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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heparan sulfate (HS) is one of the components of extracellular matrix and a potent anti-growth factor in various cells. Heparin has a similar structure to HS and is demonstrated to inhibit myocardial cell hypertrophy. We examined the intracellular signal mechanisms linking to the inhibitory effects of heparin and HS on endothelin-1 (ET-1)-induced hypertrophy in cultured rat neonatal myocardial cells (MCs). Heparin inhibited ET-1-induced c-fos mRNA expression. Heparin and HS inhibited ET-1-induced activation of c-fos promoter/enhancer in MCs. Although heparin and HS inhibited ET-1-induced activation of the wild-type c-fos serum response element (SRE), the activation of a mutated c-fos SRE that contains an intact binding site for the serum response factor (SRF) but lacks the ternary complex factor (TCF) binding site, was not inhibited. In addition, heparin and HS inhibited the activation of TPA response element (TRE). However, heparin did not inhibit the activation of cyclic AMP response element (CRE). Furthermore, heparin and HS inhibited ET-1-induced activation of extracellular signal-regulated kinase (ERK) and phosphorylation of Elk-1, which is one of the TCFs. These results indicate that heparin and HS inhibited ET-1-induced ERK activation, resulting in suppression of Elk-1 phosphorylation, and lead to inhibition of c-fos gene expression through SRF-independent manner. Moreover, heparin and HS inhibited ET-1-induced [3H] leucine incorporation. These results suggest that heparin and HS inhibit ET-1 induced myocardial cell hypertrophy through the inhibition of gene expression and protein synthesis.
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PMID:Heparin and heparan sulfate inhibit extracellular signal-regulated kinase activation and myocardial cell hypertrophy induced by endothelin-1. 1159 24

Soluble mitogens and adhesion-dependent organization of the actin cytoskeleton are required for cells to enter S phase in fibroblasts. The induction of cyclin A is also required for S-phase entry, and we now report that distinct effects of mitogens and the actin cytoskeleton on the phosphorylation of CREB and pocket proteins regulate the extent and timing of cyclin A promoter activity, respectively. First, we show that CREB phosphorylation and binding to the cyclic AMP response element (CRE) determines the extent, but not the timing, of cyclin A promoter activity. Second, we show that pocket protein inactivation regulates the timing, but not the extent, of cyclin A promoter activity. CREB phosphorylation and CRE occupancy are regulated by soluble mitogens alone, while the phosphorylation of pocket proteins requires both mitogens and the organized actin cytoskeleton. Mechanistically, cytoskeletal integrity controls pocket protein phosphorylation by allowing for sustained ERK signaling and, thereby, the expression of cyclin D1. Our results lead to a model of cyclin A gene regulation in which mitogens play a permissive role by stimulating early G(1)-phase phosphorylation of CREB and a distinct regulatory role by cooperating with the organized actin cytoskeleton to regulate the duration of ERK signaling, the expression of cyclin D1, and the timing of pocket protein phosphorylation.
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PMID:Distinct effects of mitogens and the actin cytoskeleton on CREB and pocket protein phosphorylation control the extent and timing of cyclin A promoter activity. 1160 97

In vivo activation of group I metabotropic glutamate receptors (mGluRs) upregulates phosphorylation of cyclic AMP response element-binding protein (CREB), Elk-1 and extracellular signal-regulated kinases (ERK) in striatal neurons. To evaluate putative roles of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in CREB, Elk-1 and ERK phosphorylation, the CaMKII inhibitor, KN62, was infused simultaneously with the group I mGluR agonist, 3,5-dihydroxyphenylglycine (DHPG), into the rat dorsal striatum. The results showed that DHPG (125, 250, and 500 nmol) increased phosphorylated (p) CaMKII immunoreactivity (IR) in a dose-dependent manner. KN62 (50 nmol) significantly attenuated 500 nmol DHPG-induced pERK, pElk-1 and pCREB IR in the ipsilateral dorsal striatum. These data indicate that pCaMKII is a possible upstream effector that is responsible for the regulation of CREB, Elk-1 and ERK phosphoproteins in response to group I mGluR stimulation in striatal neurons.
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PMID:Group I metabotropic glutamate receptors control phosphorylation of CREB, Elk-1 and ERK via a CaMKII-dependent pathway in rat striatum. 1168 44

In the present study, we investigated the effect of glucocorticoid on neuronal differentiation of hippocampal progenitor HiB5 cells. Dexamethasone (DEX), a synthetic glucocorticoid, inhibited platelet-derived growth factor (PDGF)-induced differentiation of HiB5 cells. The inhibitory effect of DEX was antagonized by RU486, a glucocorticoid receptor (GR) antagonist, indicating the GR-mediated processes. Nestin mRNA level was decreased and midsize neurofilament (NF-M) mRNA level was increased as a function of neuronal differentiation. DEX significantly blocked PDGF-induced down-regulation of nestin mRNA level, and up-regulation of NF-M mRNA level, which were similar to those of undifferentiated cells. DEX inhibited PDGF-induced activation of cyclic AMP-responsive element binding protein (CREB) and AP-1, suggesting that glucocorticoid interfered with signal transduction cascades linking the PDGF receptor and downstream transcription factors. Indeed, DEX reduced PDGF-induced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2). Tyrosine phosphatase inhibitor reversed the effect of DEX on ERK1/2. In accordance with this finding, blockage of ERK1/2 signaling pathway with PD098059, a potent inhibitor for Ras/ERK pathway, mimicked the inhibitory effect of DEX on differentiation processes. Taken together, these results indicate that glucocorticoid inhibits PDGF-induced differentiation of hippocampal progenitor HiB5 cells by inhibiting the ERK1/2 signaling cascade via a tyrosine phosphatase-dependent mechanism.
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PMID:Glucocorticoid inhibits growth factor-induced differentiation of hippocampal progenitor HiB5 cells. 1173 13

It has been proposed that binding of ligand to the estrogen receptor (ER) releases its association with transcriptional corepressors, allowing the ER to recruit coactivators, which possess histone acetylase activity, and induce transcription of gene promoters containing estrogen response elements. It has also been proposed that the antiestrogen tamoxifen recruits transcriptional corepressors to the AF-2 region of the hormone-binding domain of the ER, thus blocking ER-mediated transcription. The ER cross-talks with a number of mitogenic signaling pathways and second messengers, like the epidermal growth factor receptor, the insulin-like growth factor-I receptor, mitogen-activated protein (MAP) kinase, phosphatidylinositol-3 kinase/Akt, dopamine, and cyclic AMP. Some of these molecules may: (a) support ligand-independent ER transcription; (b) increase the association of ER with coactivators of transcription; and/or (c) reduce the antiestrogen-induced association of ER with corepressors. These events either alone or in combination may result in hormone independence and/or antiestrogen resistance. We have examined whether signaling by HER2/neu (erbB-2) receptor tyrosine kinase, which can induce antiestrogen resistance, can also disrupt the tamoxifen-induced interaction of ER with transcriptional corepressors. Notably, tamoxifen-induced association of ER with the transcriptional corepressors N-CoR or SMRT was reduced in HER2-overexpressing breast tumor cells but not in cells with low HER2 levels. Small molecule inhibitors of the HER2 kinase or MAP extracellular signal-regulated kinase 1/2 or dominant-negative MAP extracellular signal-regulated kinase 1/2 constructs restored the inhibitory effect of tamoxifen on both ER-mediated transcription and tumor cell proliferation. Treatment with both tamoxifen and the small molecule HER1/2 kinase inhibitor AG1478 reduced mitogen-activated protein kinase activity and markedly reduced growth of established MCF-7/HER2 xenografts in athymic nude mice. Similar results have been obtained with ZD1839 ("Iressa"), an epidermal growth factor receptor (HER1) tyrosine kinase inhibitor. Taken together, these data suggest that exogenous inhibitors of the HER-signaling network and other mitogenic pathways can abrogate or delay the emergence of antiestrogen resistance, thus providing an evaluable therapeutic strategy in human breast carcinoma.
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PMID:Inhibition of erbB receptor (HER) tyrosine kinases as a strategy to abrogate antiestrogen resistance in human breast cancer. 1191 37

Little is known about the mechanisms by which protein-derived nutrients regulate hormone gene expression in the intestine. We have previously reported that protein hydrolysates (i.e. peptones), which are representative of the protein fraction in the lumen, increased cholecystokinin (CCK) gene transcription in the STC-1 enteroendocrine cell line. In the present work, we examined the intracellular events evoked by peptones to stimulate CCK gene transcription. In STC-1 cells, peptones stimulated cyclic AMP production and protein kinase A (PKA) activity. This was associated with a nuclear translocation of the PKA catalytic subunit and with a PKA-dependent phosphorylation of the CRE-binding protein (CREB) at Ser(133). Using transient transfection experiments and reporter luciferase assays, we show that peptone-stimulated transcriptional activity of the CCK gene promoter was significantly decreased when the PKA pathway was inhibited. Furthermore, the intracellular calcium chelator 1,2-bis-(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-tetra(acetoxymethyl)ester completely inhibited peptone-induced stimulation of the CCK gene promoter activity, phosphorylation of CREB, and PKA activity. Peptones increased, in a calcium-dependent manner, the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and the MEK inhibitor PD98059 decreased the peptone-induced stimulation of CCK gene promoter activity. This stimulation was also reduced by 30% in the presence of the calcium/calmodulin-dependent protein kinase (CaMK) inhibitor KN-93. Total inhibition was obtained when the PKA, ERK, and CaMK pathways were simultaneously blocked with appropriate inhibitors to these pathways. These results demonstrate the simultaneous involvement of cAMP- and calcium-dependent protein kinases in the stimulation of intestinal CCK gene transcription by protein-derived nutrients.
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PMID:Co-requirement of cyclic AMP- and calcium-dependent protein kinases for transcriptional activation of cholecystokinin gene by protein hydrolysates. 1195 Aug 43

The Raf-1 kinase activates the ERK (extracellular-signal-regulated kinase) pathway. The cyclic AMP (cAMP)-dependent protein kinase (PKA) can inhibit Raf-1 by direct phosphorylation. We have mapped all cAMP-induced phosphorylation sites in Raf-1, showing that serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo. Serine 43 phosphorylation decreased the binding to Ras in serum-starved but not in mitogen-stimulated cells. However, the kinase activity of a RafS43A mutant was fully inhibited by PKA. Mutation of serine 259 increased the basal Raf-1 activity and rendered it largely resistant to inhibition by PKA. cAMP increased Raf-1 serine 259 phosphorylation in a PKA-dependent manner with kinetics that correlated with ERK deactivation. PKA also decreased Raf-1 serine 338 phosphorylation of Raf-1, previously shown to be required for Raf-1 activation. Serine 338 phosphorylation of a RafS259A mutant was unaffected by PKA. Using RafS259 mutants we also demonstrate that Raf-1 is the sole target for PKA inhibition of ERK and ERK-induced gene expression, and that Raf-1 inhibition is mediated mainly through serine 259 phosphorylation.
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PMID:Cyclic AMP-dependent kinase regulates Raf-1 kinase mainly by phosphorylation of serine 259. 1197 57

Recent studies suggest a crucial role for protein kinase A (PKA) in the regulation of growth factor signaling. However, the effect of PKA on the transcription of growth factor-responsive genes has drawn far less attention. Here we have investigated the signaling mechanisms involved in the activation of an activator protein-1 (AP-1)-driven, growth factor-specific enhancer element, fibroblast growth factor-inducible response element (FiRE). The activation was found to be mediated by three phorbol 12-O-tetradecanoate-13-acetate-response element-related DNA elements of FiRE, including motif 4 and two distinct elements of motif 5 (referred to as M5-1 and M5-2). All three elements were required for full FiRE activity. Stimulation of cells with fibroblast growth factor-2 (FGF-2) induced the binding of AP-1 to motif 4 and M5-2, whereas M5-1 did not show detectable binding. The FGF-2-induced FiRE activation appeared to require cooperational function of the Ras/ERK and PKA pathways. Inhibition of either of the pathways abolished the binding of AP-1 complexes to motif 4 and motif 5 and the subsequent FiRE activation. By contrast, costimulation of cells with FGF-2 and the PKA activator 8-bromo-cyclic AMP increased the binding of AP-1 to FiRE and potentiated the level of transcriptional activity. The cooperational function of these two pathways was confirmed by experiments with cell lines stably expressing 4-hydroxytamoxifen-inducible oncogenic Raf-1 (DeltaRaf-1:ER[DD]). Noticeably, the induction systems showed variations with respect to regulation of AP-1-driven activation of FiRE. These differences were likely to originate from the ability of these two systems to induce the differential activation pattern of the Ras/ERK pathway.
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PMID:Cooperation of protein kinase A and Ras/ERK signaling pathways is required for AP-1-mediated activation of fibroblast growth factor-inducible response element (FiRE). 1200 54

While classically viewed as a prototypic G(s) and adenylyl cyclase-coupled G protein-coupled receptor, recent studies have indicated that some aspects of beta(2)-adrenergic receptor (beta(2)-AR) signaling are inhibited by pertussis toxin, indicating that they are mediated by G(i)/G(o) proteins. These signals include activation of ERK MAPKs and Akt activation, as well as hypertrophic and anti-apoptotic pathways in cardiac myocytes. Studies in cultured cells have suggested the hypothesis that protein kinase A (PKA)-mediated phosphorylation of the beta(2)-AR regulates its coupling specificity with respect to G(s) and G(i). Using a Chinese hamster ovary cell system, we show that mutant beta(2)-ARs with Ala substituted for Ser at consensus PKA sites stimulate robust cyclic AMP accumulation (G(s)) but are unable to activate ERK (G(i)). In contrast, Ser --> Asp mutants are dramatically impaired in their ability to activate adenylyl cyclase but are significantly more active than wild type receptor in activating ERK. Activation of adenylyl cyclase by wild type and Ser --> Ala mutant receptors is not altered by pertussis toxin, whereas adenylyl cyclase stimulated through the Ser --> Asp mutant is enhanced. Activation of ERK by wild type and Ser --> Asp receptors is inhibited by pertussis toxin. To further rigorously test the hypothesis, we utilized a completely reconstituted system of purified recombinant wild type and PKA phosphorylation site mutant beta(2)-ARs and heterotrimeric G(s) and G(i). G protein coupling was measured by receptor-mediated stimulation of GTPgammaS binding to the G protein. PKA-mediated phosphorylation of the beta(2)-AR significantly decreased its ability to couple to G(s), while simultaneously dramatically increasing its ability to couple to G(i). These results are reproduced when a purified recombinant Ser --> Asp mutant beta(2)-AR is tested, whereas the Ser --> Ala receptor resembles the unphosphorylated wild type. These results provide strong experimental support for the idea that PKA-mediated phosphorylation of the beta(2)-adrenergic receptor switches its predominant coupling from G(s) to G(i).
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PMID:Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system. 1206 55

Heregulin-beta1 (HRG), a combinatorial ligand for human epidermal growth factor receptor 3 (HER3) and HER4, is a regulatory polypeptide having distinct biological effects, such as growth stimulation, differentiation, invasiveness, and migration in mammary epithelial cells. The mechanism underlying the diverse functions of HRG is not well established but is believed to depend on induced changes in the expression of specific cellular gene products, their modification, or both. Here, we identified the basic leucine zipper transcription factor, the growth-arrest and DNA-damage 153 (GADD153)/CCAAT-enhancer binding protein (C/EBP) homologous protein (CHOP) as one of the HRG-inducible genes. We demonstrated that HRG stimulation of mammary epithelial cells induces the expression of GADD153 mRNA and protein and transcription of GADD153 promoter. The transcriptional activity of the GADD153 promoter as well as transcription from the C/EBP-activating transcription factor (ATF) composite motif in the GADD153 promoter was also stimulated by HRG-inducible ATF-4 and activated HER2 but not wild-type HER2. GADD153 expression was upregulated by the lactogenic hormones insulin and progesterone and associated with differentiation of normal mammary epithelial cells. Consistent with its role as transcriptional modifier, GADD153 stimulated transcription of beta-casein promoter activity in a STAT5a-sensitive manner in mammary epithelial cells. Analysis of mouse mammary gland development revealed that GADD153 expression was predominantly restricted in the early lactating stages. Because cyclic AMP responsive element and ATF binding sites are present in a variety of growth-regulating cellular genes, these findings suggest that stimulation of GADD153 expression and its transactivating functions may constitute an important mechanism of regulation of putative genes having diverse functions during cell growth and differentiation.
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PMID:Expression and transactivating functions of the bZIP transcription factor GADD153 in mammary epithelial cells. 1208 16


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