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21.
目的筛选与Rap GAP相互作用的蛋白质,为进一步研究人源Rap1GAP介导的信号转导通路、揭示其与肿瘤的关系提供实验依据。方法选用与Rap1GAP同源的来自美丽线虫的Rap GAP作为饵蛋白,以来源于美丽线虫的c DNA文库作为靶蛋白,应用p PC97、p PC86组成的酵母双杂交系统筛选c DNA文库中与Rap GAP相互作用的蛋白质。结果通过营养缺陷平板(-LTH)筛选出63个拟似阳性菌落。经过Lac Z鉴定,19个菌落为阳性,其中7个为强阳性。提取来自19个酵母菌落中的重组DNA,经PCR扩增,12个菌落出现阳性结果。将该19个重组DNA分别电转化入DH5α细菌,涂板培养后,每板挑取4~10个克隆,通过Sal I和Not I双酶切鉴定进行阳性克隆筛选。将阳性克隆的重组DNA进行序列测定。测序结果与Gen Bank比较,其中4个克隆的DNA片段为Y39b6a基因片段、2个为Rap GAP、1个为苯丙氨酸-4-羟化酶、1个为细胞色素C氧化酶,还有1个DNA片段编码美丽线虫特有的小分子蛋白的基因片段,其余11个DNA片段不编码已知蛋白质。结论初步筛选出与Rap GAP相互作用的蛋白质,特别是其中有2个克隆为Rap GAP,提示Rap GAP可能以二聚体的方式存在。 相似文献
22.
Thomas D Niehaus Svetlana Gerdes Kelsey Hodge-Hanson Aleksey Zhukov Arthur JL Cooper Mona ElBadawi-Sidhu Oliver Fiehn Diana M Downs Andrew D Hanson 《BMC genomics》2015,16(1)
Background
It is now recognized that enzymatic or chemical side-reactions can convert normal metabolites to useless or toxic ones and that a suite of enzymes exists to mitigate such metabolite damage. Examples are the reactive imine/enamine intermediates produced by threonine dehydratase, which damage the pyridoxal 5''-phosphate cofactor of various enzymes causing inactivation. This damage is pre-empted by RidA proteins, which hydrolyze the imines before they do harm. RidA proteins belong to the YjgF/YER057c/UK114 family (here renamed the Rid family). Most other members of this diverse and ubiquitous family lack defined functions.Results
Phylogenetic analysis divided the Rid family into a widely distributed, apparently archetypal RidA subfamily and seven other subfamilies (Rid1 to Rid7) that are largely confined to bacteria and often co-occur in the same organism with RidA and each other. The Rid1 to Rid3 subfamilies, but not the Rid4 to Rid7 subfamilies, have a conserved arginine residue that, in RidA proteins, is essential for imine-hydrolyzing activity. Analysis of the chromosomal context of bacterial RidA genes revealed clustering with genes for threonine dehydratase and other pyridoxal 5''-phosphate-dependent enzymes, which fits with the known RidA imine hydrolase activity. Clustering was also evident between Rid family genes and genes specifying FAD-dependent amine oxidases or enzymes of carbamoyl phosphate metabolism. Biochemical assays showed that Salmonella enterica RidA and Rid2, but not Rid7, can hydrolyze imines generated by amino acid oxidase. Genetic tests indicated that carbamoyl phosphate overproduction is toxic to S. enterica cells lacking RidA, and metabolomic profiling of Rid knockout strains showed ten-fold accumulation of the carbamoyl phosphate-related metabolite dihydroorotate.Conclusions
Like the archetypal RidA subfamily, the Rid2, and probably the Rid1 and Rid3 subfamilies, have imine-hydrolyzing activity and can pre-empt damage from imines formed by amine oxidases as well as by pyridoxal 5''-phosphate enzymes. The RidA subfamily has an additional damage pre-emption role in carbamoyl phosphate metabolism that has yet to be biochemically defined. Finally, the Rid4 to Rid7 subfamilies appear not to hydrolyze imines and thus remain mysterious.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1584-3) contains supplementary material, which is available to authorized users. 相似文献23.
Carl PC Chen Chih-Chin Hsu Wen-Lin Yeh Hsiu-Chu Lin Sen-Yung Hsieh Shih-Cherng Lin Tai-Tzung Chen Max JL Chen Simon FT Tang 《Proteome science》2011,9(1):1-10
Background
Prenatal screening for Down Syndrome (DS) would benefit from an increased number of biomarkers to improve sensitivity and specificity. Improving sensitivity and specificity would decrease the need for potentially risky invasive diagnostic procedures.Results
We have performed an in depth two-dimensional difference gel electrophoresis (2D DIGE) study to identify potential biomarkers. We have used maternal plasma samples obtained from first and second trimesters from mothers carrying DS affected fetuses compared with mothers carrying normal fetuses. Plasma samples were albumin/IgG depleted and expanded pH ranges of pH 4.5 - 5.5, pH 5.3 - 6.5 and pH 6 - 9 were used for two-dimensional gel electrophoresis (2DE). We found no differentially expressed proteins in the first trimester between the two groups. Significant up-regulation of ceruloplasmin, inter-alpha-trypsin inhibitor heavy chain H4, complement proteins C1s subcomponent, C4-A, C5, and C9 and kininogen 1 were detected in the second trimester in maternal plasma samples where a DS affected fetus was being carried. However, ceruloplasmin could not be confirmed as being consistently up-regulated in DS affected pregnancies by Western blotting.Conclusions
Despite the in depth 2DE approach used in this study the results underline the deficiencies of gel-based proteomics for detection of plasma biomarkers. Gel-free approaches may be more productive to increase the number of plasma biomarkers for DS for non-invasive prenatal screening and diagnosis. 相似文献24.
Nutritional aspects of manganese homeostasis 总被引:4,自引:0,他引:4
Manganese (Mn) is an essential mineral. It is present in virtually all diets at low concentrations. The principal route of intake for Mn is via food consumption, but in occupational cohorts, inhalation exposure may also occur (this subject will not be dealt with in this review). Humans maintain stable tissue levels of Mn. This is achieved via tight homeostatic control of both absorption and excretion. Nevertheless, it is well established that exposure to high oral, parenteral or ambient air concentrations of Mn can result in elevations in tissue Mn levels. Excessive Mn accumulation in the central nervous system (CNS) is an established clinical entity, referred to as manganism. It resembles idiopathic Parkinson's disease (IPD) in its clinical features, resulting in adverse neurological effects both in laboratory animals and humans. This review focuses on an area that to date has received little consideration, namely the potential exposure of parenterally fed neonates to exceedingly high Mn concentrations in parenteral nutrition solutions, potentially increasing their risk for Mn-induced adverse health sequelae. The review will consider (1) the essentiality of Mn; (2) the concentration ranges, means and variation of Mn in various foods and infant formulas; (3) the absorption, distribution, and elimination of Mn after oral exposure and (4) the factors that raise a theoretical concern that neonates receiving total parenteral nutrition (TPN) are exposed to excessive dietary Mn. 相似文献
25.
Menetti F Tohno S Tohno Y Azuma C Moriwake Y Satoh H Minami T Mahakkanukrauh P Oishi T Hayashi M 《Biological trace element research》2005,106(3):231-245
In order to maintain normal functioning of the brain, glutamate homeostasis and extracellular levels of excitotoxic amino
acids (EAA) must be tightly controlled. This is accomplished, in large measure, by the astroglial high-affinity Na+-dependent EAA transporters glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1). Methylmercury (MeHg)
is a potent neurotoxicant. Astrocytes are known targets for MeHg toxicity, representing a site for mercury localization. Mehg
is known to cause astrocytic swelling, EAA release, and uptake inhibition in astrocytes, leading to increased extracellular
glutamate levels and ensuing neuronal excitotoxicity and degeneration. However, the mechanisms and contribution of specific
glutamate transporters to MeHg-induced glutamate dyshomeostasis remain unknown. Accordingly, the present study was carried
out to investigate the effects of MeHg on the transport of [d-2, 3-3H]-d-aspartate, a nonmetabolizable glutamate analog in Chinese hamster ovary cells (CHO) transfected with the glutamate transporter
subtypes GLAST or GLT-1. Additional studies examined the effects of MeHg on mRNA and protein levels of these transporters.
Our results indicate the following (1) MeHg selectively affects glutamate transporter mRNA expression. MeHg treatment (6 h)
led to no discernible changes in GLAST mRNA expression; however, GLT-1 mRNA expression significantly (p<0.001) increased following treatments with 5 or 10 μM MeHg. (2) Selective changes in the expression of glutamate transporter protein levels were also noted. GLAST transporter
protein levels significantly (p<0.001, both at 5 and 10 μM MeHg) increased and GLT-1 transporter protein levels significantly (p<0.001) decreased followign MeHg exposure (5 μM). (3) MeHg exposure led to significant inhibition (p<0.05) of glutamate uptake by GLAST (both 5 and 10 μM MeHg), whereas GLT-1 transporter activity was significantly (p<0.01) increased following exposure to 5 and 10 μM MeHg. These studies suggest that MeHg contributes to the dysregulation of glutamate homeostasis and that its effects are
distinct for GLAST and GLT-1. 相似文献
26.
27.
28.
Studies on Gulf War veterans with depleted uranium (DU) fragments embedded in their soft tissues have led to suggestions of
possible DU-induced neurotoxicity. We investigated DU uptake into cultured rat brain endothelial cells (RBE4). Following the
determination that DU readily enters RBE4 cells, cytotoxic effects were analyzed using assays for cell volume increase, heat
shock protein 90 (Hsp90) expression, 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) reduction, and lactate
dehydrogenase (LDH) activity. The results of these studies show that uptake of the U3O8 uranyl chloride form of DU into RBE4 cells is efficient, but there are little or no resulting cytotoxic effects on these
cells as detected by common biomarkers. Thus, the present experimental paradigm is rather reassuring and provides no indication
for overt cytotoxicity in endothelial cells exposed to DU. 相似文献
29.
Mutkus L Aschner JL Syversen T Shanker G Sonnewald U Aschner M 《Biological trace element research》2006,109(3):267-280
Glutamate is removed mainly by astrocytes from the extracellular fluid via high-affinity astroglial Na+-dependent excitatory amino acid transporters, glutamate/aspartate transporter (GLAST), and glutamate transporter-1 (GLT-1).
Mercuric chloride (HgCl2) is a highly toxic compound that inhibits glutamate uptake in astrocytes, resulting in excessive extracellular glutamate
accumulation, leading to excitotoxicity and neuronal cell death. The mechanisms associated with the inhibitory effects of
HgCl2 on glutamate uptake are unknown. This study examines the effects of HgCl2 on the transport of 3H-d-aspartate, a nonmetabolizable glutamate analog, using Chinese hamster ovary cells (CHO) transfected with two glutamate transporter
subtypes, GLAST (EAAT1) and GLT-1 (EAAT2), as a model system. Additionally, studies were undertaken to determine the effects
of HgCl2 on mRNA and protein levels of these transporters. The results indicate that (1) HgCl2 leads to significant (p<0.001) inhibition of glutamate uptake via both transporters, but is a more potent inhibitor of glutamate transport via GLAST
and (2) the effect of HgCl2 on inhibition of glutamate uptake in transfected CHO cells is not associated with changes in transporter protein levels despite
a significant decrease in mRNA expression; thus, (3) HgCl2 inhibition is most likely related to its direct binding to the functional thiol groups of the transporters and interference
with their uptake function. 相似文献
30.
The effects of manganese on glutamate, dopamine and gamma-aminobutyric acid regulation 总被引:6,自引:0,他引:6
Exposure to high levels of manganese (Mn) results in a neurological disorder, termed manganism, which shares a similar phenotype to Parkinson's disease due to the involvement of the basal ganglia circuitry in both. The initial symptoms of manganism are likely due to the involvement of the globus pallidus, a region rich in gamma-aminobutyric acid (GABA) projections, while those of Parkinson's disease are related to the degeneration of the substantia nigra, a dopaminergic nucleus. Additionally, it is known that glutamate regulation is affected by increases in brain Mn levels. As Mn predominantly accumulates in the basal ganglia, it potentially could affect the regulation and interactions of all three neurotransmitters. This review will focus on the circuitry of these neurotransmitters within the basal ganglia and address potential sites for, as well as the temporal relationship, between Mn exposure and changes in the levels of these neurotransmitters. While most research has focused on perturbations in the dopaminergic system, there is evidence to support that early consequences of manganism also include disturbances in GABA regulation as well as glutamatergic-related excitotoxicity. Finally, we suggest that current research focus on the interdependence of these basal ganglial neurochemicals, with a greater emphasis on the GABAergic and glutamatergic systems. 相似文献