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)

A recent in vitro study has suggested that overexpression of ERBB2 may mediate breast tumour progression and metastasis by inhibiting the transcription of the E-cadherin (E-CD) gene. To test this hypothesis in human breast cancer in vivo, we studied the relationship between the expression of both molecules in 247 breast carcinomas immunohistochemically. Five ductal carcinomas in situ overexpressed ERBB2 and showed preserved E-CD expression. Forty-four of 226 infiltrating ductal carcinomas (19.47%) showed ERBB2 overexpression, and a statistically significant relationship was found between ERBB2 overexpression and high histological grade. E-CD expression was preserved in 111 cases (49.1%) and correlated with the histological grade. However, no significant relationship was found between ERBB2 and E-CD expression. None of the 16 infiltrating lobular carcinomas expressed ERBB2 or E-CD. These observations in different histological types of breast carcinoma strongly argue against a role for ERBB2 as a transcriptional regulator of E-CD expression in most human breast carcinomas in vivo.
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PMID:Relationship between ERBB2 and E-cadherin expression in human breast cancer. 749 94

Recent studies have indicated that serine phosphorylation regulates the activities of STAT1 and STAT3. However, the kinase(s) responsible and the role of serine phosphorylation in STAT function remain unresolved. In the present studies, we examined the growth factor-dependent serine phosphorylation of STAT1 and STAT3. We provide in vitro and in vivo evidence that the ERK family of mitogen-activated protein (MAP) kinases, but not JNK or p38, specifically phosphorylate STAT3 at serine 727 in response to growth factors. Evidence for additional mitogen-regulated serine phosphorylation is also provided. STAT1 is a relatively poor substrate for all MAP kinases tested both in vitro and in vivo. STAT3 serine phosphorylation, not its tyrosine phosphorylation, results in retarded mobility of the STAT3 protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Importantly, serine 727 phosphorylation negatively modulates STAT3 tyrosine phosphorylation, which is required for dimer formation, nuclear translocation, and the DNA binding activity of this transcriptional regulator. Interestingly, the cytokine interleukin-6 also stimulates STAT3 serine phosphorylation, but in contrast to growth factors, this occurs by an ERK-independent process.
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PMID:STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. 934 14

Juvenile hormone analog (JHA) insecticides are relatively nontoxic to vertebrates and offer effective control of certain insect pests. Recent reports of resistance in whiteflies and mosquitoes demonstrate the need to identify and understand genes for resistance to this class of insect growth regulators. Mutants of the Methoprene-tolerant (Met) gene in Drosophila melanogaster show resistance to both JHAs and JH, and previous biochemical studies have demonstrated a mechanism of resistance involving an intracellular JH binding-protein that has reduced ligand affinity in Met flies. We cloned the Met+ gene by transposable P-element tagging and found reduced transcript level in several mutant alleles, showing that underproduction of the normal gene product can lead to insecticide resistance. Transformation of Met flies with a Met+ cDNA resulted in susceptibility to methoprene, indicating that the cDNA encodes a functional Met+ protein. MET shows homology to the basic helix-loop-helix (bHLH)-PAS family of transcriptional regulators, implicating MET in the action of JH at the gene level in insects. This family also includes the vertebrate dioxin receptor, a transcriptional regulator known to bind a variety of environmental toxicants. Because JHAs include a diverse array of chemicals with JH activity, a mechanism whereby they can exert effects in insects through a common pathway is suggested.
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PMID:Insect juvenile hormone resistance gene homology with the bHLH-PAS family of transcriptional regulators. 950 Nov 55

Heat shock factor 1 (HSF1) is the key transcriptional regulator of the heat shock genes that protect cells from environmental stress. However, because heat shock gene expression is deleterious to growth and development, we have examined mechanisms for HSF1 repression at growth temperatures, focusing on the role of phosphorylation. Mitogen-activated protein kinases (MAPKs) of the ERK family phosphorylate HSF1 and represses transcriptional function. The mechanism of repression involves initial phosphorylation by MAP kinase on serine 307, which primes HSF1 for secondary phosphorylation by glycogen synthase kinase 3 on a key residue in repression (serine 303). In vivo expression of glycogen synthase kinase 3 alpha or beta thus represses HSF1 through phosphorylation of serine 303. HSF1 is also phosphorylated by MAPK in vitro on a second residue (serine 363) adjacent to activation domain 1, and this residue is additionally phosphorylated by protein kinase C. In vivo, HSF1 is repressed through phosphorylation of this residue by protein kinase Calpha or -zeta but not MAPK. Regulation at 37 degrees C, therefore, involves the action of three protein kinase cascades that repress HSF1 through phosphorylation of serine residues 303, 307, and 363 and may promote growth by suppressing the heat shock response.
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PMID:Transcriptional activity of heat shock factor 1 at 37 degrees C is repressed through phosphorylation on two distinct serine residues by glycogen synthase kinase 3 and protein kinases Calpha and Czeta. 966 Aug 38

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcriptional regulator that heterodimerizes with Per-ARNT-Sim (PAS) proteins. ARNT also dimerizes with hypoxia inducible factor1alpha (HIF1alpha), inducing expression of vascular endothelial cell growth factor (VEGF) to promote angiogenesis. The angiogenesis/vasculogenesis pathway is required for embryonic survival and includes several receptors (VEGFR1, VEGFR2, Tie2) and ligands (VEGF, Ang1, Ang2, neuropillin). Transgenic knockout of ARNT in mice is lethal due to abnormal placentation. This study examines the VEGF pathway in GD9.5 embryos of wild-type (+/+), heterozygous (+/-), or knockout (-/-) ARNT genotype. All genotypes expressed abundant VEGF in trophoblastic giant cells. However, -/- conceptuses had less VEGFR2 in placental labyrinth and trophoblastic giant cells. Ang1 and Tie2 decreased in trophoblastic giant cells and Ang2 was decreased in placental endothelial cells. Abnormal development of the labyrinth correlated with decreased binding of VEGF and decreased expression of VEGFR2. In addition, VEGFR2 seemed to be the primary VEGF binding receptor in the labyrinth and blood lacunae of the placenta, as binding could be eliminated by masking the VEGFR2 receptor with inactive antibody complex. VEGFR1 may be primarily responsible for binding of VEGF to yolk sac and embryonic tissues, as masking VEGFR2 did not reduce VEGF binding in those areas, and it is interesting that major structural defects were also not found in those regions. In summary, in the ARNT knockout conceptus, the impact of ARNT deficiency on placental expression of VEGFR2 seems to provide an explanation for the failure of the placental labyrinth to progress, whereas the vascularization of the yolk sac and embryo appear relatively unaffected on GD9.5. Published 2000 Wiley-Liss, Inc.
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PMID:Placental defects in ARNT-knockout conceptus correlate with localized decreases in VEGF-R2, Ang-1, and Tie-2. 1108 52

Cyclic AMP response element-binding protein (CREB) is a major transcriptional activator at the calcium and cAMP response-element (CaCRE). Phosphorylated (p)CREB facilitates gene expression in striatal neurons. Elk-1 is another transcriptional regulator at the serum response element in the upstream promoter region of the CaCRE. Elk-1 is phosphorylated by extracellular signal-regulated kinases (ERK) and may also contribute to the regulation of gene expression. To evaluate putative roles of group I metabotropic glutamate receptors (mGluRs) in CREB, Elk-1, and ERK phosphorylation, the group I selective agonist, 3,5-dihydroxyphenylglycine (DHPG), was infused into the dorsal striatum at doses of 125, 250, or 500 nmol in freely moving rats. Semi-quantitative immunohistochemistry demonstrated that DHPG significantly increased levels of pCREB, pElk-1, and pERK immunoreactivity of ipsilateral dorsal striatum in a dose dependent manner. The increased immunoreactivity by 500 nmol DHPG was significantly blocked by intrastriatal infusion of the group I selective antagonist, n-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC, 25 nmol), but not by the group II/III antagonist, (RS)-alpha-methylserine-o-phosphate monophenyl ester (MSOPPE, 25 nmol). These data suggest that group I mGluR activation is positively linked to signaling cascades resulting in CREB, Elk-1, and ERK phosphorylation in the striatum in vivo.
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PMID:Group I metabotropic glutamate receptor activation increases phosphorylation of cAMP response element-binding protein, Elk-1, and extracellular signal-regulated kinases in rat dorsal striatum. 1159 67

Early growth response gene 1 (Egr1) codes for a transcriptional regulator that contains a zinc-finger DNA binding domain. Egr1 expression is induced by a variety of extracellular stimuli including TCR-ligand interactions. Its pattern of expression in the thymus and dependence on ERK activation have led to speculation that it has a role in T cell development, but the exact nature of this role has been undefined. To more clearly define the role of Egr1 in thymocyte development, we have analyzed thymocytes from Egr1-deficient mice. We find that thymuses from Egr1-deficient mice contain twice as many cells as age-matched controls, and the increase in thymocyte number is apparent at the early CD4/CD8 double negative stage of development. Subsequent maturation to the CD4/CD8 double positive stage and survival of the double positive cells both appear normal in Egr1-deficient animals. We also find that Egr1 promotes positive selection of both CD4 and CD8 single positive cells without playing a major role in negative selection. Egr1 influences positive selection by enhancing expression of the helix-loop-helix inhibitor Id3 and the anti-apoptosis molecule bcl-2. Thus, Egr1 translates developmental signals into appropriate changes in gene expression at multiple stages of thymocyte development.
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PMID:Thymocyte development in early growth response gene 1-deficient mice. 1216 91

Recent studies have suggested that infection with Chlamydia pneumoniae (C pneumoniae) may contribute to the instability of atherosclerotic plaques and thrombosis and is associated with acute coronary events. Tissue factor (TF), a potent prothrombotic molecule, is expressed by macrophages and other cell types within atherosclerotic lesions and plays an essential role in thrombus formation after plaque rupture. Therefore the effects of C pneumoniae on induction of TF expression in macrophages were investigated. Infection of RAW mouse macrophages with C pneumoniae induced a time-dependent increase in procoagulant activity, expression of TF protein, and TF mRNA. C pneumoniae infection stimulated increased binding of nuclear proteins to the consensus DNA sequence for Egr-1, a key response element within the TF promoter, and increased the expression of Egr-1 protein. Transient transfections of RAW cells with mutated TF promoter constructs showed that the Egr-1 binding region is an important transcriptional regulator of C pneumoniae-induced TF expression. Furthermore, C pneumoniae-stimulated phosphorylation of ERK1/2 and Elk-1 and pharmacological inhibition of mitogen-activated protein kinase activity reduced the expression of TF and Egr-1. Antibody and polymyxin B blocking of the Toll-like receptor 4 (TLR4) partially reduced the C pneumoniae-induced expression of TF and Egr-1. In conclusion, the C pneumoniae-induced increase in TF expression in macrophages is mediated in part by Egr-1, signaling through TLR4, and activation of the MEK-ERK1/2 pathway.
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PMID:Chlamydia pneumoniae induces tissue factor expression in mouse macrophages via activation of Egr-1 and the MEK-ERK1/2 pathway. 1275 Mar 7

The molecular mechanisms by which neurotrophins such as nerve growth factor (NGF) induce neurite outgrowth and differentiation remain unclear, although multiple intracellular signaling pathways are known to participate. Recent studies have shown that nuclear transcription factors play an important role in NGF-stimulated neuritic outgrowth in PC12 cells. We investigated whether FAC1, a novel transcriptional regulator that exhibits altered subcellular distribution during brain development, is responsive to NGF-induced neurite outgrowth of PC12 cells. Our studies demonstrate that NGF induces a rapid, transient increase in FACI mRNA that is dependent upon ERK activation, and that FAC1 protein exhibits altered subcellular distribution during neurite outgrowth. These findings suggest that FAC1 expression and subcellular localization are regulated by NGF signaling pathways during neurite outgrowth.
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PMID:Altered expression and distribution of FAC1 during NGF-induced neurite outgrowth of PC12 cells. 1263 1

Between 30% and 50% of patients with advanced-stage anaplastic large-cell lymphoma (ALCL) harbor the balanced chromosomal rearrangement t(2;5)(p23;q35), which results in the generation of the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). To further study survival signaling by NPMALK, we generated Ba/F3 cell lines with either inducible or constitutive expression of NPM-ALK and examined the regulation of the AKT target FOXO3a. We hypothesized that NPM-ALK signaling through phosphoinositol 3-kinase (PI 3-kinase) and AKT would regulate FOXO3a, a member of the forkhead family of transcription factors, thereby stimulating proliferation and blocking programmed cell death in NPM-ALK-transformed cells. In Ba/F3 cells with induced or constitutive expression of NPM-ALK, concomitant AKT activation and phosphorylation of its substrate, FOXO3a, was observed. In addition, transient expression of NPM-ALK in U-20S cells inhibited FOXO3a-mediated transactivation of reporter gene expression. Furthermore, NPM-ALK-induced FOXO3a phosphorylation in Ba/F3 cells resulted in nuclear exclusion of this transcriptional regulator, up-regulation of cyclin D2 expression, and down-regulation of p27(kip1) and Bim-1 expression. NPMALK reversal of proliferation arrest and of p27(kip1) induction was dependent on the phosphorylation of FOXO3a. Thus, FOXO3a is a barrier to hematopoietic transformation that is overcome by phosphorylation and cytoplasmic relocalization induced by the expression of NPM-ALK.
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PMID:NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a. 1496 11


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