R mRNA stability was slightly reduced by beta2AR stimulation, although this was not significant. The decrease of H1R mRNA by beta2AR stimulation was blocked by the protein kinase A (PKA) inhibitor KT5720, suggesting the involvement of PKA. These results indicate that the beta2AR is involved in the down-regulation of human H1R by inhibiting H1R gene transcription through a PKA-dependent process.
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PMID:Down-regulation of histamine H1 receptors by beta2-adrenoceptor-mediated inhibition of H1 receptor gene transcription. 1849 11

During cell aging, proteins accumulate damages, which affect their structure and activity. The protein l-isoaspartyl methyltransferase (PIMT) is involved in the repair of proteins containing abnormal L-isoaspartyl residues. Although its mechanism of action is well defined, little is known about the pathways involved in the regulation of PIMT expression. In this study, we demonstrated that glycogen synthase kinase-3 (GSK-3) and beta-catenin are involved in the regulation of PIMT expression. Treatment of astrocytoma cells (U-87) with direct pharmacological GSK-3 inhibitors such as lithium, SB-216763 and SB-415286 stimulated PIMT expression ( approximately twofold). As expected, GSK-3 inhibition led to an increase of phosphorylated GSK-3beta (Ser9) and to beta-catenin accumulation. PIMT induction by lithium was dependent on increased protein synthesis. In addition, RT-PCR analysis showed higher level of PIMT mRNA following GSK-3 inhibition, which was abolished by the transcriptional inhibitor actinomycin D. These results demonstrated regulation of PIMT expression by lithium at both the transcriptional and the translational levels. Additionally, inhibition by siRNA of GSK-3 and beta-catenin modulated the expression of the PIMT in accordance with GSK-3 pharmacological inhibition. Valproic acid, an antiepileptic drug with mood-stabilizing properties, up-regulated phospho-GSK-3beta (Ser9), beta-catenin and PIMT levels similarly to lithium. This study reports that PIMT expression is up-regulated by GSK-3 inhibition and beta-catenin stabilization upon treatments with lithium and valproic acid. These findings suggest a possible therapeutic role for PIMT in certain brain diseases including epilepsy.
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PMID:Up-regulation of protein L-isoaspartyl methyltransferase expression by lithium is mediated by glycogen synthase kinase-3 inactivation and beta-catenin stabilization. 1858 78

Relatively little is known about the molecular changes that promote the formation or growth of pilocytic astrocytomas. We investigated genomic alterations in 25 pilocytic astrocytomas, including 5 supratentorial and 20 posterior fossa tumors, using oligonucleotide array comparative genomic hybridization. Large changes were identified in 7 tumors and included gains of chromosomes 5, 6, and 7 and losses of chromosomes 16, 17, 19, and 22. The most common alteration was a 1.9-MB region of low-level gain at chromosome 7q34 identified in 17 of 20 posterior fossa tumors. In most tumors, the region of gain ended within the BRAF locus and encompassed only exons that encode the BRAF kinase domain. We confirmed copy number increase at the 7q34 locus using quantitative polymerase chain reaction with primers adjacent to the HIPK2, RAB19B, and BRAF genes. Western blot analysis revealed that 3 of 6 pilocytic astrocytomas with 7q34 gain contained high levels of phosphorylated extracellular signal-related kinase (ERK) and nitrogen-activated protein kinase/ERK kinase (MEK), while 1 tumor lacking 7q34 gain and 2 normal brain specimens did not. Immunohistochemical stains of a tissue microarray containing 43 pilocytic astrocytoma identified ERK phosphorylation in 35 (81%). These data indicate that focal gains at chromosome 7q34 and increased BRAF-MEK-ERK signaling are common findings in sporadic pilocytic astrocytomas.
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PMID:Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. 1871 56

Matrix metalloproteinase-9 (MMP-9) is an important angiogenic and prognostic factor in malignant tumors. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as the death ligand, which induces preferential apoptosis of transformed tumor cells. In this study, we investigated the biological functions of TRAIL, other than its role in induction of apoptosis. We demonstrated that TRAIL induces MMP-9 expression in human astrocytoma cells, which is preceded by activation of extracellular signal-regulated protein kinase (ERK). In addition, TRAIL induces the DNA-binding activity of NF-kappaB, an important transcription factor for MMP-9 induction. The specific MEK inhibitor, U0126, significantly blocks TRAIL-mediated NF-kappaB activation and subsequent MMP-9 induction. These findings indicate that TRAIL treatment in human astrocytoma cells leads to the activation of NF-kappaB and subsequent expression of MMP-9, which are dependent on ERK activation. Collectively, these results suggest that TRAIL has alternative biological functions in addition to its role in inducing apoptosis in human malignant astrocytoma cells.
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PMID:TRAIL induces MMP-9 expression via ERK activation in human astrocytoma cells. 1883 56

1-Bromopropane (1-BP) has been widely used as an alternative to ozone-depleting chlorofluorocarbons in various industries. Although the neurotoxicity of 1-BP has been recently reported, there is little information about the effect of 1-BP on the cells in brain by experimental approach. Here we studied the effect of 1-BP on brain-derived neurotrophic factor (BDNF) expression in astrocytes in vitro. The BDNF mRNA level was remarkably decreased by 1-BP in a human astrocytoma cell line, U251, and in mouse primary astrocytes. The DNA-binding and specific reporter activity of cAMP response element-binding transcription factor (CREB), which is one of the key molecules regulating BDNF expression, were reduced by 1-BP in U251 and/or mouse primary astrocytes. Additionally, protein kinase A (PKA) activity was suppressed by 1-BP in U251. These results suggest that BDNF expression was affected by 1-BP through at least PKA.
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PMID:Effects of 1-bromopropane, a substitute for chlorofluorocarbons, on BDNF expression. 1918 64

Proteins are susceptible to various non-enzymatic post-translational modifications occurring during aging and in certain pathological states. The protein L-isoaspartyl methyltransferase (PIMT) is an enzyme that recognizes and repairs the abnormal L-isoaspartyl residues in proteins. Recently, we reported that PIMT expression was stimulated by the anti-epileptic drug valproic acid and that this was mediated through the glycogen synthase kinase-3 (GSK-3)/beta-catenin pathway. In this study, to gain further insights into which of the signaling pathways activated by valproic acid regulate PIMT abundance, astrocytoma U-87 MG and neuroblastoma SH-SY5Y cells were treated with this drug to investigate the possible involvement of the extracellular-regulated kinase (ERK) pathway in PIMT induction. Valproic acid increased ERK1/2 phosphorylation on Thr202/Tyr204 and Thr185/Tyr187, respectively. Pharmacological inhibitors against the kinases Src, c-Raf, MEK1/2 and ERK1/2 abolished the ERK1/2 phosphorylation stimulated by valproic acid, thus preventing PIMT induction by the drug. Furthermore, MEK1/2 inhibition with U0126 blocked the higher phosphorylation of RSK-1 on Thr359/Ser363 and of GSK-3beta on Ser9 as well as the increased expression of RSK-1, beta-catenin and PIMT upon treatment with valproic acid. RSK-1 knockdown by interfering RNA abrogated the increased expression of RSK-1, beta-catenin and PIMT as well as the induced phosphorylation of RSK-1 and GSK-3beta due to valproic acid. Thus, our findings demonstrated that PIMT up-regulation by valproic acid required the activation of the ERK signaling pathway including RSK-1 the latter being responsible for inactivating GSK-3 and subsequently leading to beta-catenin stabilization.
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PMID:Valproic acid enhances protein L-isoaspartyl methyltransferase expression by stimulating extracellular signal-regulated kinase signaling pathway. 1937 92

Although the introduction of highly active antiretroviral therapy (HAART) has resulted in a significant decrease of acquired immunodeficiency syndrome (AIDS) morbidity and mortality, the prevalence of human immunodeficiency virus (HIV)-associated dementia (HAD) has actually risen, due to the increasing life expectancy of the infected subjects. To date, several aspects of the HAD pathogenesis remain to be dissected. In particular, the viral-cellular protein interplay is still under investigation. Given their specific features, two viral proteins, Tat and Nef, have been mainly hypothesized to play a role in HIV neuropathology. Here we show that HIV-1 Nef has an effect on the transcriptional levels of a cellular protein, anaplastic lymphoma kinase (ALK), that is preferentially expressed in the central and peripheral nervous system at late embryonic stages. By its overexpression along with Nef, the authors demonstrate ALK ability to influence, at least in the U87MG astrocytic glioma cells, the mytogen-activated protein kinase (MAP-K)-dependent pathway. Moreover, although in the absence of a physical direct interaction, Nef and ALK activate matrix metalloproteinases (MMPs), which are likely to contribute to blood-brain barrier (BBB) damage in HAD. Finally, in the in vitro model of glioblastoma cells adopted, Nef and ALK show similar effects by increasing different cytochines/chemokines that may be relevant for HAD pathogenesis. If confirmed in vivo, these data may indicate that, thanks to its ability to interfere with specific cellular pathways involved in BBB damage and in central nervous system (CNS) integrity, Nef, along with specific cellular counterparts, could be one of the viral players implicated in HAD development.
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PMID:Nef and cell signaling transduction: a possible involvement in the pathogenesis of human immunodeficiency virus-associated dementia. 1945 69

Human group IIA secreted phospholipase A(2) (sPLA(2)-IIA) has been characterized in numerous inflammatory and neoplastic conditions. sPLA(2)-IIA can either promote or inhibit cell growth depending on the cellular type and the specific injury. We have previously demonstrated that exogenous sPLA(2)-IIA, by engagement to a membrane structure, induces proliferation and activation of mitogen-activated protein kinases cascade in human astrocytoma cells. In this study, we used human astrocytoma 1321N1 cells to investigate the key molecules mediating sPLA(2)-IIA-induced cell proliferation. We found that sPLA(2)-IIA promoted reactive oxygen species (ROS) accumulation, which was abrogated in the presence of allopurinol and DPI, but not by rotenone, discarding mitochondria as a ROS source. In addition, sPLA(2)-IIA triggered Ras and Raf-1 activation, with kinetics that paralleled ERK phosphorylation, and co-immunoprecipitation assays indicated an association between Ras, Raf-1 and ERK. Additionally, Akt, p70 ribosomal protein S6 kinase, and S6 ribosomal protein were also phosphorylated upon sPLA(2)-IIA treatment, effect that was abrogated by N-acetylcysteine or LY294002 treatment indicating that ROS and phosphatidylinositol 3 kinase are upstream signaling regulators. As the inhibitors N-acetylcysteine, PD98059, LY294002 or rapamycin blocked sPLA(2)-IIA-induced proliferation without activation of the apoptotic program, we suggest that inhibition of these intracellular signal transduction elements may represent a mechanism of growth arrest. Our results reveal new potential targets for therapeutic intervention in neuroinflammatory disorders and brain cancer in particular.
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PMID:Secreted phospholipase A2-IIA modulates key regulators of proliferation on astrocytoma cells. 1973 48

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family of cytokines, causes apoptosis by caspase activation in various cell types, particularly in transformed cells. Numerous types of tumors are relatively resistant to TRAIL-induced cytotoxicity; however, the reasons for this are not yet fully understood. We report here a new signal transduction pathway involving protein kinase Cdelta (PKCdelta), NADPH oxidase 4 (NOX4) and reactive oxygen species (ROS), that inhibits caspase-dependent cell death induced by TRAIL ligation in human malignant astrocytoma cells. In our experiments, TRAIL ligation-induced generation of intracellular ROS through caspase-dependent proteolytic activation of PKCdelta and subsequent activation of the NOX4 complex. Suppression of intracellular ROS induction using various pharmacological inhibitors or PKCdelta- or NOX4-specific RNA interference enhanced the enzymatic activity of caspase-3 by blocking the oxidative modification of its catalytic cysteine residue, resulting in marked augmentation of TRAIL-mediated cell death. These results collectively indicate that TRAIL-induced activation of PKCdelta and NOX4 can modulate TRAIL-mediated apoptosis by promoting oxidative modification of active caspase-3 in a negative-feedback manner.
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PMID:Caspase-dependent generation of reactive oxygen species in human astrocytoma cells contributes to resistance to TRAIL-mediated apoptosis. 1987 66

During neuropathological conditions such as infections and degenerative diseases, astrocytes can be activated by infiltrating immune cells. Activated astrocytes can produce chemokines, cytokines and adhesion molecules. In this study, the production of IL-6 and adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1) and E-selectin by human astroglioma cells stimulated with Gram-negative surface components was investigated. Haemophilus influenzae type b porin P2 and its selected active peptide, loop L7, were found to induce MEK1-MEK2/ mitogen-activated protein kinase phosphorylation in U87-MG cells as demonstrated by ELISA, and up-regulate cellular adhesion molecule and interleukin-6 (IL-6) production as shown by RT-PCR and ELISA. Using two potent and selective inhibitors of MEK activation by Raf-1 (PD-098059) and p38 (SB-203580), it was also demonstrated that both ERK1/2 and p38 pathways play key roles in the production of IL-6 as well as in ICAM-1, VCAM-1 and E-selectin expression by Hib porin.
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PMID:P2 porin and loop L7 from Haemophilus influenzae modulate expression of IL-6 and adhesion molecules in astrocytes. 2128 61


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