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)

Much of the total genomic variation in eukaryotic organisms may be due to genes other than those coding the primary translation product. Allelic variation, especially as detectable by electrophoresis, in the post-translational processing of enzymes has been briefly reviewed with considerable attention given to a mouse gene (Neu-1) and its pleiotropic effects on several lysosomal hydrolases. Liver acid phosphatase, alpha-mannosidase, arylsulfatase B, and alpha-glucosidase are differentially sialylated as the result of allelic variation for a gene controlling liver neuraminidase activity. Strain SM/J has only 15-20% of the total neuraminidase activity of control strains and is almost totally deficient in the more heat labile of two components of liver activity. The locus controlling this variation (Neu-1) maps very near the D end of H-2 on chromosome 17, apparently within the S region of H-2. A homologous gene has been mapped near the MHC of the rat. The exact nature of the mouse mutant and its relationship to several human diseases characterized by neuraminidase deficiency has not been determined.
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PMID:Post-translational modification of enzymes: processing genes. 635 Feb 18

The low activity of liver neuraminidase that is characteristic of mouse strain SM/J is inherited as a single gene on chromosome 17, near the major histocompatibility complex. This gene, neuraminidase-1 (Neu-1), is represented by the low activity allele Neu-1s in SM/J and the high activity allele Neu-1b in C57BL/6J and most other strains. Previously described variations in the posttranslational processing of acid phosphatase, alpha-mannosidase, arylsulfatase-B, and alpha-glucosidase are attributed to pleiotropic effects of this gene.
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PMID:Gene for neuraminidase activity on mouse chromosome 17 near h-2: pleiotropic effects on multiple hydrolases. 720 20

A deficiency of the enzyme arylsulfatase B results in the lysosomal storage disorder Maroteaux-Lamy syndrome or mucopolysaccharidosis type VI. Severe, intermediate and mild forms of this autosomal recessively inherited disease can be clinically differentiated. To determine the molecular defect in a patient with the intermediate form of the disorder, DNA fragments generated from the patient's mRNA by reverse transcription and subsequent amplification by the polymerase chain reaction were subcloned and sequenced. The mRNA transcribed from one allele contains a 244-base pair deletion causing a frameshift and a truncation of the open reading frame. The C-terminal third of the encoded mutant polypeptide has a nonsense sequence. This mutation is due to a deletion of exon 5 in this allele. A silent A to G transition at nucleotide 1191 was present in the same allele, and the second allele was characterized by a T to C transition at nucleotide 1600 causing a mutation of the translational stop codon to a glutamine codon (*534Q) and extending the encoded polypeptide by 50 amino acids. Stable expression of the *534Q allele in LTK- cells resulted in a mutant precursor 4 kDa larger than the wild-type precursor. The majority of the mutant precursor appears to be degraded before reaching the trans Golgi. This is consistent with an altered polypeptide structure, where a number of missing or masked epitopes were observed in an enzyme immunobinding assay using a panel of monoclonal antibodies. Immunoquantification analysis showed that epitopes were most likely masked, as missing epitopes could be reformed by binding the mutant protein to a polyclonal antibody of arylsulfatase B. It is suggested that the additional amino acids at the C terminus of the arylsulfatase B polypeptide induce a protein conformational change. *534Q mutant polypeptide escaping degradation is sorted to dense lysosomes. The mutant polypeptide has an approximately 9-fold higher catalytic efficiency than wild-type arylsulfatase B.
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PMID:Juvenile form of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). A C-terminal extension causes instability but increases catalytic efficiency of arylsulfatase B. 814 52

In serum, urine and amniotic fluid obtained from the 52. women divided into three groups the arylsulphatase A (EC 3.1.6.1) activity was measured by the modified Lee-Vaupel and Conzelmann method. It was noticed in serum from the pregnant women with EPH-gestosis the statistically significant (p < 0.05) increase in the enzyme activity comparing to the results from non-pregnant women and pregnant with normal course of pregnancy. It was no statistically significant differences in the urine from pregnant with EPH-gestosis and from the healthy pregnant, but there was the increase (p < 0.01) in the enzyme activity in amniotic fluid from pregnant women with EPH-gestosis comparing to the physiological course of pregnancy. According to our data, the arylsulphatase A activity assay could be recommended as a diagnostic marker in the EPH-gestosis.
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PMID:[The arylsulphatase A (EC 3.1.6.1) activity in serum, urine and amniotic fluid from pregnant women with EPH-gestosis]. 1089 95

Recently, we cloned a novel sulfatase domain-containing downregulated gene, HSulf-1, which modulates heparin-binding growth factor signaling in ovarian cancer. Based on the pilot data showing the loss of HSulf-1 in head and neck squamous cell carcinoma cell lines (SCCHN), we sought to employ SCCHN as a model to define the role of HSulf-1 in the molecular regulation of tumorigenicity. Three SCCHN lines (012SCC, WMMSCC, and 015SCC) had no detectable HSulf-1 mRNA. Clonal lines of HSulf-1-expressing 012SCC attenuated the activation of ERK/mitogen-activated protein kinase (MAPK) signaling mediated by fibroblast growth factor (FGF-2) and both ERK/MAPK and Akt signaling mediated by hepatocyte growth factor (HGF). Consistent with this downregulation, phosphorylation of HGF receptor, c-Met, which is frequently overexpressed in SCCHN, was also attenuated in HSulf-1 clonal 012SCC cell lines. HGF markedly enhanced the motility and migration of vector-transfected cells in a transwell invasion chamber. However, HGF-mediated motility and invasion was attenuated in HSulf-1 clonal 012SCC cell lines. In addition, transfected cells displayed significant growth inhibition concomitant with a decrease in mitogenicity, as measured by thymidine incorporation and increased sensitivity to staurosporine- and cisplatin-induced apoptosis. These data suggest that HSulf-1 normally functions as a negative regulator in cell growth and loss of HSulf-1 in SCCHN potentiates growth factor signaling, enhances motility, invasiveness and inhibits stress-induced apoptosis, with a resulting increase in tumorigenicity.
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PMID:HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma. 1497 53

Genetic influences and endurance exercise have been shown to alter circulating concentrations of dehydroepiandrosterone (DHEA) and its sulfated conjugate, DHEAS. We hypothesized that acute resistance exercise (RE) and training (RET) would increase DHEA steroids, and the magnitude of the increase would be influenced by a steroid sulfatase (STS) gene variation. Fasting blood samples were collected before and after the first (S1) and last (S30) session of a 10-wk RET program in 62 men and 58 women [age: 21.0 yr (2.4)]. Acute RE increased both DHEA [+2.8 (0.4), S1; +1.6 ng/ml (0.4), S30; P < 0.001] and DHEAS [+154 (24), S1; +166 ng/ml (15), S30; P < 0.001] and decreased DHEAS:DHEA [-27 (8), S1; -15 (7), S30; P < 0.01]. RET reduced resting DHEAS (-122 ng/ml, P < 0.01) and decreased DHEA response to RE (-50%, P < 0.05). Subjects with an STS "G" allele (n = 36) had greater acute changes in DHEA [+4.4 (0.7) vs. +2.0 ng/ml (0.5), S1; +3.2 (0.6) vs. +1.0 ng/ml (0.4), S30; P < 0.01] and DHEAS:DHEA [-37 (11) vs. 5 (7), S30, P < 0.05] than those subjects with only an "A" allele (n = 84). The observed increase in DHEA and DHEAS and decrease in DHEAS:DHEA suggest RE-induced STS activation which is influenced by the STS polymorphism.
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PMID:Steroid sulfatase gene variation and DHEA responsiveness to resistance exercise in MERET. 1515 80

Heparan sulfate proteoglycans cooperate with basic fibroblast growth factor (bFGF/FGF2) signaling to control osteoblast growth and differentiation, as well as metabolic functions of osteoblasts. FGF2 signaling modulates the expression and activity of Runt-related transcription factor 2 (Runx2/Cbfa1), a key regulator of osteoblast proliferation and maturation. Here, we have characterized novel Runx2 target genes in osteoprogenitors under conditions that promote growth arrest while not yet permitting sustained phenotypic maturation. Runx2 enhances expression of genes related to proteoglycan-mediated signaling, including FGF receptors (e.g., FGFR2 and FGFR3) and proteoglycans (e.g., syndecans [Sdc1, Sdc2, Sdc3], glypicans [Gpc1], versican [Vcan]). Runx2 increases expression of the glycosyltransferase Exostosin-1 (Ext1) and heparanase, as well as alters the relative expression of N-linked sulfotransferases (Ndst1 = Ndst2 > Ndst3) and enzymes mediating O-linked sulfation of heparan sulfate (Hs2st > Hs6st) or chondroitin sulfate (Cs4st > Cs6st). Runx2 cooperates with FGF2 to induce expression of Sdc4 and the sulfatase Galns, but Runx2 and FGF2 suppress Gpc6, thus suggesting intricate Runx2 and FGF2 dependent changes in proteoglycan utilization. One functional consequence of Runx2 mediated modulations in proteoglycan-related gene expression is a change in the responsiveness of bone markers to FGF2 stimulation. Runx2 and FGF2 synergistically enhance osteopontin expression (>100 fold), while FGF2 blocks Runx2 induction of alkaline phosphatase. Our data suggest that Runx2 and the FGF/proteoglycan axis may form an extracellular matrix (ECM)-related regulatory feed-back loop that controls osteoblast proliferation and execution of the osteogenic program.
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PMID:The osteogenic transcription factor Runx2 regulates components of the fibroblast growth factor/proteoglycan signaling axis in osteoblasts. 1925 85

The novel melatonin agonist Neu-P11 is used in treatment of physiological insomnia. In animal studies Neu-P11 showed sleep-promoting effects. In a phase 1 study Neu-P11 was administered to cohorts of healthy young male volunteers in an ascending single dose study. Up to now the metabolism of this new drug in humans has not been investigated. The first aim of this study was to identify possible metabolites in pooled urine samples of the first collecting period (0-8 h) of volunteers with the highest Neu-P11 oral dosage (200 mg). The objective of the second part of the study was to estimate the concentrations of the main metabolites of Neu-P11 - in this urine sample. The analyte Neu-P11 and metabolites were separated from human urine using dilution and precipitation with acetonitrile. Samples were analyzed for formation of both phase I and phase II metabolites using LC-MS/MS in precursor ion mode, product ion mode, neutral loss mode and the multi-reaction monitoring mode (MRM). Urine samples were analyzed before and after addition of beta-glucuronidase and sulfatase. In the pooled urine sample eight metabolites could be proved. The parent drug, the sulfated demethylated Neu-P11, the sulfated 6OH-Neu-P11 and the di-oxygenated product gave the highest signals in these urine samples and probably had the highest concentration. But quantification without reference substances is not possible. So in the second part of the study the urine samples were additionally analyzed with UV-detection for a better estimation of the metabolite concentrations. The concentration of the sulfated metabolites was more than ten times higher than the concentration of the unchanged drug in urine. Other metabolites were not measurable with UV-detection. The di-oxygenated Neu-P11 and an additional mono-oxygenated Neu-P11 showed relatively high signals in MS/MS. Probably the other metabolites, namely glucuronides, unconjugated demethylated Neu-P11 and unconjugated 6OH-Neu-P11, were formed at a lesser extent.
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PMID:Elucidation of Neu-P11 metabolism in urine of volunteers by liquid chromatography-tandem mass spectrometry. 2333 48

Increased autophagic vacuoles (AVs) occur in injured or degenerating neurons, under both developmental and pathological situations. Although an induced autophagy has been shown in inflammation response to cell factors, the underlying mechanism(s) remain(s) unknown. Here, we show that both cell factor IL-6 and environmental toxin MPP(+) promote the formation of vacuolation in SHSY5Y cells. By electron and immunofluorescent microscopy analyses, we showed that these structures are acid autolysosomes, containing cellular debris, and labeled by LC3 or LAMP1, markers of autophagosomes or lysosomes, respectively. Combining MPP(+) and IL-6 do not further increase vacuolation of SHSY5Y cells, and the vacuolation is less than that in the MPP(+)-treated group. MPP(+)-induced vacuolation results from significant increase in autophagy formation and delay in autophagy degradation, in relation to a decline of the lysosomal activity of arylsulfatase A. At molecular level, we show that this defect in autolysosomal maturation is independent of mammalian target of rapamycin and p38 inhibitions. Most importantly, we provide the first evidence that activation of ERK pathway is sufficient to commit cell to autophagic vacuolation. The sustained activation is required for MPP(+) to disrupt the autophagic pathway. IL-6 also induces a temporary and significant activation of ERK, but not sustained activation, and change sustained activation in MPP(+)-treated group into temporary activation. Taken together, these findings strongly support that IL-6 promotes the maturation of autophagosomes into functional autolysosomes by regulating ERK.
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PMID:Promotion of autophagy at the maturation step by IL-6 is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity. 2367 97

MicroRNAs (miRNAs) have been believed to associate with malignant progression including cancer cell proliferation, apoptosis, differentiation, angiogenesis, invasion and metastasis. However, the functions of miRNAs are intricate, one miRNA can directly or indirectly target multiple genes and function as oncogene or tumor suppressor gene. In this study, we found that miR-21 inhibits PTEN and human sulfatase-1 (hSulf-1) expression in hepatocellular carcinoma (HCC) cells. The hSulf-1 is a heparin-degrading endosulfatase, which can inhibit the heparin binding growth factor-mediated signaling transduction into cells. Therefore, miR-21-mediated suppression of both hSulf-1 and PTEN led to activation of AKT/ERK pathways and epithelial-mesenchymal transition (EMT) in HCC cells, and finally enhance the activity of HCC cell proliferation and movement and promote HCC xenograft tumor growth in mouse models. These findings may provide candidate targets for prevention and treatment of HCC.
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PMID:MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways. 3198 28


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