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)

Trichothecene mycotoxins and other translational inhibitors activate mitogen-activated protein kinase (MAPKs) by a mechanism called the "ribotoxic stress response," which drives both cytokine gene expression and apoptosis in macrophages. The purpose of this study was to identify upstream kinases involved in the ribotoxic stress response using the trichothecene deoxynivalenol (DON) and the RAW 264.7 macrophage as models. DON (100 to 1000 ng/ml) dose-dependently induced phosphorylation of c-Jun N-terminal protein kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPKs. MAPK phosphorylation in response to DON exposure occurred as early as 5 min, was maximal from 15 to 30 min, and lasted up to 8 h. Preincubation with inhibitors of protein kinase C, protein kinase A, or phospholipase C had no effect on DON-induced MAPK phosphorylation. In contrast, the Src family tyrosine kinase inhibitors, PP1 (4-amino-5-[4-methylphenyl)]-7-[t-butyl]pyrazolo[3,4-d]-pyrimidine) and, PP2 (4-amino-5-[4-chlorophenyl]-7-[t-butyl]pyrazolo[3,4-d]-pyrimidine) concentration-dependently impaired phosphorylation of all three MAPK families. PP1 suppressed DON-induced phosphorylation of the MAPK substrates c-jun, ATF-2, and p90(Rsk). MAPK phosphorylation by two other translational inhibitors, anisomycin and emetine, were similarly Src-dependent. PP1 reduced DON-induced increases in nuclear levels and binding activities of several transcription factors (NF-kappaB, AP-1, and C/EBP), which corresponded to decreases in TNF-alpha production, caspase-3 activation, and apoptosis. Tyrosine phosphorylation of hematopoeitic cell kinase (Hck), a Src found in macrophages, was detectable within 1 to 5 min after DON addition, and this was suppressed by PP1. Knockdown of Hck expression with siRNAs confirmed involvement of this Src in DON-induced TNF-alpha production and caspase activation. Taken together, activation of Hck and possibly other Src family tyrosine kinases are likely to be critical signals that precede both MAPK activation and induction of resultant downstream sequelae by DON and other ribotoxic stressors.
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PMID:Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. 1577 66

CCAAT enhancer-binding protein (C/EBP)beta, C/EBPalpha, and peroxisome proliferator activated receptor (PPAR)gamma act in a cascade where C/EBPbeta activates expression of C/EBPalpha and PPARgamma, which then function as pleiotropic activators of genes that produce the adipocyte phenotype. When growth-arrested 3T3-L1 preadipocytes are induced to differentiate, C/EBPbeta is rapidly expressed but still lacks DNA-binding activity. After a long (14-hour) lag, glycogen synthase kinase 3beta enters the nucleus, which correlates with hyperphosphorylation of C/EBPbeta and acquisition of DNA-binding activity. Concurrently, 3T3-L1 preadipocytes synchronously enter S phase and undergo mitotic clonal expansion, a prerequisite for terminal differentiation. Ex vivo and in vitro experiments with C/EBPbeta show that phosphorylation of Thr-188 by mitogen-activating protein kinase "primes" C/EBPbeta for subsequent phosphorylation on Ser-184 and Thr-179 by glycogen synthase kinase 3beta, acquisition of DNA-binding function, and transactivation of the C/EBPalpha and PPARgamma genes. The delayed transactivation of the C/EBPalpha and PPARgamma genes by C/EBPbeta appears necessary to allow mitotic clonal expansion, which would otherwise be prevented, because C/EBPalpha and PPARgamma are antimitotic.
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PMID:Sequential phosphorylation of CCAAT enhancer-binding protein beta by MAPK and glycogen synthase kinase 3beta is required for adipogenesis. 1598 51

Interleukin-6 (IL-6), and the related cytokines IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), are potent stimulators of osteoclastic bone resorption. In the present study, we have addressed the possibility that the neuropeptide vasoactive intestinal peptide (VIP) may regulate the production of and/or sensitivity to the IL-6 family of cytokines in mouse calvarial osteoblasts. VIP stimulated IL-6 mRNA expression and protein release in a time- and concentration-dependent manner, whereas mRNA expression of the IL-6 receptor, as well as mRNA expressions of IL-11, LIF, OSM and their cognate receptors, were unaffected by VIP. In cells transfected with the IL-6 promoter coupled to luciferase, VIP increased transcriptional activity. The effects of VIP were shared by the related neuropeptide PACAP-38, belonging to the same superfamily of neuropeptides, whereas secretin did not have any effect, indicating that the effects were mediated by VPAC2 receptors. The effects of VIP were potentiated by the cyclic AMP phosphodiesterase inhibitor rolipram and mimicked by forskolin, indicating the involvement of the cyclic AMP/protein kinase A pathway. This was further demonstrated by the facts that the stimulatory effect of VIP on luciferase activity could be reversed by the PKA inhibitors H-89 and KT5720 and was mimicked by cyclic AMP analogues selective for PKA, but not by those selective for Epac. In addition, VIP enhanced the phosphorylation of CREB, as assessed by both immunocytochemical analysis and Western blot. The DNA binding activity of nuclear extracts to C/EBP was increased by VIP, whereas binding to AP-1 was decreased. In contrast, DNA binding to NF-kappaB, as well as nuclear translocation of NF-kappaB and C/EBP, were unaffected by VIP. The mRNA expressions of C/EBPbeta, C/EBPdelta, C/EBPgamma, c-Jun, JunB, c-Fos, Fra-1 and IkappaBalpha and protein level of IkappaBalpha were all unaffected by VIP. These observations, together, demonstrate that VIP stimulates IL-6 production in osteoblasts by a mechanism likely to be mediated by VPAC2 receptors and dependent on cyclic AMP/protein kinase A/CREB activation and also involving the transcription factors C/EBP and AP-1.
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PMID:Increased expression of interleukin-6 by vasoactive intestinal peptide is associated with regulation of CREB, AP-1 and C/EBP, but not NF-kappaB, in mouse calvarial osteoblasts. 1608 72

We previously reported that cardiac fibroblasts, but not cardiomyocytes, are served as the predominant source of IL-6 after isoproterenol stimulation in mouse myocardium. The present study investigated the molecular mechanism of isoproterenol-mediated secretion of IL-6 in mouse cardiac fibroblasts. Treatment of cells with isoproterenol-induced a time-dependent accumulation of IL-6, which was mediated by beta(2)-adrenergic receptor (AR), the preponderant beta-AR subtype in cardiac fibroblasts. Isoproterenol-induced secretion of IL-6 was mainly mediated by Gs-AC-cAMP signaling cascade and could be negatively regulated by Gi and PI3K. Surprisingly, the effect of cAMP was independent of protein kinase A and the exchange protein directly activated by cAMP (Epac)-Rap1 pathway and suggests the existence of a novel cAMP-dependent mechanism. p38 MAPK inhibitor SB203580, but not extracellular regulated protein kinase inhibitor, abrogated isoproterenol-induced IL-6 release in cardiac fibroblasts and mouse myocardium. Interestingly, p38 MAPK could also be positively regulated by Gs-AC-cAMP but negatively regulated by Gi-PI3K pathway. Finally, multiple transcription factors (AP-1, C/EBP, NF-kappaB and CREB) regulating the IL-6 gene are activated in response to isoproterenol stimulation, which may provide essential linkage between upstream cAMP-p38 MAPK signaling cascade and downstream IL-6 gene transcription. The present results suggest that beta(2)-AR mediates IL-6 production through a noncanonical cAMP responsible pathway and p38 MAPK.
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PMID:Noncanonical cAMP pathway and p38 MAPK mediate beta2-adrenergic receptor-induced IL-6 production in neonatal mouse cardiac fibroblasts. 1646 39

We examined whether the unfolded protein response is activated in cells expressing incorrectly folded cystic fibrosis transmembrane conductance regulator. Airway epithelial cells from three control and three CF patients homozygous for the deltaF508 mutation were tested. There were no differences in protein expression of the pro-apoptotic factor C/EBP homologous protein (CHOP) or the endoplasmic reticulum (ER) chaperone binding Ig protein. Nor were there differences in phosphorylation of protein kinase R-like ER kinase or eukaryotic initiation factor-2alpha, or the splicing of X-box binding protein (XBP)-1. However, CF cells showed increased mRNA expression of CHOP and XBP-1. A proteasome inhibitor increased CHOP expression in CF cells, suggesting that enhanced proteasome activation is responsible for the observed post-transcriptional regulation. Finally, CF cells were resistant to apoptosis, suggesting that post-transcriptional regulation of CHOP prevents apoptosis. While CHOP and XBP-1 mRNA expression is increased in CF cells, the classic UPR is not present.
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PMID:Absence of typical unfolded protein response in primary cultured cystic fibrosis airway epithelial cells. 1653 Jan 68

Nerve growth factor (NGF) synthesis in the rat cerebral cortex is induced by the beta2-adrenergic receptor agonist clenbuterol (CLE). Because NGF is a crucial neurotrophic factor for basal forebrain cholinergic neurons, defining the mechanisms that regulate its transcription is important for developing therapeutic strategies to treat pathologies of these neurons. We previously showed that the transcription factor CCAAT/enhancer-binding protein delta (C/EBPdelta) contributes to NGF gene regulation. Here we have further defined the function of C/EBPdelta and identified a role for cAMP response element-binding protein (CREB) in NGF transcription. Inhibition of protein kinase A in C6-2B glioma cells suppressed CLE induction of an NGF promoter-reporter construct, whereas overexpression of protein kinase A increased NGF promoter activity, particularly in combination with C/EBPdelta. A CRE-like site that binds CREB was identified in the proximal NGF promoter, and C/EBPdelta and CREB were found to associate with the NGF promoter in vivo. Deletion of the CRE and/or C/EBP sites reduced CLE responsiveness of the promoter. In addition, ectopic expression of C/EBPdelta in combination with CLE treatment increased endogenous NGF mRNA levels in C6-2B cells. C/EBPdelta null mice showed complete loss of NGF induction in the cerebral cortex following CLE treatment, demonstrating a critical role for C/EBPdelta in regulating beta2-adrenergic receptor-mediated NGF expression in vivo. Thus, our findings demonstrate a critical role for C/EBPdelta in regional expression of NGF in the brain and implicate CREB in CLE-induced NGF gene transcription.
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PMID:CAAT/enhancer-binding protein delta and cAMP-response element-binding protein mediate inducible expression of the nerve growth factor gene in the central nervous system. 1663 69

The expression of carbamoylphosphate synthetase-I (CPS), the first and rate-determining enzyme of the urea cycle, is regulated at the transcriptional level by glucocorticoids and glucagon, the latter acting via cyclic AMP (cAMP). The hormonal response is mediated by a distal enhancer located 6.3 kb upstream of the transcription-start site. Within this enhancer, a cAMP-response unit (CRU) is responsible for mediating cAMP-dependent transcriptional activity. The CPS CRU contains binding sites for cAMP-response element (CRE)-binding protein (CRE-BP), forkhead box A (FoxA), CCAAT/enhancer-binding protein (C/EBP), and an unidentified protein P1. To gain insight in the protein-DNA interactions that activate the CPS CRU in living cells, we have employed in vivo footprinting assays. Comparison of the fibroblast cell line Rat-1 and the hepatoma cell lines FTO-2B and WT-8 showed that FoxA binds the CPS CRU constitutively in CPS-expressing cells only. Comparison of FTO-2B and WT-8 hepatoma cells, which only differ in cAMP responsiveness, demonstrated that the binding of the other transcription factors is dependent on cAMP-dependent protein kinase (PKA) activity. Finally, we observed a footprint between the CRE and the P1-binding site in the in vivo footprint assay that was not detectable by in vitro footprint assays, implying a major change in CRU-associated chromatin conformation upon CRU activation. These findings indicate that activation of the CRU is initiated in a tissue-specific manner by the binding of FoxA. When cellular cAMP and glucocorticoid levels increase, CRE-BP becomes activated, allowing the binding of the remaining transcription factors and the transactivation of the CPS promoter.
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PMID:In vivo footprinting of the carbamoylphosphate synthetase I cAMP-response unit indicates important roles for FoxA and PKA in formation of the enhanceosome. 1682 61

Long-term memory requires transcriptional regulation by a combination of positive and negative transcription factors. Aplysia activating factor (ApAF) is known to be a positive transcription factor that forms heterodimers with ApC/EBP and ApCREB2. How these heterodimers are regulated and how they participate in the consolidation of long-term facilitation (LTF) has not, however, been characterized. We found that the functional activation of ApAF required phosphorylation of ApAF by PKA on Ser-266. In addition, ApAF lowered the threshold of LTF by forming a heterodimer with ApCREB2. Moreover, once activated by PKA, the ApAF-ApC/EBP heterodimer transactivates enhancer response element-containing genes and can induce LTF in the absence of CRE- and CREB-mediated gene expression. Collectively, these results suggest that PKA-activated ApAF-ApC/EBP heterodimer is a core downstream effector of ApCREB in the consolidation of LTF.
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PMID:PKA-activated ApAF-ApC/EBP heterodimer is a key downstream effector of ApCREB and is necessary and sufficient for the consolidation of long-term facilitation. 1696 24

CCAAT enhancer binding protein beta (C/EBPbeta) plays an essential role in the cascade that triggers adipocyte differentiation. C/EBPbeta activates transcription of C/EBPalpha and peroxisome proliferator-activated receptor-gamma, transcriptional activators of genes that give rise to the adipocyte phenotype. Sequential phosphorylation of C/EBPbeta/liver activating protein (LAP) on Thr(188) by MAPK and on Ser(184) or Thr(179) by glycogen synthase kinase beta (GSK3beta) is required for acquisition of DNA binding activity and transcriptional activation. To investigate how phosphorylation and dimerization of C/EBPbeta/LAP alter these activities, wild-type (Wt) and mutant rC/EBPbetas were prepared and purified to assess DNA binding and transcription in cell-free systems. rC/EBPbeta/LAP, phosphorylated by MAPK and GSK3beta in vitro, produced a >100-fold increase in DNA binding activity. Mutation of the phosphorylation to Glu increased DNA binding activity. Using a cell-free transcription system with nuclear extract from 3T3-L1 preadipocytes and rC/EBPbeta/LAP, only doubly phosphorylated rC/EBPbeta/LAP (by MAPK and GSK3beta) activated transcription driven by Wt C/EBPalpha, 422/aP2, and SCD1 promoters. Oxidation-induced dimerization of doubly phosphorylated Wt rC/EBPbeta/LAP increased DNA binding, whereas unphosphorylated Wt rC/EBPbeta/LAP lacked DNA binding activity. Mutation of the C-terminal Cys(296) adjacent to the leucine zipper and Cys(143) just upstream of the DNA binding domain eliminated phosphorylation-, oxidation-, and dimerization-dependent DNA binding activity, whereas mutation of Cys(201) within the basic DNA binding domain had little effect on DNA binding. These findings indicate that dual phosphorylation of C/EBPbeta/LAP caused a conformational change that facilitates S-S bond formation and dimerization, rendering the basic region accessible to the C/EBP regulatory element.
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PMID:Effect of phosphorylation and S-S bond-induced dimerization on DNA binding and transcriptional activation by C/EBPbeta. 1726 4

Repeated pulses of serotonin (5-HT) induce long-term facilitation (LTF) of the synapses between sensory and motor neurons of the gill-withdrawal reflex in Aplysia. To explore how apCAM downregulation at the plasma membrane and CREB-mediated transcription in the nucleus, both of which are required for the formation of LTF, might relate to each other, we cloned an apCAM-associated protein (CAMAP) by yeast two-hybrid screening. We found that 5-HT signaling at the synapse activates PKA which in turn phosphorylates CAMAP to induce the dissociation of CAMAP from apCAM and the subsequent translocation of CAMAP into the nucleus of sensory neurons. In the nucleus, CAMAP acts as a transcriptional coactivator for CREB1 and is essential for the activation of ApC/EBP required for the initiation of LTF. Combined, our data suggest that CAMAP is a retrograde signaling component that translocates from activated synapses to the nucleus during synapse-specific LTF.
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PMID:Nuclear translocation of CAM-associated protein activates transcription for long-term facilitation in Aplysia. 1751 12


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