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471.
Protein kinase B (PKB), a serine/threonine protein kinase, prevents apoptosis and promotes cellular transformation. PKB activity is stimulated by insulin. In this report, we examined the relative amounts of expression, location, and translocation upon insulin stimulation of PKBalpha in normal primary hepatocytes and carcinoma cells, HepG2 cells. Non-phosphorylated PKBalpha was present in both types of unstimulated cells. The phosphorylated form of the enzyme was present in the nucleus of unstimulated HepG2 cells but not in normal hepatocytes. In the cytoplasm, PKBalpha was found in greater abundance in the hepatocytes as compared in HepG2 cells. Insulin induced the translocation of phosphorylated PKBalpha from the nucleus to the nuclear membrane in HepG2 cells. In contrast, insulin caused translocation and phosphorylation of PKBalpha from the cytosol to the plasma membrane in normal hepatocytes. In addition, there is a higher expression of PKBalpha in the HepG2 cells as compared to normal primary hepatocytes. These findings provide an important distinction between hepatocellular HepG2 cells and normal liver cells and suggest that the presence of constitutively active nuclear PKB in the transformed cells might be an important contributor in cell transformation and immortality of hepatoma cells. 相似文献
472.
Protamine is a polycationic amine used clinically to reverse heparin overdose. Here we characterized the actions of protamine on the cardiovascular system of anesthetized rats and in isolated Langendorff rat hearts in order to define a possible mechanism of action on cardiovascular tissue. In anesthetized rats, protamine reduced blood pressure in a dose-dependent fashion and reduced heart rate. Only at a dose of 32 mg/kg did protamine increase the Q-aT interval of the electrocardiogram (EKG) to 62 +/- 6 msec from a control of 54 +/- 5 msec (p < 0.05). Protamine dose-dependently reduced cardiac output by 74 +/- 5% and stroke volume by 62 +/- 15 %, suggesting that it directly affects cardiac contractility. An analysis of blood chemistry suggests that protamine does not alter plasma electrolyte or serum enzyme levels at the doses administered. Protamine produced aberrant rhythms in normal rat hearts when administered between 1-32 mg/kg. The P-Q segment of the EKG for each of the arrhythmic complexes was reduced to 24 +/- 1 msec compared to 32 +/- 3 msec in normal EKG complexes suggestive of anomalous atrio-ventricular or pre-excitation conduction. Isolated rat heart studies confirmed that protamine produced a reduction in cardiac contractility. Our studies suggest that the cardiovascular depressant actions of protamine result from a direct effect on the heart and that protamine may produce aberrant conduction within the heart which may result in deleterious effects in heart function, especially conditions associated with myocardial disease. 相似文献
473.
Rab5-mediated endosome-endosome fusion regulates hemoglobin endocytosis in Leishmania donovani
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Singh SB Tandon R Krishnamurthy G Vikram R Sharma N Basu SK Mukhopadhyay A 《The EMBO journal》2003,22(21):5712-5722
To understand the trafficking of endocytosed hemoglobin (Hb) in Leishmania, we investigated the characteristics of in vitro fusion between endosomes containing biotinylated Hb (BHb) and avidin-horseradish peroxidase (AHRP). We showed that early endosome fusion in Leishmania is temperature and cytosol dependent and is inhibited by ATP depletion, ATPgammaS, GTPgammaS and N-ethylmaleimide treatment. The Rab5 homolog from Leishmania donovani, LdRab5, was cloned and expressed. Our results showed that homotypic fusion between the early endosomes in Leishmania is Rab5 dependent. Early endosomes containing BHb fused efficiently with late endosomes in a process regulated by Rab7, whereas no fusion between early and late endosomes was detected using fluid phase markers. Pre-treatment of early endosomes containing BHb with monoclonal antibody specific for the C-terminus of the Hb receptor (HbR) or the addition of the C-terminal cytoplasmic fragment of the HbR specifically inhibited the fusion with late endosomes, suggesting that signal(s) mediated through the HbR cytoplasmic tail promotes the fusion of early endosomes containing Hb with late endosomes. 相似文献
474.
Teo SK Stirling DI Hoberman AM Christian MS Thomas SD Khetani VD 《Birth defects research. Part B, Developmental and reproductive toxicology》2003,68(2):162-171
BACKGROUND: D ,L ‐threo‐Methylphenidate (D ,L ‐MPH) is marketed currently for attention deficit hyperactivity disorder in children. D ‐threo‐methylphenidate (dexmethylphenidate; D ‐MPH) is a refined formulation of D ,L ‐methylphenidate containing only the active enantiomer and was recently approved in the U.S. for the same condition. D ‐Methylphenidate has been shown to be efficacious in patients at half the dose of D ,L ‐MPH with a potentially improved therapeutic profile. The developmental toxicity of both compounds was determined and compared in rats and rabbits according to current International Conference on Harmonization (ICH) guidelines. METHODS: Groups of pregnant rats were orally dosed twice daily 6 hr apart from Days 7 to 17 of presumed gestation (DG 7–17) for total daily doses of 2, 6 and 20 mg/kg D ‐MPH and 40 mg/kg D ,L ‐MPH. Groups of presumed pregnant rabbits were similarly dosed from DG 6 to 18 for total daily doses of 4, 20 and 100 mg/kg D ‐MPH and 200 mg/kg D ,L ‐MPH. Control groups for both studies were given water vehicle. Comprehensive clinical and developmental measurements were made. Satellite groups of animals were included in the main rat and rabbit studies for toxicokinetic assessment. RESULTS: No drug‐related mortality was seen in the F0 rats and rabbits. The number of rats with repetitive pawing, dilated pupil and aggression was significantly greater for the 40 mg/kg D ,L ‐MPH compared to the 20 mg/kg D ‐MPH dosed rats. Maternal body weight and body weight gain were significantly reduced for both D ‐MPH and D ,L ‐MPH groups compared to control. Maternal reproductive and litter parameters were unaffected by both drugs. No gross external, soft tissue, or skeletal alterations related to both compounds were seen in the fetuses. In rabbits, head‐bobbing and hyperpnea were significantly greater for the 200 mg/kg D ,L ‐MPH compared to 100 mg/kg D ‐MPH. No other maternal or fetal effects related to both compounds were seen. Exposure to D ‐MPH (as assessed by AUC) showed no teratogenic effects at exposures of up to 5.6 and 1.7 times for the rat and rabbit respectively compared to children taking the maximum therapeutic dose of 20 mg/day (10 mg twice a day). No teratogenic effects were seen for D ,L ‐MPH in rat and rabbit at exposures of up to 3.7 to 11.7 times that of the maximum therapeutic pediatric dose of 60 mg/day. CONCLUSIONS: Rats and rabbits dosed with D ,L ‐MPH exhibited significantly greater incidence of maternal clinical observations at twice the dose of D ‐MPH. Both D ‐MPH and D ,L ‐MPH were not teratogenic in rats and rabbits at higher exposure levels compared to humans. © 2003 Wiley‐Liss, Inc. 相似文献
475.
Munson AM Love SL Shu J Palanivel VR Rosenwald AG 《Biochemical and biophysical research communications》2004,315(3):617-623
ATC1/LIC4, previously identified as a suppressor of the Li(+)-sensitive phenotype of calcineurin mutants, was also identified as a suppressor of the hygromycin B-sensitive phenotype of strains lacking the G protein gene, ARL1. Although loss of ARL1 confers several phenotypes, including sensitivity to hygromycin B and Li(+), reduced influx of K(+), and increased secretion of carboxypeptidase Y (CPY), loss of ATC1 was without effect by these and other measures. However, loss of ATC1 in an arl1 background exacerbated ion sensitivities, although not the CPY phenotype. Moreover, overexpression of ATC1 in an arl1 background partially suppressed ion sensitivities, but not the CPY phenotype. Additionally, expression of ENA1, the Na(+)/Li(+) efflux ATPase, and activated calcineurin, but not normal calcineurin, suppressed the Li(+)-sensitive phenotype of the arl1 atc1 double mutant. These results show ARL1 and ATC1 interact to control intracellular ion levels, but ATC1 has little influence on other functions of ARL1. 相似文献
476.
Epidermal growth factor receptor-dependent regulation of integrin-mediated signaling and cell cycle entry in epithelial cells
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Bill HM Knudsen B Moores SL Muthuswamy SK Rao VR Brugge JS Miranti CK 《Molecular and cellular biology》2004,24(19):8586-8599
Integrin-mediated adhesion of epithelial cells to extracellular matrix (ECM) proteins induces prolonged tyrosine phosphorylation and partial activation of epidermal growth factor receptor (EGFR) in an integrin-dependent and EGFR ligand-independent manner. Integrin-mediated activation of EGFR in epithelial cells is required for multiple signal transduction events previously shown to be induced by cell adhesion to matrix proteins, including tyrosine phosphorylation of Shc, Cbl, and phospholipase Cgamma, and activation of the Ras/Erk and phosphatidylinositol 3'-kinase/Akt signaling pathways. In contrast, activation of focal adhesion kinase, Src, and protein kinase C, adhesion to matrix proteins, cell spreading, migration, and actin cytoskeletal rearrangements are induced independently of EGFR kinase activity. The ability of integrins to induce the activation of EGFR and its subsequent regulation of Erk and Akt activation permitted adhesion-dependent induction of cyclin D1 and p21, Rb phosphorylation, and activation of cdk4 in epithelial cells in the absence of exogenous growth factors. Adhesion of epithelial cells to the ECM failed to efficiently induce degradation of p27, to induce cdk2 activity, or to induce Myc and cyclin A synthesis; subsequently, cells did not progress into S phase. Treatment of ECM-adherent cells with EGF, or overexpression of EGFR or Myc, resulted in restoration of late-G(1) cell cycle events and progression into S phase. These results indicate that partial activation of EGFR by integrin receptors plays an important role in mediating events triggered by epithelial cell attachment to ECM; EGFR is necessary for activation of multiple integrin-induced signaling enzymes and sufficient for early events in G(1) cell cycle progression. Furthermore, these findings suggest that EGFR or Myc overexpression may provoke ligand-independent proliferation in matrix-attached cells in vivo and could contribute to carcinoma development. 相似文献
477.
Chhokar VS Sun Y Bhattacharya SK Ahokas RA Myers LK Xing Z Smith RA Gerling IC Weber KT 《American journal of physiology. Heart and circulatory physiology》2004,287(5):H2023-H2026
Congestive heart failure (CHF) is a clinical syndrome with origins rooted in a salt-avid state largely mediated by effector hormones of the circulating renin-angiotensin-aldosterone system. Other participating neurohormones include catecholamines, endothelin-1, and arginine vasopressin. CHF is accompanied by a systemic illness of uncertain causality. Features include the appearance of oxidative/nitrosative stress and a wasting of tissues including bone. Herein we hypothesized that inappropriate (relative to dietary Na+) elevations in plasma aldosterone (Aldo) contribute to an altered redox state, augmented excretion of divalent cations, and in turn, a loss of bone minerals and strength. In uninephrectomized rats that received chronic Aldo and 1% NaCl treatment for 4-6 wk, we monitored plasma alpha1-antiproteinase activity, which is an inverse correlate of oxidative/nitrosative stress; plasma concentrations of ionized Mg2+ and Ca2+; urinary Mg2+ and Ca2+ excretion; and bone mineral composition and strength to flexure stress. Compared with controls, we found reductions in plasma alpha1-antiproteinase activity and ionized Mg2+ and Ca2+ together with persistently elevated urinary Mg2+ and Ca2+ excretion, a progressive loss of bone mineral density and content with reduced Mg2+ and Ca2+ concentrations, and a reduction in cortical bone strength. Thus the hypermagnesuria and hypercalciuria that accompany chronic Aldo-1% NaCl treatment contribute to the systemic appearance of oxidative/nitrosative stress and a wasting of bone minerals and strength. 相似文献
478.
479.
Frueh J Maimari N Lui Y Kis Z Mehta V Pormehr N Grant C Chalkias E Falck-Hansen M Bovens S Pedrigi R Homma T Coppola G Krams R 《FEBS letters》2012,586(15):2164-2170
Atherosclerosis is intimately coupled to blood flow by the presence of predilection sites. The coupling is through mechanotransduction of endothelial cells and approximately 2000 gene are associated with this process. This paper describes a new platform to study and identify new signalling pathways in endothelial cells covering an atherosclerotic plaque. The identified networks are synthesized in primary cells to study their reaction to flow. This synthetic approach might lead to new insights and drug targets. 相似文献
480.