Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta (TGF-beta) plays complex roles in carcinogenesis, as it may exert both tumor suppressor and pro-oncogenic activities depending on the stage of the tumor. SMAD proteins transduce signals from the TGF-beta receptors to regulate the transcription of specific target genes. Crosstalks with other signaling pathways may contribute to the specificity of TGF-beta effects. In this report, we have investigated the effects of cyclic adenosine 3',5'-monophosphate (cAMP), a key second messenger in the cellular response to various hormones, on SMAD-dependent signaling in human HaCaT keratinocytes. Using either an artificial SMAD3/4-dependent reporter construct or the natural TGF-beta target, plasminogen activator inhibitor-1, we show that membrane-permeable dibutyryl cAMP, and other intracellular cAMP-elevating agents such as the phosphodiesterase inhibitor isobutyl-methylxanthine, the adenylate cyclase activator forskolin, or exogenous prostaglandin E2 (PGE2), interfere with TGF-beta-induced SMAD-specific gene transactivation. Inhibition of protein kinase A (PKA), the main downstream effector of cAMP, with H-89, suppressed cAMP-dependent repression of SMAD-driven gene expression. Inversely, coexpression of either an active PKA catalytic subunit or that of the cAMP response element (CRE)-binding protein (CREB) blocked SMAD-driven gene transactivation. cAMP-elevating agents did not inhibit nuclear translocation and DNA binding of SMAD3/4 complexes, but abolished the interactions of SMAD3 with the transcription coactivators CREB-binding protein (CBP) and p300 in a PKA-dependent manner. These results suggest that suppression of TGF-beta/SMAD signaling and resulting gene transactivation by cAMP-inducing agents occurs via PKA-dependent, CREB-mediated, disruption of SMAD-CBP/p300 complexes.
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PMID:Cyclic adenosine 3',5'-monophosphate-elevating agents inhibit transforming growth factor-beta-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism. 1465 84

The ability of CREB binding protein (CBP) and p300 co-activators to stimulate transcription has previously been shown to be enhanced by treatment of cardiac cells with the hypertrophic agent phenylephrine (PE). This effect is dependent on activation of the mitogen activated protein kinase pathway (p42/44 MAPK). Here, we demonstrate the first identification of potential phosphorylation sites targeted by PE within the proteins CBP and p300. We show that serine 2015 of CBP and serine 89 of p300 are necessary for PE to stimulate the transcriptional activity of these proteins. Furthermore, we have shown that PE is capable of mediating phosphorylation of endogenous p300 at serine 89. This phosphorylation mediated regulation of CBP and p300 suggests a potential signal transduction pathway for the induction of cardiac cell hypertrophy by PE.
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PMID:Distinct serine residues in CBP and p300 are necessary for their activation by phenylephrine. 1500 41

We demonstrate here that growth hormone (GH) stimulates the activation of RhoA and its substrate Rho kinase (ROCK) in NIH-3T3 cells. GH-stimulated formation of GTP-bound RhoA requires JAK2-dependent dissociation of RhoA from its negative regulator p190 RhoGAP. Inactivation of RhoA does not affect GH-stimulated JAK2 tyrosine phosphorylation nor p44/42 MAPK activity. However, RhoA and ROCK activities are required for GH-stimulated, Stat5-mediated transcription. RhoA-dependent enhancement of GH-stimulated, Stat5-mediated transcription is due to repression of histone deacetylase 6 activity recruited by transcription cofactor p300 that negatively regulates GH-stimulated, Stat5-mediated transcription. We also demonstrate that RhoA is the pivot for cAMP-dependent protein kinase inhibition of GH-stimulated, Stat5-mediated transcription as a consequence of cAMP-dependent protein kinase inactivation of RhoA through serine residue 188 of RhoA. We have therefore provided a novel mechanism by which a Ras-like small GTPase, RhoA, can regulate Stat5-mediated transcription.
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PMID:RhoA/ROCK activation by growth hormone abrogates p300/histone deacetylase 6 repression of Stat5-mediated transcription. 1510 57

The androgen receptor (AR) regulates ligand-dependent gene transcription upon binding specific DNA sequences. The AR conveys both trans-activation and trans-repression functions, which together contribute to prostate cellular growth, differentiation, and apoptosis. Like histone H3, the AR is post-translationally modified by both acetylation and phosphorylation. The histone acetyltransferase p300 transactivates the AR and directly acetylates the AR in vitro at a conserved motif. Point mutations of the AR acetylation motif that abrogate acetylation reduce trans-activation by p300 without affecting the trans-repression function of the AR. The current studies assessed the functional relationship between acetylation and phosphorylation of the AR. Herein trans-activation of the AR acetylation site mutants were enhanced by the p42/p44 MAPK pathway but were defective in regulation by protein kinase A (PKA) signaling. PKA inhibition augmented ARwt activity but not AR acetylation mutant gene reporter activity and association at an androgen response element in chromatin immunoprecipitation assays. Mutations of the lysine residues at the AR acetylation site reduced trichostatin A (TSA) responsiveness and ligand-induced phosphorylation of the AR. The AR acetylation site mutant formed ligand-induced phosphorylation-dependent isoforms with distinguishable characteristics from wild type AR as determined with two-dimensional electrophoresis. Conversely, point mutation of a subset of AR phosphorylation sites reduced trichostatin A responsiveness and trans-activation by histone acetyltransferases. Together these studies suggest that acetylation and phosphorylation of the AR are linked events and that the conserved AR lysine motif contributes to a select subset of pathways governing AR activity.
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PMID:The androgen receptor acetylation site regulates cAMP and AKT but not ERK-induced activity. 1512 87

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

Recruitment of a RNA polymerase II complex by the glutamine-rich Q2 domain of cAMP response element-binding protein (CREB) allows basal transcriptional activity, while recruitment of CBP/p300 through signal-induced phosphorylation of the kinase-inducible domain at serine-133 enhances CREB-dependent transcription. Here we demonstrate that co-administration of forskolin and phorbol ester TPA to NIH3T3 cells provoked a dose-dependent increase in phosphoserine-133. CREB- and Q2-dependent transcription, as well as transcription by other glutamine-rich transcription factors, but not by transcription factors lacking glutamine-rich regions, augmented synergistically in the presence of both stimuli. Synergistic activation was abograted by specific inhibition of protein kinase C (PKC), but not of PKA. Co-stimulation increased the basal activity of a minimal, CREB-independent promoter. Therefore, Q2, which directly interacts with the RNA polymerase II initiation complex, may transmit the increased basal promoter activity provoked by these stimuli to CREB, thereby contributing to synergistic activation of CREB-mediated transcription. This synergism may have important implications on glutamine-rich transcription factor-target genes.
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PMID:Synergistic activation of CREB-mediated transcription by forskolin and phorbol ester requires PKC and depends on the glutamine-rich Q2 transactivation domain. 1524 13

We examined whether antithrombin (AT) inhibits tumor necrosis factor (TNF)-alpha-induced endothelial cell activation to elucidate molecular mechanism(s) of the anti-inflammatory activity of AT. AT inhibited the increase in E-selectin expression in cultured human umbilical vein endothelial cells (HUVECs) stimulated with TNF-alpha. In contrast, chemically modified AT that lacks affinity for heparin did not. AT inhibited the TNF-alpha-induced interaction of NF-kappaB p65 with p300, a homologue of cAMP-responsive element binding protein (CREB)-binding protein (CBP). AT increased both intracellular levels of cAMP and binding of phosphorylated-CREB to DNA in HUVECs. Forskolin showed the inhibitory effect similar to that of AT and pretreatment of HUVECs with KT-5720, an inhibitor of protein kinase A, reversed the inhibitory effect of AT. These observations suggested that AT inhibited the TNF-alpha-induced increase in E-selectin expression in HUVECs by inhibiting the interaction of NF-kappaB with CBP/p300 through cAMP-dependent protein kinase A-induced CREB activation. This inhibitory activity of AT might depend on its binding to heparin-like substances on the endothelial cell. Such an inhibitory effect of AT on TNF-alpha-induced endothelial cell activation might at least partly contribute to its anti-inflammatory activity.
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PMID:Inhibition of the endothelial cell activation by antithrombin in vitro. 1558 52

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] induces the synthesis of 25-hydroxyvitamin D(3) 24-hydroxylase [24(OH)ase], an enzyme involved in its catabolism, thereby regulating its own metabolism. Here we demonstrate that CCAAT enhancer binding protein beta (C/EBPbeta) is induced by 1,25(OH)(2)D(3) in kidney and in osteoblastic cells and is a potent enhancer of vitamin D receptor (VDR)-mediated 24(OH)ase transcription. Transfection studies indicate that 1,25(OH)(2)D(3) induction of 24(OH)ase transcription is enhanced a maximum of 10-fold by C/EBPbeta. Suppression of 1,25(OH)(2)D(3)-induced 24(OH)ase transcription was observed with dominant negative C/EBP or osteoblastic cells from C/EBPbeta(-/-) mice. A C/EBP site was identified at positions -395 to -388 (-395/-388) in the rat 24(OH)ase promoter. Mutation of this site inhibited C/EBPbeta binding and markedly attenuated the transcriptional response to C/EBPbeta. We also report the cooperation of CBP/p300 with C/EBPbeta in regulating VDR-mediated 24(OH)ase transcription. We found that not only 1,25(OH)(2)D(3) but also parathyroid hormone (PTH) can induce C/EBPbeta expression in osteoblastic cells. PTH potentiated the induction of C/EBPbeta and 24(OH)ase expression in response to 1,25(OH)(2)D(3) in osteoblastic cells. Data with the human VDR promoter (which contains two putative C/EBP sites) indicate a role for C/EBPbeta in the protein kinase A-mediated induction of VDR transcription. From this study a fundamental role has been established for the first time for cooperative effects and cross talk between the C/EBP family of transcription factors and VDR in 1,25(OH)(2)D(3)-induced transcription. These findings also indicate a novel role for C/EBPbeta in the cross talk between PTH and 1,25(OH)(2)D(3) that involves the regulation of VDR transcription.
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PMID:Functional cooperation between CCAAT/enhancer-binding proteins and the vitamin D receptor in regulation of 25-hydroxyvitamin D3 24-hydroxylase. 1560 67

Androgen-independent prostate cancer is a lethal form of the disease that is marked by metastasis and rapid proliferation in its final stages. As no effective therapy for this aggressive tumor currently exists, it is imperative to elucidate and target the mechanisms involved in the progression to androgen independence. Accumulating evidence indicates that aberrant activation of androgen receptor (AR) via signal transduction pathways, AR gene mutation and/or amplification, and/or coregulator alterations may contribute to the progression of prostate cancer. In the present study, the effects of protein kinase A (PKA) signaling and its downstream factors on AR activity at the prostate-specific antigen (PSA) gene were tested. Activation of PKA by forskolin resulted in enhanced androgen-induced expression of the PSA gene, an effect that was blocked by the AR antagonist, bicalutamide. Interestingly, when either p300 or CBP was overexpressed, PKA activation was sufficient to stimulate PSA promoter-driven transcription in the absence of androgen, which was not inhibited by bicalutamide. PKA activation did not significantly alter AR protein levels but significantly increased the phosphorylated form of its downstream effector, cAMP responsive element-binding protein (CREB) in the presence of androgen. Furthermore, chromatin immunoprecipitation showed that the combination of androgen and forskolin increased phosphorylated CREB occupancy, which was accompanied by histone acetylation, at the putative cAMP responsive element located in the 5' upstream regulatory region of the PSA gene. Remarkably, mammalian two-hybrid assay indicated that p300/CBP may bridge the interaction between AR and CREB, suggesting a novel enhanceosomal cooperation. These results demonstrate an intriguing interplay between a signal transduction pathway, coactivator overexpression and AR signaling as a possible combined mechanism of progression to androgen-independent prostate cancer.
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PMID:The role of protein kinase A pathway and cAMP responsive element-binding protein in androgen receptor-mediated transcription at the prostate-specific antigen locus. 1569 81

The signal transducers and activators of transcription 1 (Stat1) are essential for the majority of interferon-gamma (IFN-gamma)-regulated gene expression. Phosphorylation of serine 727 in the transcription activation domain of Stat1 is induced in response to IFN-gamma for maximal transcription activity. In this report, we show that crosslinking of B cell antigen receptor (BCR) or T cell antigen receptor (TCR) can enhance S727 phosphorylation in Stat1 and result in increased expression of Stat1 target genes. We further demonstrate that this enhancement by BCR cross-linking involves the widely used secondary messenger Ca2+ and simultaneous activation of multiple serine kinase pathways. When cells are exposed to both IFN-gamma and a Ca2+ fluxing reagent, the level of S727 phosphorylation is enhanced, resulting in increased transcription activation of Stat1 target genes. We directly demonstrate that the biochemical function of phospho-Ser-727 is to enhance the recruitment of transcription coactivator CBP/p300 to the promoters of Stat1 target genes. Furthermore, we show that both the p38 mitogen-activated protein kinase (MAPK) and the Ca(2+)/calmodulin-dependent kinase (CaMKII) are activated in response to BCR signaling to converge on Stat1 S727 for maximal gene expression. These studies demonstrate that a wide variety of noncytokine signaling pathways can modulate cytokine signaling through modulation of Stat1 serine phosphorylation.
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PMID:B cell antigen receptor signaling enhances IFN-gamma-induced Stat1 target gene expression through calcium mobilization and activation of multiple serine kinase pathways. 1569 32


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