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151.
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153.
PKN3 is required for malignant prostate cell growth downstream of activated PI 3-kinase 总被引:3,自引:0,他引:3
Leenders F Möpert K Schmiedeknecht A Santel A Czauderna F Aleku M Penschuck S Dames S Sternberger M Röhl T Wellmann A Arnold W Giese K Kaufmann J Klippel A 《The EMBO journal》2004,23(16):3303-3313
Chronic activation of the phosphoinositide 3-kinase (PI3K)/PTEN signal transduction pathway contributes to metastatic cell growth, but up to now effectors mediating this response are poorly defined. By simulating chronic activation of PI3K signaling experimentally, combined with three-dimensional (3D) culture conditions and gene expression profiling, we aimed to identify novel effectors that contribute to malignant cell growth. Using this approach we identified and validated PKN3, a barely characterized protein kinase C-related molecule, as a novel effector mediating malignant cell growth downstream of activated PI3K. PKN3 is required for invasive prostate cell growth as assessed by 3D cell culture assays and in an orthotopic mouse tumor model by inducible expression of short hairpin RNA (shRNA). We demonstrate that PKN3 is regulated by PI3K at both the expression level and the catalytic activity level. Therefore, PKN3 might represent a preferred target for therapeutic intervention in cancers that lack tumor suppressor PTEN function or depend on chronic activation of PI3K. 相似文献
154.
Imre Weisz John Roboz J. George Bekesi 《Bioorganic & medicinal chemistry letters》1995,5(24):2985-2988
L-m-sarcolysin, L-3-[bis(2-chloroethyl) amino]-L-phenylalanine was synthesized by converting 3-nitro-L-tyrosine to L-N-acetyl-3-aminophenyl-alanine Me-ester which was hydroxyethylated and converted into the N-mustard with mesyl chloride and LiCl; the title compound was obtained by hydrolysis of the protecting groups. The tritiated compound was specifically labeled on the benzyl group. 相似文献
155.
Tim Eiseler Christoph Wille Conny Koehler Anett Illing Thomas Seufferlein 《The Journal of biological chemistry》2016,291(1):462-477
Vesicle formation and fission are tightly regulated at the trans-Golgi network (TGN) during constitutive secretion. Two major protein families regulate these processes: members of the adenosyl-ribosylation factor family of small G-proteins (ARFs) and the protein kinase D (PKD) family of serine/threonine kinases. The functional relationship between these two key regulators of protein transport from the TGN so far is elusive. We here demonstrate the assembly of a novel functional protein complex at the TGN and its key members: cytosolic PKD2 binds ARF-like GTPase (ARL1) and shuttles ARL1 to the TGN. ARL1, in turn, localizes Arfaptin2 to the TGN. At the TGN, where PKD2 interacts with active ARF1, PKD2, and ARL1 are required for the assembly of a complex comprising of ARF1 and Arfaptin2 leading to secretion of matrix metalloproteinase-2 and -7. In conclusion, our data indicate that PKD2 is a core factor in the formation of this multiprotein complex at the TGN that controls constitutive secretion of matrix metalloproteinase cargo. 相似文献
156.
The ability of breast cancer tissues from postmenopausal women to form catechol estrogens was examined by using a product isolation assay. Initial assays were carried out in the presence of either: (a) NADPH, the co-factor for monooxygenase mediated catecholestrogen (CE) formation or; (b) light-activated Tween 80 (LAT-80), a putative organic hydroperoxide co-factor for peroxidatic activity. Under monooxygenase conditions, CE formation by homogenates of 10 tumors did not exceed that obtained with heat denatured tissue. In contrast, 17 of 20 tumors incubated with LAT-80 synthesized significant amounts of CE (8.5 +/- 1.17 2-hydroxyestradiol [2-OH-E2] and 12.8 +/- 2.4 nmol/g protein/10 min 4-hydroxyestradiol [4-OH-E2]). Substitution of cumene hydroperoxide, an organic hydroperoxide, for LAT-80 enhanced estrogen 2/4 hydroxylase (E-2/4-H) activity over 200-fold, making it possible to characterize systematically the peroxidatic activity. The properties of peroxidatic E-2/4-H activity were similar to those of soluble peroxidases isolated from brain, including an acidic pH optimum, localization in the soluble fraction, an apparent Km in the range of 80 microM and an apparent Vmax in the range of 4000 nmol/g/protein/10 min for both 2- and 4-OH-E2. Under optimal assay conditions, peroxidatic E-2/4-H activity was identified in 10 of 13 tumors (2480 +/- 580 nmol/g protein/10 min for 2-OH-E2 and 2790 +/- 600 for 4-OH-E2). The level of activity detected suggests a biological relevance for CE formation by breast cancer tissue. 相似文献
157.
Regulation of soybean nitrogen fixation in response to rhizosphere oxygen: I. Role of nodule respiration 总被引:8,自引:4,他引:4
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Nitrogen fixation (acetylene reduction) rates of nodules on intact field-grown soybean (Glycine max) subjected to altered oxygen concentration (0.06-0.4 cubic millimeter per cubic millimeter) returned to initial rates during an 8-hour transitory period. Hydroponically grown soybean plants also displayed a transitory (1-4 hours) response to changes in the rhizosphere oxygen concentration after which the fixation rates returned to those observed under ambient oxygen concentrations. It was hypothesized that soybean nodules contain a regulatory mechanism which maintains a stable oxygen concentration inside nodules at a sufficiently low concentration to allow nitrogenase to function. A possible physiological mechanism which could account for this regulation is adjustment in nodule respiration activity such that nodule oxygen concentration and nitrogen fixation are maintained at stable levels. Experiments designed to characterize the non-steady-state oxygen response and to test for the presence of nodule respiratory control are presented. Non-steady-state acetylene reduction and nodule respiration (oxygen uptake) rates measured after alterations in the external oxygen concentration indicated that the regulatory mechanism required 1 to 4 hours to completely adjust to changes in the external oxygen concentration. Steady-state nodule respiration, however, did not respond to alterations in the rhizosphere oxygen concentration. It was concluded that soybean nodules can adjust to a wide range of rhizosphere oxygen concentrations, but the mechanism which controls nitrogen fixation rates does not involve changes in the nodule respiration rate. 相似文献
158.
J G Liehr D Roy A Ari-Ulubelen Q D Bui J Weisz H W Strobel 《Journal of steroid biochemistry》1990,35(5):555-560
Estrogens have previously been shown to induce DNA damage in Syrian hamster kidney, a target organ of estrogen-induced cancer. The biochemical mechanism of DNA adduction has been postulated to involve free radicals generated by redox cycling of estrogens. As part of an examination of this postulate, we measured the effect of chronic estrogen treatment of hamsters on renal microsomal enzymes mediating catechol estrogen formation and free radical generation by redox cycling of catechol estrogens. In addition, the activities of the same enzymes were assayed in liver in which tumors do not develop under these conditions. At saturating substrate concentration, 2- and 4-hydroxyestradiol were formed in approximately equal amounts (26 and 28 pmol/mg protein/min, respectively), which is 1-2 orders of magnitude higher than reported previously. Estradiol treatment for 2 months decreased 2-hydroxylase activity per mg protein by 75% and 4-hydroxylase activity by 25%. Hepatic 2- and 4-hydroxylase activities were 1256 and 250 pmol/mg protein/min, respectively. Estrogen treatment decreased both activities by 40-60%. Basal peroxidatic activity of cytochrome P-450, the enzyme which oxidizes estrogen hydroquinones to quinones in the redox cycle, was 2.5-fold higher in liver than in kidney and did not change with estrogen treatment. However, when normalized for specific content of cytochrome P-450 the enzyme activity in kidney was 2.5-fold higher than in liver and increased further by 2-3-fold with chronic estrogen treatment. The activity of cytochrome P-450 reductase, which reduces quinones to hydroquinones in the estrogen redox cycle, was 6-fold higher in liver than in kidney of both control and estrogen-treated animals. When normalized for cytochrome P-450, the activity of this enzyme was similar in liver and kidney, but over 4-fold higher in kidney than liver after estrogen treatment. Basal concentrations of superoxide, a product of redox cycling, were 2-fold higher in liver than in kidney. Estrogen treatment did not affect this parameter in liver, but increased it in kidney by 40%. These data provide evidence for a preferential preservation of enzymes involved in estrogen activation. 相似文献
159.
160.
A Weisz G A Puca M T Masucci C Masi R Pagnotta A Petrillo V Sica 《Biochemistry》1984,23(23):5393-5397
When rat liver cytosol containing [3H]dexamethasone-glucocorticoid receptor complex is exposed to immobilized heparin (Sepharose-heparin; Seph-hep) the steroid receptor complex binds to the substituted Sepharose avidly [Kd = 3.5 (+/- 1.7) X 10(-10) M], and 80-90% of the receptor present is adsorbed to the solid phase after 40 min at 0 degree C. The binding is enhanced by Mn2+ (10 mM) and Mg2+, whereas Ca2+ and Sr2+ are ineffective. Sodium molybdate (10 mM) does not influence the reaction but enhances receptor stability. Moreover, binding of the receptor to Seph-hep is dependent on the ionic strength of the medium, because binding is totally reversed by 300 mM KCl. The bound [3H]dexamethasone-receptor complex can be recovered from Seph-hep with solutions (4 mg/mL) of heparin (95% release), dextran sulfate (88%), and chondroitin sulfate (63%); total calf liver RNA is less effective (9%), whereas dextran, D-glucosamine, N-acetyl-D-glucosamine, D-glucuronic acid, and sheared calf thymus DNA are totally ineffective (less than 3%). Both "native" and temperature "transformed" forms of the glucocorticoid receptor interact with immobilized heparin. These results strongly suggest that the receptor site that binds heparin is distinct from that binding DNA. An immediate application of this newly found ability of the glucocorticoid receptor to interact with heparin is the use of Seph-hep for affinity chromatography purification of the glucocorticoid receptor. A purification of 10-fold, with a recovery of 55-65%, can be achieved by using either 4 mg/mL heparin or 300 mM KCl to elute [3H]dexamethasone-receptor bound to the resin. 相似文献