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)

CCAAT/enhancer binding protein beta (C/EBP beta) also named liver-enriched transcriptional activating protein (LAP) is a member of the C/EBP family of transcription factors and is involved in hepatocyte-specific gene expression and in the process of tissue differentiation. The activity of LAP/C/EBP beta can be regulated at the transcriptional and posttranslational level or by protein-protein interaction with other transcription factors. In this study we show that LAP/C/EBP beta can stimulate its own transcription. Deletion analysis of the rat LAP/C/EBP beta promoter in luciferase reporter gene experiments demonstrated that the region located between nucleotide -121 to -71, comprising two recently characterized cAMP responsive element (CRE)-like elements, is important for autoregulation. Gel shift experiments using oligonucleotides with overlapping point mutations identified the sequence GCAATGA (beta-site) adjacent to and partially overlapping the first CRE-like site as core motif for LAP/C/EBP beta binding. Analysis of a mutated beta-site in reporter gene experiments showed the functional relevance of this site for autoregulation. The composite C/EBP beta-CRE-element in the promoter enables synergistic activation of transcription by LAP/C/EBP beta and the protein kinase A (PKA)/cAMP responsive element binding protein (CREB) pathway in a cell-type specific manner. In hepatoma cells nuclear factor kappa B (NF-kappa B) increased autoregulation and therefore could mediate enhanced activation during inflammatory responses. In summary, our results demonstrated that the assembly of the three binding sites in the promoter and thus the interaction between LAP/C/EBP beta and members of the CREB or NF-kappa B family allows the control of LAP/C/EBP beta gene transcription as a response to different stimuli in a tissue specific manner.
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PMID:Autoregulation enables different pathways to control CCAAT/enhancer binding protein beta (C/EBP beta) transcription. 1139 64

The essential role of CCAAT/enhancer binding proteins (C/EBPs) beta and delta for adipocyte differentiation has been clearly established. In preadipocytes, their expression is up-regulated by the activation of leukemia inhibitory factor receptor (LIF-R) and prostacyclin receptor (IP-R) via the extracellular signal-regulated kinase (ERK) pathway and cAMP production, respectively. However, the molecular mechanisms by which LIF and prostacyclin-induced signals are propagated to the nucleus and the transcription factors mediating ERK and cAMP-induced C/EBP gene expression were unknown. Here we report that both pathways share cAMP responsive element binding protein/activation transcription factor 1 (CREB/ATF-1) as common downstream effectors. LIF-R and IP-R activation induced binding of CREB and/or ATF-1 to C/EBP promoters and CREB-dependent transcription. Expression of dominant negative forms of CREB dramatically reduced the LIF- and prostacyclin-stimulated C/EBP beta and C/EBP delta expression. Upon stimulation of the IP-R, the ERK pathway was activated in a PKA-dependent manner. ERK activation by the PKA pathway was not required for CREB/ATF-1 phosphorylation but rather was necessary for CREB-dependent up-regulation of C/EBPs expression. Our findings suggest that ERK activation is required for CREB transcriptional activity, possibly by recruitment of a coactivator.
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PMID:Activation of extracellular signal-regulated kinases and CREB/ATF-1 mediate the expression of CCAAT/enhancer binding proteins beta and -delta in preadipocytes. 1168 32

Cyclic AMP-dependent protein kinase (PKA) signaling has been shown to be a critical regulator for neuronal or glial differentiation in the developing brain and several neuronal cell lines. However, the involvement of the PKA signaling cascade in hippocampal neuronal development and differentiation is poorly understood. The present study was performed to investigate whether activation of the PKA pathway directly regulates differentiation of hippocampal progenitor cell line, HiB5. Treatment of hippocampal HiB5 cells with 0.5 mM dibutyryl-cyclic AMP (dbcAMP) at 39 degrees C in N2 medium caused dramatic morphological changes including neurite outgrowth within 24 h and an inhibition of proliferation. During these processes, PKA activity as well as phosphorylation of the cAMP responsive element binding protein (CREB) were augmented. To characterize dbcAMP-induced differentiation of HiB5 cells, the expressions of several neuronal marker genes were investigated. After 24 h of dbcAMP treatment, the expression of NF-H and NF-M neuronal makers increased with a concomitant decrease in nestin (a marker for neural precursor cells) and GFAP an astrocyte marker expression, suggesting that HiB5 cells can develop a neuronal phenotype. Using the doxycycline-inducible, enhanced GFP-fused PKA catalytic subunit alpha (PKAcalpha-EGFP) overexpression system, we found that overexpressed PKAcalpha-EGFP induces neurite outgrowth in HiB5 cells. Taken together, these pharmacological and genetic transfection studies provide compelling evidence for the role of PKA activation on neuronal differentiation in HiB5 hippocampal progenitor cells.
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PMID:Activation of protein kinase A induces neuronal differentiation of HiB5 hippocampal progenitor cells. 1253 23

The second messenger cAMP stimulates transcription with burst-attenuation kinetics that mirror the PKA-dependent phosphorylation and subsequent protein phosphatase 1 (PP1)-mediated dephosphorylation of the cAMP responsive element binding protein (CREB) at Ser133. Phosphorylation of Ser133 promotes recruitment of the co-activator histone acetylase (HAT) paralogs CBP and P300, which in turn stimulate acetylation of promoter-bound histones during the burst phase. Remarkably, histone deacetylase (HDAC) inhibitors seem to potentiate CREB activity by prolonging Ser133 phosphorylation in response to cAMP stimulus, suggesting a potential role for HDAC complexes in silencing CREB activity. Here we show that HDAC1 associates with and blocks Ser133 phosphorylation of CREB during pre-stimulus and attenuation phases of the cAMP response. HDAC1 promotes Ser133 dephosphorylation via a stable interaction with PP1, which we detected in co-immunoprecipitation and co-purification studies. These results illustrate a novel mechanism by which signaling and chromatin-modifying activities act coordinately to repress the activity of a phosphorylation-dependent activator.
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PMID:Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex. 1260 16

Activation of cAMP responsive element binding protein (CREB) has been increasingly implicated in the formation and maintenance of long-term memory. To elucidate molecular mechanisms that underlie the persisting alterations in motor response occurring with levodopa (L-dopa) treatment of parkinsonian patients, we evaluated the time course of these changes in relation to the activation of striatal CREB in 6-hydroxydopamine (6-OHDA) lesioned animals. Three weeks of twice-daily L-dopa treatment reduced the duration of the rotational response to acute L-dopa challenge in hemiparkinsonian rats, which lasted about 5 weeks after withdrawal of chronic L-dopa therapy. This shortened response duration, resembling human wearing-off fluctuations, was associated with a marked increase in Ser-133 phosphorylated CREB (pCREB) immunoreactivity in medium spiny neurons in dorsolateral striatum in response to acute dopaminomimetic challenge. Intermittent treatment with the D1 receptor-preferring agonist SKF 38393, but not the D2 receptor-preferring agonist quinpirole, produced a similar rise in CREB phosphorylation. The time course of changes in CREB phosphorylation correlated with the time course of changes in motor behavior after cessation of chronic L-dopa therapy. Both the altered motor response duration and the degree of CREB phosphorylation were attenuated by the intrastriatal administration of CREB antisense or protein kinase A inhibitor Rp-cAMPS. The results suggest that region-specific Ser-133 CREB phosphorylation in D1 receptor containing spiny neurons contributes to the persistence of the motor response alterations produced by intermittent stimulation of striatal dopaminergic receptors.
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PMID:Cyclic AMP responsive element binding protein phosphorylation and persistent expression of levodopa-induced response alterations in unilateral nigrostriatal 6-OHDA lesioned rats. 1277 17

cAMP responsive element binding protein (CREB) is a stimulus induced transcription factor with possible relevance for the pathophysiology of the heart. In the present study, we provide evidence that the hypertrophic agonist, phenylephrine (PE), promotes phosphorylation of CREB in adult rat cardiac myocytes through alpha(1)- and beta-adrenergic receptors. PE-induced phosphorylation of CREB was partially inhibited by Ro318220 and H89, which were shown to be potent inhibitors of mitogen- and stress-activated protein kinase-1 (MSK1) activation, implicating the involvement of this kinase in the response. Similar results were obtained when cardiac myocytes were treated with the inhibitors of ERK1/2 and p38 MAPK pathways. In addition, inhibition of protein kinase A by RpcAMP reduced phosphorylation of CREB, suggesting that this pathway is also involved. Furthermore, PE stimulation was accompanied by an increase in CRE-binding activity, which was reduced by drugs that prevented phosphorylation of CREB. An enhanced CBP/phospho-CREB complex formation was also observed, suggesting recruitment of CBP to phosphorylated CREB. These results suggest that PE stimulates phosphorylation and DNA binding activity of CREB in adult rat ventricular myocytes through multiple signaling pathways involving ERK1/2, p38 MAPK, MSK1 and PKA. The same pathways seem to regulate atrial natriuretic peptide (ANF) mRNA expression, a highly conserved marker gene of cardiac hypertrophy, suggesting that the PE-stimulated activation of CREB is likely to play an important role in the hypertrophic response.
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PMID:Phenylephrine induces activation of CREB in adult rat cardiac myocytes through MSK1 and PKA signaling pathways. 1552 77

In antidiuresis, vasopressin (AVP) occupation of V2 receptors in renal collecting ducts activates adenylyl cyclase, resulting in increased intracellular cAMP levels, which activates protein kinase A (PKA). PKA phosphorylates both the cAMP responsive element binding protein, which induces aquaporin-2 (AQP2) transcription, and AQP2, which then is translocated to the apical membrane, allowing urine concentration. Lithium treatment often causes nephrogenic diabetes insipidus (NDI), which coincides with decreased AQP2 expression and which generally is ascribed to reduced adenylyl cyclase activity. However, the underlying mechanism by which lithium causes NDI is poorly understood. This study demonstrated that the mouse cortical collecting duct mpkCCD(c14) cells are a good model; the deamino-8 D-arginine vasopressin (dDAVP)-induced endogenous AQP2 expression and plasma membrane localization was time-dependently reduced by treatment with clinically relevant lithium concentrations. Lithium did not affect AQP2 stability but decreased its mRNA levels. Surprising, the effect of lithium was cAMP independent; it did not alter AVP-stimulated cAMP production or PKA-dependent phosphorylation of AQP2 or cAMP responsive element binding protein. In vivo, kidney tissue of rats with lithium-induced NDI indeed generated less dDAVP-induced cAMP than that of controls, but this could be due to elevated blood AVP levels in rats with lithium-induced NDI. Indeed, Brattleboro rats, which lack endogenous AVP, with clamped blood dDAVP levels, showed no difference in dDAVP-generated cAMP generation between kidneys of rats with lithium-induced NDI and control rats. In conclusion, the first proper cell model to study lithium-induced NDI was developed, and it was demonstrated that the lithium-induced downregulation of AQP2 and development of NDI occur independent of adenylyl cyclase activity in vitro and in vivo.
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PMID:Development of lithium-induced nephrogenic diabetes insipidus is dissociated from adenylyl cyclase activity. 1654 May 56

Fluid shear stress plays a critical role in vascular health and disease. While protein kinase A (PKA) has been implicated in shear-stimulated signaling events in endothelial cells, it remains unclear whether and how PKA is stimulated in response to shear stress. This issue was addressed in the present study by monitoring the phosphorylation of endogenous substrates of PKA. Shear stress stimulated the phosphorylation of cAMP responsive element binding protein (CREB) in a PKA-dependent manner. Western blot analysis using the antibody reactive against the consensus motif of PKA substrates detected two proteins, P135 and P50, whose phosphorylation was increased by shear stress. The phosphorylation of P135 was blocked by a PKA inhibitor, H89, but not by a phosphoinositide 3-kinase inhibitor, wortmannin. Expression of a constitutively active PKA subunit stimulated P135 phosphorylation, supporting the potential of P135 as a PKA substrate. P135 was identified as endothelial nitric oxide synthase (eNOS) by immunoprecipitation study. PKA appeared to mediate shear stress-stimulated eNOS activation. Shear stress stimulated intracellular translocation of PKA activity from 'soluble' to 'particulate' fractions without involving cellular cAMP increase. Taken together, this study suggests that shear stress stimulates PKA-dependent phosphorylation of target proteins including eNOS, probably by enhancing intracellular site-specific interactions between protein kinase and substrates.
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PMID:Shear stress stimulates phosphorylation of protein kinase A substrate proteins including endothelial nitric oxide synthase in endothelial cells. 1698 8

Substrate recognition and specificity are essential for the reliability and fidelity of protein kinase function. GSK-3 has a unique substrate specificity that requires prior phosphorylation of its substrates. However, how the enzyme selects its phosphorylated substrates is unknown. Here, we combined in silico modeling with mutagenesis and biological studies to identify GSK-3-substrate interaction sites located within its binding cleft. Protein-protein docking of GSK-3beta and the phosphorylated cAMP responsive element binding protein (pCREB) (using the available experimentally determined structures), identified Phe67, Gln89, and Asn95 of GSK-3beta as putative binding sites interacting with the CREB phosphorylation motif. Mutations of these residues to alanine impaired GSK-3beta phosphorylation of several substrates, without abrogating its autocatalytic activity. Subsequently, expression of the GSK-3beta mutants in cells resulted in decreased phosphorylation of substrates CREB, IRS-1, and beta-catenin, and prevented their suppression of glycogen synthase activity as compared with cells expressing the wild-type GSK-3beta. Our studies provide important additional understanding of how GSK-3beta recognizes its substrates: In addition to prior phosphorylation typically required in GSK-3 substrates, substrate recognition involves interactions with GSK-3beta residues: Phe67, Gln89, and Asn95, which confer a common basis for substrate binding and selectivity, yet allow for substrate diversity.
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PMID:Identification of novel glycogen synthase kinase-3beta substrate-interacting residues suggests a common mechanism for substrate recognition. 1689 89

The present study was undertaken to characterize neuronal activity-dependent expression and release of vascular endothelial growth factor (VEGF) from rat hippocampal neurons and its contribution to neuronal functions. Increased levels of VEGF164 mRNA were evident both in cultured neurons and slices, but not astrocytes, following membrane depolarization with KCl. Activity-dependent expression of VEGF, as well as its release, was dependent on the activation of the N-methyl-d-aspartate receptors or L-type voltage-activated calcium channels. A brief (10 min) application of recombinant VEGF165 to neurons elicited a slow rise in cytosolic Ca2+ in a VEGFR2 dependent manner. The VEGF-induced Ca2+ responses required Ca2+ influx, phospholipase Cgamma and Ca2+ stores. An inhibitor of transient receptor potential canonical channels reduced the VEGF-induced Ca2+ responses by 50%, suggesting the involvement of transient receptor potential canonical channels in the VEGF-mediated responses. The same brief stimulus with VEGF led to long-term synaptic enhancement dependent on protein synthesis. VEGF had prominent effects on the activation calcium/calmodulin protein kinase II and cAMP responsive element binding protein as well as extracellular signal-regulated protein kinase and mammalian target of rapamycin-all in a VEGFR2 dependent manner. Our findings suggest that VEGF released from neuronal cells plays a local role in Ca2+ influx and synaptic transmission that may influence the generation of long-term changes in synaptic efficacy.
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PMID:Vascular endothelial growth factor (VEGF) signaling regulates hippocampal neurons by elevation of intracellular calcium and activation of calcium/calmodulin protein kinase II and mammalian target of rapamycin. 1822 55


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