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)

The activity of transcription factors is often modulated by signal responsive protein kinases. Rel/NF-kappaB transcription factors are regulated by IkappaB inhibitors, the phosphorylation of which causes ubiquitination and degradation, resulting in nuclear translocation of NF-kappaB and activation of target genes. Here we report pulldown and immunoprecipitation experiments showing that a mammalian 66 kDa protein kinase binds murine c-Rel, both in vitro and in vivo. This kinase appears to have at least two binding sites on c-Rel, a proline-directed serine/ threonine substrate specificity similar to MAP kinases and to specifically phosphorylate the C-terminal domain of murine c-Rel at an ERK consensus site.
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PMID:cRel-TD kinase: a serine/threonine kinase binding in vivo and in vitro c-Rel and phosphorylating its transactivation domain. 1082 72

We show that radicicol, a fungal antibiotic, produces a marked inhibition of p38 kinase, nuclear factor-kappaB/Rel (NF-kappaB/Rel), and inducible nitric-oxide synthase (iNOS) transcription by the macrophage line RAW 264.7 in response to lipopolysaccharide (LPS). Treatment of RAW 264.7 with radicicol inhibited LPS-stimulated p38 kinase phosphorylation in a dose-related manner. iNOS transcription, which is regulated in part by the NF-kappaB/Rel family of transcription factors, has been shown to be under the control of the p38 kinase signaling cascade. Our data also show that the p38 kinase pathway is specifically involved in LPS-induced NF-kappaB/Rel activation and iNOS expression because NF-kappaB/Rel DNA binding and iNOS mRNA production in the presence of a specific inhibitor of p38 kinase, SB203580, were dramatically diminished. In contrast, PD98059, a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase 1 had no effect on NF-kappaB/Rel activation and iNOS expression. LPS-induced loss of inhibitory proteins IkappaB-alpha and IkappaB-beta and translocation of p65, c-Rel, and p50 was inhibited by radicicol. Collectively, this series of experiments indicates that radicicol inhibits iNOS gene expression by blocking p38 kinase signaling. Due to the critical role that NO release plays in mediating inflammatory responses, the inhibitory effects of radicicol on iNOS suggest that this potent antifungal agent may represent a useful anti-inflammatory agent.
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PMID:Radicicol suppresses expression of inducible nitric-oxide synthase by blocking p38 kinase and nuclear factor-kappaB/Rel in lipopolysaccharide-stimulated macrophages. 1090 Feb 31

The cyclins are a family of proteins that are centrally involved in cell cycle regulation and which are structurally identified by conserved "cyclin box" regions. They are regulatory subunits of holoenzyme cyclin-dependent kinase (CDK) complexes controlling progression through cell cycle checkpoints by phosphorylating and inactivating target substrates. CDK activity is controlled by cyclin abundance and subcellular location and by the activity of two families of inhibitors, the cyclin-dependent kinase inhibitors (CKI). Many hormones and growth factors influence cell growth through signal transduction pathways that modify the activity of the cyclins. Dysregulated cyclin activity in transformed cells contributes to accelerated cell cycle progression and may arise because of dysregulated activity in pathways that control the abundance of a cyclin or because of loss-of-function mutations in inhibitory proteins.Analysis of transformed cells and cells undergoing mitogen-stimulated growth implicate proteins of the NF-kappaB family in cell cycle regulation, through actions on the CDK/CKI system. The mammalian members of this family are Rel-A (p65), NF-kappaB(1) (p50; p105), NF-kappaB(2) (p52; p100), c-Rel and Rel-B. These proteins are structurally identified by an amino-terminal region of about 300 amino acids, known as the Rel-homology domain. They exist in cytoplasmic complexes with inhibitory proteins of the IkappaB family, and translocate to the nucleus to act as transcription factors when activated. NF-kappaB pathway activation occurs during transformation induced by a number of classical oncogenes, including Bcr/Abl, Ras and Rac, and is necessary for full transforming potential. The avian viral oncogene, v-Rel is an NF-kappaB protein. The best explored link between NF-kappaB activation and cell cycle progression involves cyclin D(1), a cyclin which is expressed relatively early in the cell cycle and which is crucial to commitment to DNA synthesis. This review examines the interactions between NF-kappaB signaling and the CDK/CKI system in cell cycle progression in normal and transformed cells. The growth-promoting actions of NF-kappaB factors are accompanied, in some instances, by inhibition of cellular differentiation and by inhibition of programmed cell death, which involve related response pathways and which contribute to the overall increase in mass of undifferentiated tissue.
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PMID:NF-kappaB and cell-cycle regulation: the cyclin connection. 1131 20

Surface-expressed BCR mediates the proliferation and expansion of antigen-specific B lymphocytes during a humoral immune response. Although several studies extensively characterize BCR proliferative signaling, the mechanisms linking these pathways to the cell cycle remain elusive. Using knockout mice, we show that c-Rel, a proto-oncogenic member of the NF-kappaB transcription factor family, is essential to BCR-mediated proliferation and cell cycle progression. Splenic B cells obtained from gene-targeted c-Rel knockout mice display a defective proliferation response to antigen receptor cross-linking, resulting in G(1) arrest. At the molecular level, we see that BCR stimulation of resting c-Rel(-/-) B cells fails to induce proper cyclin D3 and cyclin E expression, thereby negatively impacting G(1) phase cyclin-dependent kinase (CDK) activity. c-Rel-deficient B cells also exhibit incomplete phosphorylation of the Retinoblastoma protein (pRb) and poor expression of E2Fs, thus impeding the G(1) to S phase transition. Down-regulation of the pRb-related p130 protein during the G(0) to G(1) transition and removal of the CDK inhibitor p27(KIP1) in late G(1) parallel that of wild-type cells, suggesting that Rel-deficient B cells can exit the G(0) resting state and enter G(1) phase normally. Finally, we demonstrate that restoration of proliferation can be achieved partially upon reintroduction of cyclin E using a protein transduction method to reconstitute primary B cells. Collectively, these studies emphasize the importance of c-Rel in lymphocyte proliferation and oncogenesis, and highlight a requirement for c-Rel in establishing an effective humoral immune response.
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PMID:c-Rel regulation of the cell cycle in primary mouse B lymphocytes. 1214 27

Bacteria-derived synthetic lipoproteins constitute potent macrophage activators in vivo and are effective stimuli, enhancing the immune response especially with respect to low or non-immunogenic compounds. N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteinyl-seryl-(lysyl)3-lysine (P3CSK4), exhibiting one of the most effective lipopeptide derivatives, represents a highly efficient immunoadjuvant in parenteral, oral, nasal and genetic immunization either in combination with or after covalent linkage to antigen. In order to further elucidate its molecular mode of action with respect to the transcriptional level, we focused our investigations on the P3CSK4-induced modulation of gene transcription. We could show that P3CSK4 activates/represses an array of at least 140 genes partly involved in signal transduction and regulation of the immune response. P3CSK4 activates the expression of tumor suppressor protein p53 (p53), c-rel, inhibitor of nuclear factor kappa B (NFkappaB) alpha (IkappaB alpha), type 2 (inducible) nitric oxide (NO) synthase (iNOS), CD40-LR, intercellular adhesion molecule-1 (ICAM-1) and interleukin 1/6/15 (IL-1/6/15). We detected no activation of heat shock protein (HSP) 27, 60, 84 and 86, osmotic stress protein 94 (Osp 94), IL-12, extracellular signal-regulated protein kinase 1 (ERK1), p38 mitogen activated protein (MAP)-kinase (p38), c-Jun NH2-terminal kinase (JNK), signal transducer and activator of transcription 1 (STAT1), CD14 and caspase genes. Furthermore, we monitored inhibition of STAT6, Janus kinase 3 (Jak3) and cyclin D1/D3 gene transcription after stimulating bone marrow-derived macrophages (BMDM) with lipopeptide. In addition, we monitored significant differences after lipopeptide and lipopolysaccharide (LPS) stimulation of bone marrow-derived murine macrophages. Our findings are of importance for further optimizing both conventional and genetic immunization, and for the development of novel synthetic vaccines.
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PMID:Lipopeptide adjuvants: monitoring and comparison of P3CSK4- and LPS-induced gene transcription. 1234 44

We have created two mutants of mouse transcription factor c-Rel (c-G29E and c-R266H) that are analogous to mutants previously shown to have temperature-sensitive (ts) functions for the homologous Drosophila protein Dorsal and the retroviral oncoprotein v-Rel. In vitro, c-R266H shows both a ts and a concentration-dependent ability to bind DNA, suggesting that the lesion affects the ability of c-Rel to form homodimers. In contrast, the ability of mouse c-G29E to bind DNA in vitro is not ts. c-Rel mutant c-R266H also shows a ts ability to activate transcription from a kappaB-site reporter plasmid, whereas c-G29E activates transcription well above control levels at both 33 and 39 degrees C. Insertion of two amino acids (Pro-Trp) between amino acids 266 and 267 in mouse c-Rel (mutant c-SPW) also creates a c-Rel protein with distinct properties: mutant c-SPW is partially defective in that it cannot form DNA-binding homodimers but can form DNA-binding heterodimers with p50. Interestingly, the mutations in c-Rel that affect homodimer formation (c-R266H and c-SPW) fall within a consensus protein kinase A recognition sequence but are not predicted to lie in the dimer interface. Conditional and partially defective mutants such as those described herein may be useful for identifying physiological responses and genes regulated by specific Rel/NF-kappaB family members.
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PMID:Mutations within a conserved protein kinase A recognition sequence confer temperature-sensitive and partially defective activities onto mouse c-Rel. 1284 86

Besides being expressed on endothelial cells, vascular endothelial growth factor receptors (VEGFRs) are also functional on subsets of leukemias, resulting in autocrine loops that sustain leukemia migration and proliferation. While recent evidence suggests that VEGF supports hematopoietic stem cell survival via an internal loop, the molecular mechanisms whereby autocrine stimulation of VEGFR-2 (KDR) promotes leukemia growth are not well understood. Here we show on acute myeloid primary leukemias and cell lines that VEGF/KDR autocrine loops operate both internally and externally. First, we demonstrate that KDR is constitutively phosphorylated and located at the nucleus of VEGF-producing leukemias. Treatment with anti-VEGF antibody, which acts externally, blocked KDR nuclear translocation and inhibited nuclear factor kappa B (NF-kappaB; p65 and c-rel) activation. In contrast, a KDR-specific intracellular inhibitor failed to block KDR nuclear translocation, but inhibited the constitutive activation of mitogen activated protein kinase (MAPK)/Erk and the phosphatidylinositol 3-kinase/AKT pathways. Notably, treatment with the anti-VEGF antibody alone had little effect on cell survival, while the internal inhibitor induced leukemia apoptosis, and the 2 drugs produced synergistic effects, together and with chemotherapy, reducing cell survival to a larger extent than either agent alone. Our results demonstrate that internal and external VEGF/KDR autocrine loops regulate leukemia survival via different mechanisms, and suggest that blocking both may have therapeutic potential.
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PMID:Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways. 1472 93

Nuclear factor kappaB (NF-kappaB) is a eukaryotic transcription factor which responds to different extracellular signals. It is involved in immune response, inflammation, and cell proliferation. Increased expression of c-Rel (or its viral homolog v-Rel), one component of the NF-kappaB factors, induces tumorigenesis in different systems. The activity of NF-kappaB can be regulated by protein kinase A (PKA) in a cAMP-independent manner. Our previous results showed that c-MYC induces the activity of PKA by inducing the transcription of the gene encoding the PKA catalytic subunit beta (PKA-Cbeta). Constitutive expression of PKA-Cbeta in Rat1a cells induces their transformation. Here we show that CREB is unlikely to be a phosphorylation target of PKA-Cbeta as characterized by different cell lines. Electrophoretic mobility shift assays showed that c-Rel is present as a significant component of the NF-kappaB factors in c-MYC overexpressing status. The transcriptional activity of c-Rel was significantly stimulated by PKA-Cbeta. Coactivators p300/CBP are at least partially responsible for the enhanced activation mediated by c-Rel and PKA-Cbeta. Interaction between c-Rel and PKA-Cbeta was demonstrated using coimmunoprecipitation assays. Immunoprecipitation-in vitro phosphorylation assays showed the direct phosphorylation of c-Rel by PKA-Cbeta. These results indicate that c-Rel is a reasonable phosphorylation target of PKA-Cbeta, and that the transcriptional activity of c-Rel is stimulated by PKA-Cbeta possibly through the interaction with p300/CBP.
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PMID:Stimulation of c-Rel transcriptional activity by PKA catalytic subunit beta. 1519 57

Interaction of Leishmania donovani with macrophages antagonizes host defense mechanisms by interfering with a cascade of cell signaling processes in the macrophages. An early intracellular signaling event that follows receptor engagement is the activation of transcription factor NF-kappaB. It has been reported earlier that NF-kappaB-dependent signaling pathway regulates proinflammatory cytokine release. We therefore investigated the effect of L. donovani infectivity on this nuclear transcription factor in macrophage cell line J774A.1. Both L. donovani and its surface molecule lipophosphoglycan (LPG) resulted in a dose- and time-dependent activation of NF-kappaB-DNA binding activity in an electrophoretic mobility shift assay. We also report the involvement of IkappaB-alpha and IkappaB-beta in the persistent activation of NF-kappaB by L. donovani. We demonstrate that the NF-kappaB activation was independent of viability of the parasite. Electrophoretic mobility supershift assay indicated that the NF-kappaB complex consists of p65 and c-rel subunits. The interaction of parasite with the macrophages and not the cellular uptake was important for NF-kappaB activation. Both p38 and ERK mitogen activated protein kinase (MAP) activation appears to be necessary for NF-kappaB activation by LPG. Preincubation of cells with antioxidants resulted in inhibition of L. donovani induced NF-kappaB activation, thereby suggesting a potential role of reactive oxygen species in L. donovani induced intracellular signaling. The present data indicate that antioxidants could play an important role in working out various therapeutic modalities to control leishmaniasis.
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PMID:Leishmania donovani activates nuclear transcription factor-kappaB in macrophages through reactive oxygen intermediates. 1533 76

The transcription factor nuclear factor-kappa B (NF-kappaB) is an inducible regulator of genes that plays a crucial role in the nervous system. Glutamate receptor stimulation is one well-described mechanism for NF-kappaB activation. In the studies presented here we used the glutamate analog, kainate to investigate the signaling mechanisms that couple to NF-kappaB activation in hippocampus. Kainate (250 nM) application to hippocampal slices elicited a time-dependent increase in nuclear NF-kappaB levels in areas CA3 and CA1, but not dentate, compared with controls. Further analysis focused on hippocampal area CA3, revealed increased NF-kappaB DNA binding activity in response to kainate stimulation. Supershift electrophoretic mobility shift assay indicated that the kainate-mediated NF-kappaB complex binding DNA was composed of p65, p50, and c-Rel subunits. Through inhibition studies we found that extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol-3 kinase (PI3K) couple to basal and kainate-mediated NF-kappaB DNA binding activity in area CA3. Kainate elicited decreased total and increased phospho-inhibitor kappa B alpha (IkappaBalpha), suggesting that kainate-mediated activation of NF-kappaB is via the classical IkappaB kinase pathway. Interestingly, inhibition of ERK but not PI3K blocked the kainate-mediated increase in phospho-IkappaBalpha. Thus, our findings support a role for the ERK and PI3K pathways in kainate-mediated NF-kappaB activation in hippocampal area CA3, but these kinases may target the NF-kappaB pathway at different loci.
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PMID:Kainate mediates nuclear factor-kappa B activation in hippocampus via phosphatidylinositol-3 kinase and extracellular signal-regulated protein kinase. 1591 59


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