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)

Interleukin-1 (IL-1) inhibits the proliferation of A375 human melanoma cells. We have demonstrated previously that p38 mitrogen-activated protein kinase (MAPK) mediated the antiproliferative effect of IL-1 partially through the downregulation of activity and protein level of ornithine decarboxylase (ODC). In this study, we investigated the role of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), one of the p38 MAPK target transcriptional factors. The mRNA level of CHOP was not affected by IL-1 treatment in A375-6 cells. Unexpectedly, CHOP was constitutively phosphorylated, and IL-1 or p38 MAPK inhibitor, SB203580, did not affect the phosphorylation level. However, A375-6 cells exhibited enhanced sensitivity to IL-1 by transfecting CHOP expression plasmid and reduced sensitivity to IL-1 by antisense CHOP mRNA expression plasmid. Furthermore, CHOP appeared to regulate positively IL-6 production at the transcriptional level. The experiments using CHOP muteins revealed that dimerization ability - but not p38 MAPK-dependent phosphorylation or DNA binding activity - is important for the IL-6 inducing activity of CHOP. These results indicate that CHOP contributes to the IL-1 growth-inhibitory signal through augmenting IL-6 production.
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PMID:CHOP, a basic leucine zipper transcriptional factor, contributes to the antiproliferative effect of IL-1 on A375 human melanoma cells through augmenting transcription of IL-6. 1142 63

The signal transducer and activator of transcription (STAT) 3 is essential for mediating signals from the receptors for a variety of cytokines and growth factors, including IL-6 and EGF, and from cytoplasmic tyrosine kinases. Upon stimulation, STAT3 is phosphorylated at Ser727 and Tyr705. However, the role of phosphorylation at Ser727, and the kinase pathways responsible for this phosphorylation in IL-6 signaling remain obscure. Here we show that IL-6 activates at least two distinct STAT3 serine kinase pathways and that an H7-sensitive pathway is dominant over a PD98059-sensitive one in HepG2 cells stimulated with a low concentration of IL-6. The analysis, using a series of chimeric receptors containing the extracellular domain of the G-CSF receptor, the truncated form of gp 130, and additional short peptides at the gp 130 carboxy-terminus, showed that the YXXQ motif of gp 130 was sufficient for the H7-sensitive STAT3 Ser727 phosphorylation. This YXXQ-mediated pathway does not involve Erk, p38, JNK, or PKCdelta, and requires a site in the region from 533 to 711 of STAT3 for phosphorylation in vivo. Moreover, we show that Ser727 is required for full transcriptional activity of STAT3 for two different response elements. Thus, the YXXQ motif regulates STAT3 activities in two ways in response to even a low concentration of IL-6: it recruits STAT3 to the receptor for tyrosine phosphorylation, and activates an unidentified H7-sensitive pathway leading to the serine phosphorylation of STAT3.
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PMID:The YXXQ motif in gp 130 is crucial for STAT3 phosphorylation at Ser727 through an H7-sensitive kinase pathway. 1142 93

Serum amyloid A-activating factor-1 (SAF-1) is a zinc finger transcription factor that is activated by many mediators of inflammation including IL-1, IL-6, and bacterial LPS. However, the mechanism of activation is not fully understood. To identify possible activation partners for SAF-1, we used a yeast two-hybrid system that detected interaction between the catalytic subunit of cyclic AMP-dependent protein kinase (PKA-Calpha) and SAF-1. Immunofluorescence and combined immunoprecipitation-Western blot analyses revealed colocalization and interaction between SAF-1 and PKA-Calpha. In vivo evidence of SAF-1 and PKA-Calpha interaction was further revealed by coimmunoprecipitation of these two proteins in cAMP-activated liver cells. We further show that SAF-1 is phosphorylated in vitro by PKA-Calpha and that addition of cAMP markedly induces in vivo phosphorylation of SAF-1 and transcription of SAF-regulated reporter genes. These results showed that SAF1-PKA-Calpha interaction is involved in functional activation of SAF-1.
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PMID:Catalytic subunit of protein kinase A is an interacting partner of the inflammation-responsive transcription factor serum amyloid A-activating factor-1. 1149 23

The nature of the interactions between the intravascular parasite Schistosoma mansoni and the host pulmonary vasculature is critical in determining the outcome of infection. In this report, we show that lung schistosomula selectively induce the synthesis of IL-6 mRNA and protein in cultured human and mouse lung microvascular endothelial cells (EC) and that parasite excretory/secretory lipophilic compounds, particularly prostaglandin E(2), are responsible for this effect. In vivo, a striking increase of IL-6 expression is observed in the pulmonary microvasculature of S. mansoni-infected C57BL/6 mice suggesting that, in vivo, parasites also induce the synthesis of IL-6 in lung EC. In infected mice, IL-6 deficiency results in an accelerated mobilization of eosinophils into the lung tissue and in a dramatic increased number of recruited leukocytes, particularly eosinophils, in the airway. This effect is associated with an enhanced production of eotaxin (CCL11) and IL-5 in the lungs of IL-6 knockout (KO) animals. Finally, compared to wild-type mice, we detect a dramatic increased level of parasite mortality in the lungs of IL-6 KO mice. Taken together, we suggest that parasite larvae activate EC to produce IL-6 to escape the inflammatory reaction that develops in the lungs of infected hosts. Finally, we show that the parasite-induced IL-6 synthesis is mediated by a protein kinase A-dependent pathway that principally targets the cAMP-response element and the nuclear factor-kappaB sites from the -256/+20 region of the IL-6 promoter.
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PMID:Schistosoma mansoni induces the synthesis of IL-6 in pulmonary microvascular endothelial cells: role of IL-6 in the control of lung eosinophilia during infection. 1153 74

Mucin production and secretion by specialized epithelial cells is a common mechanism used by mammals to protect the underlying mucosae against various injuries (pollutants, pathogens, pH). The expression of mucin genes is cell- and tissue-specific but is submitted to variations during cell differentiation, inflammatory process, and is altered during carcinogenesis. The molecular mechanisms responsible for the control of mucin transcription and expression are beginning to be understood as mucin gene promoters and regulatory regions are characterized. The four gel-forming mucin genes, MUC2-MUC5AC-MUC5B-MUC6, are clustered on the p15 arm of chromosome 11. Common regulatory mechanisms (PKA, PKC, PKG and Ca2+ signaling, Sp1/Sp3) may account for the capability of mucous-secreting cells to express several mucin genes simultaneously. In response to an insult or during carcinogenesis, the normal pattern of expression is altered and results from specific answers of the cell by activating different intracellular signaling pathways. 11p15 mucin genes are regulated at the transcriptional level by pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha), pleiotropic cytokines (IL-4, IL-13, IL-9), bacterial exoproduct (LPS), growth factors (EGF, TGF-alpha), lipid mediator (PAF), retinoids and hormones. To date, the only downstream cascade known to activate mucin gene transcription is the Src/Ras/MAPK/pp90rsk cascade, which leads to the activation of the transcription factor NF-kappaB. Mucin gene transcription is also regulated by ATF-1, CREB and RAR-alpha transcription factors. Finally, repression of mucin transcription in cancer cells is under the control of the epigenetic mechanism of methylation. As transcriptional regulation of mucin genes begins to be unraveled, it becomes clear that many signaling pathways are involved. Our understanding of mucin gene transcriptional regulation, which awaits more data (identification of the signaling cascades and active cis-elements within promoters and introns), will most certainly lead to the use of mucin genes as molecular markers in cancer and molecular tools in human gene therapy, and to the synthesis of new therapeutic agents in inflammatory diseases of the epithelium.
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PMID:Transcriptional regulation of the 11p15 mucin genes. Towards new biological tools in human therapy, in inflammatory diseases and cancer? 1157 73

Combinations of cytokines are known to reactivate transcription and replication of latent human immunodeficiency virus type 1 (HIV-1) proviruses in resting CD4(+) T lymphocytes isolated from infected individuals. Transcription of the HIV-1 provirus by RNA polymerase II is strongly stimulated by the viral Tat protein. Tat function is mediated by a cellular protein kinase known as TAK (cyclin T1/P-TEFb) that is composed of Cdk9 and cyclin T1. We have found that treatment of peripheral blood lymphocytes and purified resting CD4(+) T lymphocytes with the combination of interleukin-2 (IL-2), IL-6, and tumor necrosis factor alpha resulted in an increase in Cdk9 and cyclin T1 protein levels and an increase in TAK enzymatic activity. The cytokine induction of TAK in resting CD4(+) T lymphocytes did not appear to require proliferation of lymphocytes. These results suggest that induction of TAK by cytokines secreted in the microenvironment of lymphoid tissue may be involved in the reactivation of HIV-1 in CD4(+) T lymphocytes harboring a latent provirus.
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PMID:Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines. 1168 14

The immune response caused by liposome stimulation was studied by assessing the level of several cytokines released from human peripheral blood cells. Liposome stimulation resulted in the release of IL-6, IL-10, IL-1beta, TNF-alpha and IFN-gamma. The size of the liposomes affected the degree of the cytokine releases with larger sized liposomes causing higher levels of cytokine induction. In addition, it appears that the lipid composition of liposomes had no effect on the degree of cytokine release. The release of cytokines occurred even in the absence of serum, suggesting that serum proteins did not contribute to liposome stimulation in peripheral blood cells. The release of cytokines induced by liposome stimulation was inhibited by the presence of either protein kinase-C (PKC) or protein tyrosine kinase (PTK) inhibitor, but not by the presence of an endocytosis inhibitor. This indicates that signal transduction via PKC or PTK is necessary, in order for human peripheral blood cells to release cytokines (IL-6, IL-10, IL-1beta, TNF-alpha and IFN-gamma) as the result of liposome stimulation. These quantitative data on the release of cytokines by liposomal stimulation provide useful information for the development of rational drug delivery systems and the safety of cytokine induction via the use of liposomes.
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PMID:HEPC-based liposomes trigger cytokine release from peripheral blood cells: effects of liposomal size, dose and lipid composition. 1189 Oct 76

Parathyroid hormone (PTH) is a promising anabolic agent for the treatment of osteoporosis. However, PTH is also potently catabolic. To help delineate the molecular mediators of PTH's opposing effects on skeletal metabolism, we have examined PTH-induced regulator of G-protein signaling-2 (RGS-2) expression and function in murine osteoblasts. RGS proteins are GTPase-activating proteins (GAPs) that regulate GTP-binding protein-coupled receptor (GPCR) signaling by enhancing the intrinsic GTPase activity of Galpha subunits. We found that 10 nmol/L PTH maximally induced RGS-2 mRNA in murine MC3T3-E1 cells, rat Py1a and ROS-17/2.8 cells, primary mouse osteoblasts (MOB cells), and mouse calvariae organ culture at 1-2 h posttreatment. PTH signaling through its receptor, PTHR1, is coupled to cAMP-protein kinase A (PKA), protein kinase C (PKC), and calcium signaling pathways. We examined the effect of selective signaling agonists and antagonists on RGS-2 expression in MOB cells to determine which pathway(s) mediates PTH-induced RGS-2 expression. Although selective activation of all three pathways led to RGS-2 expression, cAMP-PKA activation with 10 nmol/L PTH and 10 micromol/L forskolin elicited the strongest induction. Similarly, RGS-2 mRNA expression was most strongly inhibited by the PKA inhibitor, H89 (10-30 micromol/L). The phorbol ester, PMA (1 micromol/L), which activates the PKC pathway, and ionomycin (1 micromol/L), which activates the calcium pathway, produced small but detectable elevations in RGS-2 mRNA levels. Overnight treatment with 1 micromol/L PMA to deplete PKC did not affect subsequent RGS-2 induction by PTH, but significantly inhibited PMA-induced RGS-2 expression. Treatment with 1-100 nmol/L PTH(3-34), which does not activate cAMP-PKA signaling, did not induce RGS-2 expression. MOB cells pretreated with 3 microg/mL cycloheximide produced sustained RGS-2 mRNA levels 2 h after 10 nmol/L PTH treatment. Actinomycin D (5 microg/mL) completely blocked 10 nmol/L PTH-induced RGS-2 expression. Finally, we tested the effect of RGS-2 overexpression on PTH- and fluprostenol-induced interleukin (IL)-6 promoter activity in MOB cells. PTH induces IL-6 through PKA activation, whereas fluprostenol induces IL-6 through PKC activation. We found that RGS-2 overexpression significantly inhibited IL-6 promoter activity following fluprostenol treatment, but not following PTH treatment. We conclude that RGS-2 is a PTH-induced primary response gene in murine osteoblasts that is induced mainly through the cAMP-PKA pathway and specifically inhibits Galphaq-coupled receptors.
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PMID:Parathyroid hormone induces RGS-2 expression by a cyclic adenosine 3',5'-monophosphate-mediated pathway in primary neonatal murine osteoblasts. 1199 4

1. Interleukin-1 (IL-1) has been implicated in neurodegeneration and in central nervous system (CNS)-mediated host defence responses to inflammation. All actions of IL-1 identified to date appear to be mediated through its only known functional type I receptor (IL-1RI). However, our recent evidence suggests that some actions of IL-1 in the brain may be IL-1RI independent, suggesting the involvement of a new, hitherto unknown functional receptor for IL-1. 2. The objective of the present study was to determine if primary mixed glial cells express additional functional IL-1 receptors by studying the signalling mechanisms responsible for the pro-inflammatory actions of IL-1beta in cultures derived from IL-1RI-/- and wildtype mice, and to characterize the functional importance of IL-1 signalling pathways in glia. 3. IL-1beta induced marked release of IL-6 and prostaglandin-E(2) (PGE(2)) in the culture medium, and activated nuclear factor-kappa B (NFkappaB) and the mitogen-activated protein kinases (MAPK) p38, c-Jun N-terminal kinase (JNK) and the extracellular signal-regulated protein kinase (ERK1/2) in cells from wildtype mice. These responses were dependent on IL-1RI, since cells isolated from IL-1R1-/- mice did not demonstrate any of these responses. 4. In wildtype mice, inhibition of p38 or ERK1/2 MAPKs significantly reduced IL-1beta induced IL-6 release, whilst the NFkappaB inhibitor caffeic acid phenethyl ester (CAPE) modulated IL-1 induced IL-6 release by action on NFkappaB and MAPKs pathways. 5. These data demonstrate that IL-1RI is essential for IL-1beta signalling in cultured mixed glial cells. Thus IL-1 actions observed in IL-1RI-/- mice in vivo may occur via an alternative pathway and/or via different CNS cells.
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PMID:IL-1 beta signalling in glial cells in wildtype and IL-1RI deficient mice. 1201 Jul 81

We investigated the regulation of PG production in human endometrial stromal cells (ESC) by IL-1beta. We found that cyclooxygenase-2 (COX-2) mRNA and protein levels and PGE(2) production in ESC were significantly increased by IL-1beta. COX-2 mRNA, protein, and PGE(2) levels in IL-1beta-treated ESC were decreased by a PKA inhibitor, a nuclear factor (NF-kappaB) inhibitor, and an ERK1/2 inhibitor, but not by a p38 MAPK inhibitor or a PKC inhibitor, suggesting the possible involvement of PKA, NF-kappaB, and/or the ERK1/2 signaling pathway(s) in IL-1beta-mediated COX-2 gene induction in ESC. We then transiently transfected deletion mutants of the COX-2 promoter fused to the luciferase reporter gene and variants of -360/+56 bp promoter construct carrying different site-directed mutations of selected cis-acting elements. We determined that a NF-kappaB site (-222/-213 bp), a nuclear factor for IL-6 expression site (NF-IL6, -132/-124 bp), and a cAMP response element (-59/-52 bp) were essential for the baseline COX-2 gene promoter regulation. The addition of IL-1beta, however, did not affect the activity of these COX-2 promoter constructs. To investigate the potential effects of IL-1beta on COX-2 mRNA stability, ESC were treated with actinomycin D, a general transcription inhibitor, in the absence or presence of IL-1beta. We found that 1) IL-1beta significantly increased COX-2 mRNA stability; 2) continuous transcription was not required to sustain the IL-1beta-induced COX-2 mRNA levels; and 3) COX-2 mRNA was highly unstable in the absence of IL-1beta. Additionally, we found that the ERK1/2 signaling pathway was essential for stabilizing COX-2 mRNA. We conclude that levels of COX-2 mRNA, protein, and enzyme activity in ESC are controlled by various signaling pathways, including PKA, ERK1/2, and NF-kappaB. Moreover, posttranscriptional mRNA stability is an important mechanism for IL-1beta-induced elevation of COX-2 expression in ESC.
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PMID:Interleukin-1beta elevates cyclooxygenase-2 protein level and enzyme activity via increasing its mRNA stability in human endometrial stromal cells: an effect mediated by extracellularly regulated kinases 1 and 2. 1210 35


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