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)

Saccharomyces cerevisiae Cet1p is the prototype of a family of metal-dependent RNA 5'-triphosphatases/NTPases encoded by fungi and DNA viruses; the family is defined by conserved sequence motifs A, B, and C. We tested the effects of 12 alanine substitutions and 16 conservative modifications at 18 positions of the motifs. Eight residues were identified as important for triphosphatase activity. These were Glu-305, Glu-307, and Phe-310 in motif A (IELEMKF); Arg-454 and Lys-456 in motif B (RTK); Glu-492, Glu-494, and Glu-496 in motif C (EVELE). Four acidic residues, Glu-305, Glu-307, Glu-494, and Glu-496, may comprise the metal-binding site(s), insofar as their replacement by glutamine inactivated Cet1p. E492Q retained triphosphatase activity. Basic residues Arg-454 and Lys-456 in motif B are implicated in binding to the 5'-triphosphate. Changing Arg-454 to alanine or glutamine resulted in a 30-fold increase in the K(m) for ATP, whereas substitution with lysine increased K(m) 6-fold. Changing Lys-456 to alanine or glutamine increased K(m) an order of magnitude; ATP binding was restored when arginine was introduced. Alanine in lieu of Phe-310 inactivated Cet1p, whereas Tyr or Leu restored function. Alanine mutations at aliphatic residues Leu-306, Val-493, and Leu-495 resulted in thermal instability in vivo and in vitro. A second S. cerevisiae RNA triphosphatase/NTPase (named Cth1p) containing motifs A, B, and C was identified and characterized. Cth1p activity was abolished by E87A and E89A mutations in motif A. Cth1p is nonessential for yeast growth and, by itself, cannot fulfill the essential role played by Cet1p in vivo. Yet, fusion of Cth1p in cis to the guanylyltransferase domain of mammalian capping enzyme allowed Cth1p to complement growth of cet1Delta yeast cells. This finding illustrates that mammalian guanylyltransferase can be used as a vehicle to deliver enzymes to nascent pre-mRNAs in vivo, most likely through its binding to the phosphorylated CTD of RNA polymerase II.
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PMID:Mutational analyses of yeast RNA triphosphatases highlight a common mechanism of metal-dependent NTP hydrolysis and a means of targeting enzymes to pre-mRNAs in vivo by fusion to the guanylyltransferase component of the capping apparatus. 1050 29

We report a novel case of multiple endocrine neoplasia type 2A (MEN 2A) associated with two mutations of the protooncogene RET. One affects codon 634 and causes a cysteine to arginine substitution; the second at codon 640 causes an alanine to glycine substitution in the transmembrane region. The two mutations were present on the same RET allele and were detected in germline and tumor DNA. Both mutations were de novo, i.e. they were not found in the DNA of the parents or relatives. Immunohistochemical and RT-PCR analysis showed that the pheochromocytoma expressed calcitonin as well as both RET alleles. A cell line established from the tumor and propagated in culture sustained the expression of RET and calcitonin, as did the original pheochromocytoma. Because the patient presented with medullary thyroid carcinoma and pheochromocytoma without parathyroid gland involvement, we speculate that this clinical picture could be correlated with the two RET mutations and to the unusual calcitonin production. This is the first report of a MEN 2A case due to two mutations of the RET gene and associated with a calcitonin-producing pheochromocytoma.
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PMID:A novel case of multiple endocrine neoplasia type 2A associated with two de novo mutations of the RET protooncogene. 1052 89

Pheochromocytomas are rare neoplasias of the adrenal medulla which generally present with paroxysmal or sustained hypertension. Cardiogenic pulmonary edema is a common feature of these tumors, but few cases have been described with noncardiogenic pulmonary edema. We report a pheochromocytoma with the principle manifestation of noncardiogenic pulmonary edema and characterize a genetic lesion associated with the disorder. A 30-year-old man was admitted with abdominal pain and breathlessness. x-Ray examination of the chest revealed a massive, diffuse infiltration of the left lung without cardiomegaly. No paroxysmal blood pressure fluctuations or heart failure were evident during the entire course, and the infiltrate and dyspnea resolved in three days without inotropic or diuretic agents. Serum norepinephrine and epinephrine levels were elevated twenty and fifty times above normal, respectively. The patient was ultimately diagnosed with multiple endocrine neoplasia type 2A (MEN 2A). Mutations in the RET proto-oncogene have been described recently in patients with MEN 2A. Mutation analysis of selected RET exonic sequences identified a germline mutation at codon 634 in exon 11 of the RET proto-oncogene. The mutation introduces a transition encoding a non-conservative substitution from TGC (Cys) to CGC (Arg) and creates a novel restriction site recognized by HhaI. We further screened for this mutation among four of the proband's relatives by HhaI restriction analysis. One asymptomatic family member was identified who subsequently elected prophylactic total thyroid removal. Histological examination of this specimen confirmed the presence of medullary thyroid carcinoma.
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PMID:Noncardiogenic pulmonary edema as the chief manifestation of a pheochromocytoma: a case report of MEN 2A with pedigree analysis of the RET proto-oncogene. 1052 79

To evaluate the influence of individual susceptibility factors on the level of polyaromatic (PAH) hydrocarbon DNA adducts and hypoxanthine guanine phosphoribosyl transferase (HPRT) mutants in peripheral lymphocytes, 70 coke-oven workers exposed to PAH were genotyped for four metabolic enzyme polymorphisms of potential importance in PAH metabolism. The examined genetic polymorphisms concerned glutathione S-transferases M1 (GSTM1; gene deletion; 96 workers), T1 (GSTT1; gene deletion), P1 (GSTP1; Ile-->Val substitution at codon 104 or Ile-->Val at codon 104 and Val-->Ala at codon 113), and microsomal epoxide hydrolase (EPHX; Tyr-->His substitution at codon 113 and His-->Arg at codon 139). The workers were classified in a high- and low-exposure group on the basis of urinary concentration of 1-pyrenol. The GSTM1 null genotype increased the number of DNA adducts in smoking coke-oven workers with high PAH exposure. DNA adducts were affected by PAH-exposure in non-smokers and in GSTM1 null smokers and by smoking in GSTM1 null individuals. In a multiple linear regression analysis, the interaction of the GSTM1 genotype was statistically significant (p = 0.04) with smoking (yes/no) and of borderline significance (p = 0.06) with PAH-exposure (high/low). As smoking also increased urinary 1-pyrenol, the genotype modification seemed to concern DNA adducts due to smoking rather than occupational exposure. GSTT1 positive individuals showed an elevated level of DNA adducts in comparison with GSTT1 null subjects (p = 0.04), and EPHX genotypes associated with slow hydroxylation reaction yielded a higher (p = 0.05) HPRT mutant frequency than fast EPHX genotypes; these findings were, however, based on small numbers of subjects and need to be clarified in further studies. In conclusion, our findings indicate that homozygous deletion of GSTM1 results in an increased sensitivity to genotoxic PAHs in tobacco smoke, which is seen as an increase in aromatic DNA adducts in blood mononuclear cells.
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PMID:Influence of GSTM1, GSTT1, GSTP1, and EPHX gene polymorphisms on DNA adduct level and HPRT mutant frequency in coke-oven workers. 1063 83

Conditioned medium from stimulated microglia and from the monocyte/macrophage cell line (RAW 264.7; MC-CM) promotes the differentiation of cholinergic neurons from undifferentiated progenitors in the septal nuclei and adjacent basal forebrain (BF). We have studied the regulation of this process by measuring the activity of choline acetyltransferase (ChAT) in cultured BF taken from embryonic day 16 rat brain. Inhibition of either xanthine oxidase with allopurinol or nitric oxide synthase with N(G)-monomethyl-l-arginine produces a small but significant improvement in the efficacy of MC-CM while inclusion of pyrrolidine dithiocarbamate, a hydroxyl radical scavenger widely used as an antioxidant, lowers MC-CM-induced ChAT activity. Addition of nerve growth factor (NGF) but not brain-derived neurotrophic factor or glial-derived neurotrophic factor together with MC-CM has a synergistic effect on both ChAT activity and ChAT mRNA, raising ChAT activity as much as 29-fold and ChAT mRNA almost 15-fold. While MC-CM raised mRNA for trkA, the effect was not synergistic with NGF. mRNA for the common neurotrophin receptor (p75NTR) showed a modest synergistic increase. Blockade of the Ras/Raf/ERK [extracellular signal-regulated kinase, also known as mitogen-activated protein [(MAP) kinase] signal transduction pathway with either PD28059 (an inhibitor of MAP kinase/ERK kinase kinase or MEK) or N-acetyl-S-farnesyl-l-cysteine (an inhibitor of Ras farnesylation and, hence, activation) inhibited the action of MC-CM. Moreover, a subpopulation of cells responded rapidly to MC-CM with an increased appearance of phosphorylated ERK. Because NGF also utilizes this pathway, synergy may occur along this signal transduction pathway.
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PMID:Macrophage cell-conditioned medium promotes cholinergic differentiation of undifferentiated progenitors and synergizes with nerve growth factor action in the developing basal forebrain. 1068 94

The ETV6/TEL gene has been reported to fuse to PDGFRbetab MDS1/EVI1, BTL, ACS2, STL, JAK2, ABL, CDX2, TRKC, AML1, and MN1. Among them, PDGFRbeta, ABL, JAK2, and TRKC are tyrosine kinases (TK). We identified a novel ETV6 partner gene, ARG (ABL-related gene or ABL2), another TK gene in a cell line established from a patient with acute myelogenous leukemia (AML-M3) with a t(15;17)(q22;q11.2) and a t(1;12)(q25;p13), which has the remarkable feature to differentiate to mature eosinophils in culture with all-trans retinoic acid and cytokines. The ETV6/ARG transcripts consisted of exon 1 to 5 of ETV6 and the 3' portion of ARG starting from exon 1B or exon 2, resulting in an open reading frame for a fusion protein consisting of the entire PNT oligomerization domain of ETV6 and all of the functional domains of ARG including the TK domain. This is the same protein structure as identified in the other ETV6 TK fusion proteins. The reciprocal ARG/ETV6 transcript was not expressed, and the normal ETV6 allele was not deleted or rearranged. Although the ABL is known to be involved in various human malignancies, ARG has not been involved in human malignancies despite its high homology to ABL. Thus, this is the first report showing involvement of ARG in human leukemia. The ETV6/ARG protein may be involved in the unique differentiation capacity of this cell line. (Blood. 2000;95:2126-2131)
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PMID:A new ETV6/TEL partner gene, ARG (ABL-related gene or ABL2), identified in an AML-M3 cell line with a t(1;12)(q25;p13) translocation. 1070 84

The role of nitric oxide (NO) and adherent spleen cells in systemic immunosuppression developing in animals carrying malignant glioma isografts was analyzed. Rats harboring a subcutaneous glioma isograft for 3 weeks were immunized with glioma cells genetically engineered to express IFN-gamma. One week later spleen cells were tested for immune responsiveness in vitro. A decreased cytotoxic activity of NK-cells and T-cells compared to tumor-free animals immunized in parallel was shown. Spleen cell proliferative responses to tumor cells, SEA, and anti-CD3 were all significantly suppressed, as was the production of IFN-gamma and IL-10. Plastic adherent spleen cells from tumor-bearing rats suppressed the SEA-induced proliferative response and the production of IFN-gamma and IL-10 by nonadherent spleen cells from tumor-free rats. A major part of this suppression appears to be dependent on the production of NO because suppression was efficiently counteracted in vitro by the NO-synthase inhibitor N-nitro-l-arginine methyl ester. Moreover, a significantly increased level of nitrite in culture supernatants correlated with the observed suppression. We conclude that the systemic immunosuppression associated with growing gliomas is in part mediated by mechanisms dependent on NO overproduction in adherent spleen cells.
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PMID:Nitric-oxide-dependent systemic immunosuppression in animals with progressively growing malignant gliomas. 1075 3

Hereditary lymphedema is a chronic swelling of limbs due to dysfunction of lymphatic vessels. An autosomal dominant, congenital form of the disease, also known as "Milroy disease," has been mapped to the telomeric part of chromosome 5q, in the region 5q34-q35. This region contains a good candidate gene for the disease, VEGFR3 (FLT4), that encodes a receptor tyrosine kinase specific for lymphatic vessels. To clarify the role of VEGFR3 in the etiology of the disease, we have analyzed a family with hereditary lymphedema. We show linkage of the disease with markers in 5q34-q35, including a VEGFR3 intragenic polymorphism, and we describe an A-->G transition that cosegregates with the disease, corresponding to a histidine-to-arginine substitution in the catalytic loop of the protein. In addition, we show, by in vitro expression, that this mutation inhibits the autophosphorylation of the receptor. Thus, defective VEGFR3 signaling seems to be the cause of congenital hereditary lymphedema linked to 5q34-q35.
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PMID:Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. 1085 94

We previously found that a small dose (2 microg per mouse) of staphylococcal enterotoxin B (SEB) induced early emerging unresponsiveness in intrahepatic-lymphocyte populations (IHLs). The purpose of this study was to reveal the inducing role of accessory cells involved in IHLs in this phenomenon. IHLs prepared at 3 to 24 hours after SEB injection failed to proliferate in response not only to SEB but also to SEA, representing ligand-nonspecific unresponsiveness, whereas spleen cells (SPCs) and mesenteric lymph-node cells showed transient proliferation. Unresponsiveness in IHLs was related to a deficit of their accessory cell function as measured by coculture of irradiated IHLs and antigen-specific, type 1 T-helper (Th1) clone cells. High levels of nitrite were detected in the culture supernatant. Supplement of N(G)-monomethyl-L-arginine lowered nitrite levels and concurrently restored the proliferative response of Th1 cells, indicating the involvement of nitric oxide in suppression. Adherent cells prepared from IHLs well reproduced these results. As shown by flow cytometry, Mac-1(high) Ia(+) cells, which mainly included F4/80(+) cells (macrophages) and a minor population of CD11c(+) cells (dendritic cells), increased in proportion in IHLs but not in SPCs at 6 to 24 hours. Depletion of Mac-1(high) cells from IHLs with antibody-coated magnetic beads recovered the proliferative response. Depleted Mac-1(high) cells had a monocytoid appearance. In immunostained sections, Kupffer cells came to highly express both Mac-1 and Ia at 12 hours. These results indicate that Mac-1(high)Ia(+) adherent cells, largely Kupffer cells activated by SEB, nonspecifically suppress the proliferation of Th1 cells via nitric oxide production before manifestation of ligand-specific unresponsiveness.
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PMID:Unresponsiveness of intrahepatic lymphocytes to bacterial superantigen: rapid development of suppressive Mac-1(high) cells in the mouse liver. 1096 Apr 42

Cardiovascular mortality is excessive in hemodialyzed patients. Observations in atherosclerosis suggest that endothelial dysfunction and impaired nitric oxide (NO) may be involved. However, the relation of endothelial NO to its vascular effects has not been studied conclusively in uremia. Therefore, to study these questions an invasive technique was used in normotensive patients who were on hemodialysis (HD; n = 11) and in matched control subjects (n = 11). Pharmacologic agents were infused into the brachial artery to test the chain of events from NO generation to smooth muscle cell relaxation, measuring forearm blood flow by venous occlusion plethysmography. Glyceroltrinitrate (GTN 1:2.2 nmol/min; GTN 2:4.4; GTN 3:8.8), infused to establish the reaction of the vessel wall to defined doses of NO, caused a reduced response in HD patients (control subjects: 183 +/- 20 [SEM], 246 +/- 26, and 338 +/- 29%; HD patients: 161 +/- 7, 206 +/- 12, and 262 +/- 24%; baseline = 100% for each group, P: = 0.032 by ANOVA). All subsequent data were corrected for this decreased response to defined doses of NO in HD patients. L-arginine (10 mg/min), given to exclude substrate deficiency of NO synthase (NOS), caused no significant changes (control subjects: 108 +/- 4%; HD patients: 103 +/- 4%; P: = NS). Acetylcholine (ACH 1:55 nmol/min; ACH 2:110; ACH 3:220), infused to stimulate endothelial NOS, had a significantly reduced effect in HD patients (control subjects: 246 +/- 32, 340 +/- 40, and 465 +/- 52%; HD patients: 251 +/- 55, 244 +/- 36, and 318 +/- 50%; P: = 0.002). N:-monomethyl-L-arginine (LMA 1:1 micromol/min; LMA 2:2; LMA 3:4), given to block baseline NO generation, showed an enhanced response in HD patients (control subjects: 90 +/- 2, 83 +/- 2, and 74 +/- 4%; HD patients: 84 +/- 3, 73 +/- 3, and 64 +/- 4%; P: = 0.037). Vascular response to three doses of norepinephrine (60, 120, and 240 pmol/min) was comparable in both groups, which indicated similar endothelium-independent vasoconstriction. In summary, in normotensive HD patients, (1) vasodilation to defined doses of exogenous NO was reduced, (2) there was no evidence of substrate deficiency of NOS, and (3) stimulation of NOS was impaired; however, (4) baseline NO generation was increased. It is concluded that in HD patients, the NO system has a reduced capacity to regulate vascular tone and this impairment is most significant under conditions of NOS stimulation.
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PMID:Evidence in vivo showing increase of baseline nitric oxide generation and impairment of endothelium-dependent vasodilation in normotensive patients on chronic hemodialysis. 1096 98


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