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71.
T Akerström J Crona A Delgado Verdugo LF Starker K Cupisti HS Willenberg WT Knoefel W Saeger A Feller J Ip P Soon M Anlauf PF Alesina KW Schmid M Decaussin P Levillain B Wängberg JL Peix B Robinson J Zedenius M Bäckdahl S Caramuta KA Iwen J Botling P Stålberg JL Kraimps H Dralle P Hellman S Sidhu G Westin H Lehnert MK Walz G Akerström T Carling M Choi RP Lifton P Björklund 《PloS one》2012,7(7):e41926
Background
Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.Materials and Methods
The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.Results
G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005).Discussion
Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism. 相似文献72.
Bauvois C Jacquamet L Huston AL Borel F Feller G Ferrer JL 《The Journal of biological chemistry》2008,283(34):23315-23325
The crystal structure of a cold-active aminopeptidase (ColAP) from Colwellia psychrerythraea strain 34H has been determined, extending the number of crystal structures of the M1 metallopeptidase family to four among the 436 members currently identified. In agreement with their sequence similarity, the overall structure of ColAP displayed a high correspondence with leukotriene A4 hydrolase (LTA4H), a human bifunctional enzyme that converts leukotriene A4 (LTA4) in the potent chemoattractant leukotriene B4. Indeed, both enzymes are composed of three domains, an N-terminal saddle-like domain, a catalytic thermolysin-like domain, and a less conserved C-terminal alpha-helical flat spiral domain. Together, these domains form a deep cavity harboring the zinc binding site formed by residues included in the conserved HEXXHX(18)H motif. A detailed structural comparison of these enzymes revealed several plausible determinants of ColAP cold adaptation. The main differences involve specific amino acid substitutions, loop content and solvent exposure, complexity and distribution of ion pairs, and differential domain flexibilities. Such elements may act synergistically to allow conformational flexibility needed for an efficient catalysis in cold environments. Furthermore, the region of ColAP corresponding to the aminopeptidase active site of LTA4H is much more conserved than the suggested LTA4 substrate binding region. This observation supports the hypothesis that this region of the LTA4H active site has evolved in order to fit the lipidic substrate. 相似文献
73.
The relationships between structure, activity, stability and flexibility of a cold-adapted aminopeptidase produced by a psychrophilic marine bacterium have been investigated in comparison with a mesophilic structural and functional human homolog. Differential scanning calorimetry, fluorescence monitoring of thermal- and guanidine hydrochloride-induced unfolding and fluorescence quenching were used to show that the cold-adapted enzyme is characterized by a high activity at low temperatures, a low structural stability versus thermal and chemical denaturants and a greater structural permeability to a quenching agent relative to the mesophilic homolog. These findings support the hypothesis that cold-adapted enzymes maintain their activity at low temperatures as a result of increased global or local structural flexibility, which results in low stability. Analysis of the thermodynamic parameters of irreversible thermal unfolding suggests that entropy-driven factors are responsible for the fast unfolding rate of the cold-adapted aminopeptidase. A reduced number of proline residues, a lower degree of hydrophobic residue burial and a decreased surface accessibility of charged residues may be responsible for this effect. On the other hand, the reduction in enthalpy-driven interactions is the primary determinant of the weak conformational stability. 相似文献
74.
Manlay Raphaël J. Masse Dominique Chevallier Tiphaine Russell-Smith Anthony Friot Dominique Feller Christian 《Plant and Soil》2004,259(1-2):123-136
Potassium (K), calcium (Ca), iron (Fe) and aluminium (Al) release from Norway spruce (Picea abies Karsten), Scots pine (Pinus sylvestris L.) and silver birch (Betula pendula Roth.) logging residues (fine roots, foliage and small branches) were studied by means of litterbags over a period of three years in clear-cut area and adjacent uncut Norway spruce dominated mixed boreal forest in eastern Finland (63°51′ N, 28°58′ E, 220 m a.s.l) to determine the amounts and rates of release for these elements and to evaluate whether clear-cutting accelerates mineralization. Almost all K was released from logging residues already during the first year. Calcium was released from foliage and roots but accumulated in branches. Most of the roots Fe and Al content were released during three years while the absolute amounts of Fe and Al in branches and foliage generally increased with decomposition. The results indicate that mineralization is slightly accelerated as a result of clear-cutting since K from foliage and branches of all studied tree species and Ca from pine and spruce roots was released significantly faster at the clear-cut plot than at the forest plot. In three years the initial K pool in the logging residues declined by 90%, Ca by 8%, Fe by 55% and Al by 61% in the clear-cut area. These results indicate that Ca is retained a long time; but Fe, Al and in particular, K are soon released from logging residues. Fine roots of the logged trees release large amounts of Fe and Al and can significantly affect Fe and Al fluxes. 相似文献
75.
76.
S Cunningham-Rundles W F Feller C Cunningham-Rundles B Dupont H Wanebo R O'Reilly R A Good 《Cellular immunology》1976,25(2):322-327
The cell-mediated immune responses of 110 women with benign or malignant breast disease were tested in in vitro lymphocyte transformation assay with an antigen preparation made from RIII mouse milk containing mammary tumor virus. About 50% of patients responded positively to the milk preparation. In contrast, 25% of normal women or women with other gynecological malignancies responded positively to the antigen (P = 0.015). The data demonstrate a similar response pattern among women with malignant or benign breast disease. In addition, a subpopulation of normal women with positive response to this antigen is clearly defined. 相似文献
77.
78.
Menadione partially restores NADH-oxidation and ATP-synthesis in complex I deficient fibroblasts 总被引:1,自引:0,他引:1
In this paper we report our studies on the effects of menadione in cultured fibroblasts treated with rotenone to block complex I. A normalization of the lactate to pyruvate ratio after incubation with glucose, an increased production of 14CO2 from [6-14C]glucose and an increased intra-cellular concentration of ATP was observed in the presence of micromolar concentrations of menadione. These results not only demonstrate the potential value of menadione in complex I deficient patients but also suggest that this system can be used advantageously for the in vitro assessment of therapeutic agents for disorders of the mitochondrial respiratory chain. 相似文献
79.
Wolfgang Feller Hartmut Follmann 《Biochemical and biophysical research communications》1976,70(3):752-758
A ribonucleoside diphosphate reductase is demonstrated in the algae, and . In synchronized cultures an activity maximum at the 12th hour of the cell cycle coincides with maximum DNA production. Induction of reductase activity is prevented by cycloheximide. The enzyme requires dithiols for reduction of CDP ; it is not significantly stimulated by iron or magnesium ions nor dependent upon deoxyadenosylcobalamin. ATP stimulates the reaction but dATP or dTTP act as inhibitors. The ribonucleotide reductase of green algae differs from the B12-requiring enzyme characterized in . 相似文献
80.
CO2 , light and temperature influence senescence and protein degradation in wheat leaf segments 总被引:1,自引:0,他引:1
Effects of environmental conditions influencing photosynthesis and photorespiration on senescence and net protein degradation were investigated in segments from the first leaf of young wheat ( Triticum aestivum L. cv. Arina) plants. The segments were floated on H2 O at 25, 30 or 35°C in continuous light (PAR: 50 or 150 µmol m−2 s−1 ) in ambient air and in CO2 ‐depleted air. Stromal enzymes, including phosphoglycolate phosphatase, glutamine synthetase, ferredoxin‐dependent glutamate synthase, phosphoribulokinase, and the peroxisomal enzyme, glycolate oxidase, were detected by SDS‐PAGE followed by immunoblotting with specific antibodies. In general, the net degradation of proteins and chlorophylls was delayed in CO2 ‐depleted air. However, little effect of CO2 on protein degradation was observed at 25°C under the lower level of irradiance. The senescence retardation by the removal of CO2 was most pronounced at 30°C and at the higher irradiance. The stromal enzymes declined in a coordinated manner. Immunoreactive fragments from the degraded polypeptides were in most cases not detectable. However, an insolubilized fragment of glycolate oxidase accumulated in vivo, especially at 25°C in the presence of CO2 . Detection of this fragment was minimal after incubation at 30°C and completely absent on blots from segments kept at 35°C. In CO2 ‐depleted air, the fragment was only weakly detectable after incubation at 25°C. The results from these investigations indicate that environmental conditions that influence photosynthesis may interfere with senescence and protein catabolism in wheat leaves. 相似文献