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)

The human apolipoproteins are secretory proteins some of which have been shown to undergo proteolytic processing and post-translational addition of carbohydrate. Apolipoprotein A-I (apo-A-I), the predominant protein associated with high density lipoproteins, undergoes co-translational proteolytic processing as well as post-translational conversion of proapo-A-I to mature apo-A-I following cellular secretion. Utilizing the human hepatoma cell line HEP-G2, we have established that, in addition to proteolytic processing, secreted nascent apo-A-I is acylated with palmitate. Uniformly labeled [14C]palmitate and [1-14C]palmitate were each incorporated into apo-A-I when analyzed by sodium dodecyl sulfate gel electrophoresis and autoradiography. The acylation of apo-A-I with palmitate was confirmed by immunoprecipitation and gas chromatography/mass spectrometry. Hydroxylamine treatment resulted in the deacylation of apo-A-I. Although three of the apo-A-I isoforms analyzed by two-dimensional gel electrophoresis were shown to contain radio-labeled palmitate, 80% of acylated apo-A-I was in the proapolipoprotein A-I isoform. [14C]Oleate was not incorporated in secreted apo-A-I, indicating the specificity of the acylation of apo-A-I. Incubation of [14C] palmitate-acylated apo-A-I in serum and plasma under conditions in which proapo-A-I is proteolytically cleaved to mature apo-A-I did not result in deacylation. These data establish that fatty acid acylation occurs in human secretory proteins in addition to the previously reported acylation of cellular membrane proteins. These results suggest that the covalent linkage of lipids to apolipoproteins may play a critical role in apolipoprotein and lipoprotein metabolism.
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PMID:Human apolipoprotein A-I. Post-translational modification by fatty acid acylation. 300 8

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kinase gene, RET. We have recently shown an unexpected correlation between one particular RET mutation, cys634-->arg, and the probability of parathyroid involvement in families with MEN 2A. Here we use haplotype analysis in the families to show that this correlation is not explained by a single founder chromosome which carries both the cys634-->arg mutation and a separate allele conferring susceptibility to parathyroid abnormality, but is probably due to the cys634-->arg mutation itself. The results also indicate that new mutations to MEN 2 are not infrequent.
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PMID:Haplotype analysis of MEN 2 mutations. 784

Low plasma high density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD) in adults. In the field of pediatrics, subjects with low plasma HDL-C are often found among obese or dyslipidemic children. However, it is not clear whether low HDL-C in children should be considered a risk factor for CHD. The purpose of this study was to evaluate the risk for CHD in children with low HDL-C by comparing their lipid and apolipoprotein levels and physicochemical characteristics of their HDL with those of age-matched children with normal HDL-C and CHD patients with low HDL-C. Plasma lipids and apolipoproteins were measured in 206 dyslipidemic children (dyslipidemic), 65 obese children (obese), 93 CHD patients with low HDL-C (< 40 mg/dl) and 128 children with normal HDL-C (controls). To evaluate the physicochemical characteristics of HDL, molar and fractional esterification rates of cholesterol in plasma (MER(plasma) and FER(plasma)) and HDL (MER(HDL) and FER(HDL)) were determined in 128 children with normal HDL-C, 71 dyslipidemic, 33 obese and 93 CHD who allowed second blood samples to be taken. Compared to controls, children with low HDL-C showed atherogenic profiles of lipid and apolipoprotein levels and physicochemical characteristics of HDL (lower apo A-I, lower ratio of apo A-I to apo B and higher FER(HDL)). Therefore, the differences in lipid and apolipoprotein profiles between children with low HDL-C and CHD patients with low HDL-C were examined next. The two groups of subjects based on the HDL-C level (Group I: < 30 mg/dl, Group II 30 < or = HDL-C < 40 mg/dl) were studied. Compared to CHD, Group I children showed less atherogenic apolipoprotein profiles (lower apo B and higher ratio of apo A-I to apo B). Similar findings were also found in Group II children, but the differences were less prominent than those in Group I children. FER(HDL) in children with low HDL-C were similar to those in CHD. These findings suggest that the physicochemical characteristics of HDL in children with low HDL-C are similar to those in CHD, but the abnormalities of apo B-containing lipoproteins are milder than those in CHD patients. Thus, if further changes in the nature of apo B-containing lipoproteins could be prevented, children with low HDL-C might not become high risk for CHD in later life.
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PMID:Comparison of children and coronary heart disease patients with low high density lipoprotein cholesterol levels. 962 75

As part of a 60-week, open-label, nonrandomized, parallel, controlled study comparing a monthly contraceptive injection containing medroxyprogesterone acetate (MPA) 25 mg and estradiol cypionate (E(2)C) 5 mg (Lunelle Monthly Contraceptive Injection) and a norethindrone 0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol (NET/EE) triphasic oral contraceptive (Ortho-Novum(R) 7/7/7), a longitudinal examination of lipid profiles was conducted. Lipid parameters were assessed at screening and at weeks 20, 40, and 60 (or the final visit) in 114 women using MPA/E(2)C and 93 using NET/EE (lipid analysis population). Extra blood samples were obtained at weeks 21, 22, and 23 in 61 MPA/E(2)C users and 51 NET/EE users (index-cycle analysis population) to investigate lipid changes during one cycle of use. In the index-cycle population, median changes from screening to week 60 showed a decrease in apolipoprotein (apo) A-I and apo A-II in both groups. MPA/E(2)C users had a decrease in total cholesterol (C), total triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), with maintenance of the total C/HDL-C ratio. NET/EE users showed an increase in total C and LDL-C, with no change in HDL-C or the total C/HDL-C ratio. Within the index cycle (weeks 20 to 23), median changes in lipid values in both MPA/E(2)C and NET/EE users were generally greatest during the first week after the injection or the start of the pill pack. The results of this first longitudinal examination of serum lipids in US women using MPA/E(2)C confirm earlier findings in women in other countries. However, a direct comparison of the effects of MPA/E(2)C and NET/EE on lipid profiles was not possible in this study because of its design and because of the baseline and pharmacokinetic/pharmacodynamic differences between the two contraceptive groups. The results of this analysis showed that, although overall lipid values decreased, including a significant decrease in HDL cholesterol, the maintenance of the total-C/HDL-C ratio suggests that the effect of MPA/E(2)C on lipid parameters may not negatively affect CVD risk over 1 year of use. However, these results warrant further investigation, given the nature of this trial.
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PMID:Comparative effects of Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) and ortho-Novum 7/7/7 oral contraceptive (norethindrone/ethinyl estradiol triphasic) on lipid profiles. Investigators from the Lunelle Study Group. 1074 70

Regulation of macrophage activities in response to inflammatory stimuli must be finely tuned to promote an effective immune response while, at the same time, preventing damage to the host. Our lab and others have previously shown that macrophage-stimulating protein (MSP), through activation of its receptor RON, negatively regulates NO production in response to IFN-gamma and LPS by inhibiting the expression of inducible NO synthase (iNOS). Furthermore, activated macrophages from mice harboring targeted mutations in RON produce increased levels of NO both in vitro and in vivo, rendering them more susceptible to LPS-induced endotoxic shock. In this study, we demonstrate that stimulation of murine peritoneal macrophages with MSP results in the RON-dependent up-regulation of arginase, an enzyme associated with alternative activation that competes with iNOS for the substrate L-arginine, the products of which are involved in cell proliferation and matrix synthesis. Expression of other genes associated with alternative activation, including scavenger receptor A and IL-1R antagonist, is also up-regulated in MSP-stimulated murine macrophages. Stimulation of cells with IFN-gamma and LPS blocks the ability of MSP to induce arginase activity. However, pretreatment of cells with MSP results in the up-regulation of arginase and inhibits their ability to produce NO in response to IFN-gamma and LPS, even in the presence of excess substrate, suggesting that the inhibition of NO by MSP occurs primarily through its ability to regulate iNOS expression.
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PMID:Activation of the stem cell-derived tyrosine kinase/RON receptor tyrosine kinase by macrophage-stimulating protein results in the induction of arginase activity in murine peritoneal macrophages. 1177 82

L-arginine is metabolized to nitric oxide (NO) by NO synthase (NOS), or to urea and L-ornithine by arginase. L-ornithine contributes to vascular remodeling in pulmonary hypertension via metabolism to polyamines and proline. Previously we found that cytokines upregulate both NOS and arginase in pulmonary arterial endothelial cells. We hypothesized that cytokine-induced arginase I and II expression depend on epidermal growth factor (EGF) receptor (EGFR) activity. Bovine pulmonary arterial endothelial cells were treated with lipopolysaccharide and tumor necrosis factor-alpha (L/T). L/T treatment resulted in a substantial increase in urea production, and this increase in urea production was potently inhibited by both genistein and AG1478, inhibitors of EGFR. Levels of arginase I protein and arginase II mRNA were increased in response to L/T treatment, and genistein prevented the L/T-induced elevations in both arginase I protein and arginase II mRNA levels. L/T treatment increased production of nitrites and inducible NOS mRNA accumulation, and genistein and AG1478 had little effect on these changes. EGF (50 ng/ml) treatment resulted in enhanced urea production. Finally, a 170-kD protein was phosphorylated upon treatment with either EGF or L/T. Our results indicate that arginase induction by L/T depends in part on EGFR activity. We speculate that EGFR inhibitors may attenuate vascular remodeling without affecting NO release, and thus may represent novel therapeutic modalities for pulmonary hypertensive disorders.
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PMID:Cytokine-induced endothelial arginase expression is dependent on epidermal growth factor receptor. 1599 32

Inhibition of tyrosine kinase (TK) receptors by synthetic small molecules has become a promising new therapy option in oncology. The TK inhibitor imatinib mesylate selectively targets PDGFR-alpha, -beta, c-kit, c-abl and arg and has proven successful in the treatment of chronic myeloid leukaemia. In recurrent glioblastoma, phase II therapy trials using imatinib mesylate have been initiated. As only a fraction of patients seems to benefit from imatinib mesylate therapy and due to potential side effects and high costs of imatinib mesylate therapy, selection of the right patients is important. The goal of our study was to assess systematically immunohistochemical expression of the major TKs targeted by imatinib mesylate in glioblastoma, as expression of these factors could be used to select patients for imatinib mesylate therapy. In a cohort of 101 glioblastoma patients, anti-PDGFR-alpha, -beta, c-kit, c-abl and arg protein immunohistochemistry was performed. Expression of these proteins was assessed semi-quantitatively and correlated with patient survival.PDGFR-alpha and arg expression in tumor cells was widespread in 1/101 cases, respectively. Focal PDGFR-alpha, -beta, c-kit, c-abl and arg immunolabeling was detected in 25/101, 19/101, 4/101, 7/101 and 31/101 cases, respectively. Statistical analysis did not reveal any correlation between expression of the TKs and patient survival. We show here for the first time in a large series of glioblastomas that PDGFR-alpha, -beta, c-kit, c-abl and arg expression is immunohistochemically detectable in a fraction of cases. The value of anti-tyrosine kinase immunolabeling as predictive factor for patient selection remains to be clarified by comparative analysis of tumor tissue of therapy-responders versus non-responders.
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PMID:Immunohistochemical analysis of platelet-derived growth factor receptor-alpha, -beta, c-kit, c-abl, and arg proteins in glioblastoma: possible implications for patient selection for imatinib mesylate therapy. 1620 64

Blood vessel injury results in limited oxygen tension and diffusion leading to hypoxia, increased anaerobic metabolism, and elevated production of acidic metabolites that cannot be easily removed due to the reduced blood flow. Therefore, an acidic extracellular pH occurs in the local microenvironment of disrupted bone. The potential role of acidic pH and glu-leu-arg (ELR(+)) CXC chemokines in early events in bone repair was studied in human mesenchymal stem cells (hMSCs) treated with medium of decreasing pH (7.4, 7.0, 6.7, and 6.4). The cells showed a reciprocal increase in CXCL8 (interleukin-8, IL-8) mRNA levels as extracellular pH decreased. At pH 6.4, CXCL8 mRNA was induced >60x in comparison to levels at pH 7.4. hMSCs treated with osteogenic medium (OGM) also showed an increase in CXCL8 mRNA with decreasing pH; although, at a lower level than that seen in cells grown in non-OGM. CXCL8 protein was secreted into the medium at all pHs with maximal induction at pH 6.7. Inhibition of the G-protein-coupled receptor alpha, G(alphai), suppressed CXCL8 levels in response to acidic pH; whereas phospholipase C inhibition had no effect on CXCL8. The use of specific mitogen-activated protein kinase (MAPK) signal transduction inhibitors indicated that the pH-dependent increase in CXCL8 mRNA is due to activation of ERK and p38 pathways. The JNK pathway was not involved. NF-kappaB inhibition resulted in a decrease in CXCL8 levels in hMSCs grown in non-OGM. However, OGM-differentiated hMSCs showed an increase in CXCL8 levels when treated with the NF-kappaB inhibitor PDTC, a pyrrolidine derivative of dithiocarbamate.
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PMID:Acidic pH stimulates the production of the angiogenic CXC chemokine, CXCL8 (interleukin-8), in human adult mesenchymal stem cells via the extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and NF-kappaB pathways. 1827 43

Myeloid-derived suppressor cells (MDSC) producing arginase I are increased in the peripheral blood of patients with renal cell carcinoma (RCC). MDSC inhibit T-cell function by reducing the availability of L-arginine and are therefore considered an important tumor escape mechanism. We aimed to determine the origin of arginase I-producing MDSC in RCC patients and to identify the mechanisms used to deplete extracellular L-arginine. The results show that human MDSC are a subpopulation of activated polymorphonuclear (PMN) cells expressing high levels of CD66b, CD11b, and VEGFR1 and low levels of CD62L and CD16. In contrast to murine MDSC, human MDSC do not deplete L-arginine by increasing its uptake but instead release arginase I into the circulation. Activation of normal PMN induces phenotypic and functional changes similar to MDSC and also promotes the release of arginase I from intracellular granules. Interestingly, although activation of normal PMN usually ends with apoptosis, MDSC showed no increase in apoptosis compared with autologous PMN or PMN obtained from normal controls. High levels of VEGF have been shown to increase suppressor immature myeloid dendritic cells in cancer patients. Treatment of RCC patients with anti-VEGF antibody bevacizumab, however, did not reduce the accumulation of MDSC in peripheral blood. In contrast, the addition of interleukin-2 to the treatment increased the number of MDSC in peripheral blood and the plasma levels of arginase I. These results may provide new insights on the mechanisms of tumor-induced anergy/tolerance and may help explain why some immunotherapies fail to induce an antitumor response.
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PMID:Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. 1920 93

We have previously shown that peritoneal macrophages from mice bearing advanced D1-DMBA3 mammary tumors are impaired in their inflammatory functions but are not alternatively activated either and are less differentiated than the ones from normal mice. However, little is known about whether similar defects exist in their precursor stages as blood monocytes. We examined if blood monocytes from mammary tumor-bearing mice are already altered in their activation profiles before becoming macrophages and whether they correspond to inflammatory or resident monocyte subtypes. Much effort is currently devoted to reversing macrophage adverse traits in tumor hosts; as these cells reside within tissues, access is limited. Blood monocytes could be better targeted and manipulated by less invasive means. In the present study, mononuclear cells were isolated from whole blood of D1-DMBA-3 mammary tumor-bearing and normal BALB/c mice and CD115(+) monocytes were analyzed. Our results show that there is an increase in circulating monocytes in tumor hosts; these monocytes exhibit a reduced expression of several myeloid differentiation markers such as CD115, F4/80, CD68 and CD11b. Moreover, downregulation of MHC II, CD62L and the proangiogenic marker Tie-2 are observed in these cells, whereas Gr-1 and Ly6C are upregulated. Furthermore, gene microarray analysis performed for the first time in blood monocytes from tumor hosts indicates that they express a mixture of pro-inflammatory and anti-inflammatory cytokines and chemokines. Interestingly, CCR2 and CX3CR1, which are crucial in monocyte definition as inflammatory or resident, respectively, are both upregulated. Importantly, complement proteins are enhanced whereas nitric oxide production is decreased and there is no measurable arginase activity detected in these cells. Collectively, our study represents the first comprehensive analysis of blood monocytes from tumor-bearing mice; we conclude that these cells are neither completely inflammatory nor suppressive and are less differentiated, similar to the macrophages they later become.
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PMID:Blood monocytes from mammary tumor-bearing mice: early targets of tumor-induced immune suppression? 2081 11


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