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41.
Background
Wnt signaling is important in development and can also contribute to the initiation and progression of cancer. The Secreted Frizzled Related Proteins (SFRPs) constitute a family of Wnt modulators, crucial for controlling Wnt signaling. Here we investigate the expression and role of SFRP3 in melanoma.Methodology/Principal Findings
We show that SFRP3 mRNA is down-regulated in malignant melanoma tumors as compared to normal/benign tissue. Furthermore, we found that SFRP3 expression was lost in the malignant melanoma cell lines, A2058, HTB63 and A375, but not in the non-transformed melanocyte cell line, Hermes 3A. Methylated CpG rich areas were detected in the SFRP3 gene in melanoma cell lines and their SFRP3 expression could be restored using the demethylating agent, 5′aza-deoxycytidine. Addition of recombinant SFRP3 to melanoma cells had no effect on viable cell numbers, but decreased cell migration and invasion. Wnt5a signaling has been shown to increase the migration and invasion of malignant melanoma cells, and high expression of Wnt5a in melanoma tumors has been connected to a poor prognosis. We found that recombinant SFRP3 could inhibit Wnt5a signaling, and that it inhibited melanoma cell migration and invasion in a Wnt5a-dependent manner.Conclusion/Significance
We conclude that SFRP3 functions as a melanoma migration and invasion suppressor by interfering with Wnt5a signaling. 相似文献42.
Neurodegenration is a pathological hallmark of Alzheimer's disease (AD), but the underlying molecular mechanism remains elusive. Here, we present evidence that reveals a crucial role of Wnt5a signaling in this process. We showed that Wnt5a and its receptor Frizzled-5 (Fz5) were up-regulated in the AD mouse brain, and that beta-amyloid peptide (Aβ), a major constituent of amyloid plaques, stimulated Wnt5a and Fz5 expression in primary cortical cultures; these observations indicate that Wnt5a signaling could be aberrantly activated during AD pathogenesis. In support of such a possibility, we observed that inhibition of Wnt5a signaling attenuated while activation of Wnt5a signaling enhanced Aβ-evoked neurotoxicity, suggesting a role of Wnt5a signaling in AD-related neurodegeneration. Furthermore, we also demonstrated that Aβ-induced neurotoxicity depends on inflammatory processes, and that activation of Wnt5a signaling elicited the expression of proinflammatory cytokines IL-1β and TNF-α whereas inhibition of Wnt5a signaling attenuated the Aβ-induced expression of the cytokines in cortical cultures. Our findings collectively suggest that aberrantly up-regulated Wnt5a signaling is a crucial pathological step that contributes to AD-related neurodegeneration by regulating neuroinflammation. 相似文献
43.
44.
Lundström P Teilum K Carstensen T Bezsonova I Wiesner S Hansen DF Religa TL Akke M Kay LE 《Journal of biomolecular NMR》2007,38(3):199-212
A simple labeling approach is presented based on protein expression in [1-13C]- or [2-13C]-glucose containing media that produces molecules enriched at methyl carbon positions or backbone Cα sites, respectively. All of the methyl groups, with the exception of Thr and Ile(δ1) are produced with isolated 13C spins (i.e., no 13C–13C one bond couplings), facilitating studies of dynamics through the use of spin-spin relaxation experiments without artifacts
introduced by evolution due to large homonuclear scalar couplings. Carbon-α sites are labeled without concomitant labeling
at Cβ positions for 17 of the common 20 amino acids and there are no cases for which 13Cα−13CO spin pairs are observed. A large number of probes are thus available for the study of protein dynamics with the results
obtained complimenting those from more traditional backbone 15N studies. The utility of the labeling is established by recording 13C R
1ρ and CPMG-based experiments on a number of different protein systems. 相似文献
45.
Reingold JS McGavock JM Kaka S Tillery T Victor RG Szczepaniak LS 《American journal of physiology. Endocrinology and metabolism》2005,289(5):E935-E939
The primary aim of this investigation was to determine the reliability and sensitivity of 1H magnetic resonance spectroscopy (1H-MRS) as a method for quantifying myocardial triglyceride (TG) content in humans over time and in response to metabolic perturbations. Three separate experiments were designed to quantify myocardial TG content 1) over a 90-day period, 2) after a high-fat meal, and 3) after a 48-h fast. Proton spectra were collected from a 10 x 20 x 30-mm3 voxel placed within the intraventricular septum, with measurements acquired at end-systole and end-expiration, using cardiac triggering and respiratory gating. Minimal variation was observed between myocardial TG content determined 90 days apart (r = 0.98, CV = 5%), whereas TG values were unaffected by a high-fat meal despite a significant twofold increase (P < 0.05) in serum TG. In contrast, myocardial TG content increased threefold (P < 0.05) after a 48-h fast despite a 25% reduction in serum TG. Body mass index was significantly related to myocardial TG (r = 0.58, P < 0.05) and the change in myocardial TG after a 48-h fast (r2 = 0.60). 1H-MRS is a reliable method for the determination of myocardial TG in humans and is relatively unaffected by the consumption of one high-fat meal but sensitive to changes following a prolonged fast. 相似文献
46.
Regulation of microtubule-dependent recycling at the trans-Golgi network by Rab6A and Rab6A'
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Young J Stauber T del Nery E Vernos I Pepperkok R Nilsson T 《Molecular biology of the cell》2005,16(1):162-177
The small GTPase rab6A but not the isoform rab6A' has previously been identified as a regulator of the COPI-independent recycling route that carries Golgi-resident proteins and certain toxins from the Golgi to the endoplasmic reticulum (ER). The isoform rab6A' has been implicated in Golgi-to-endosomal recycling. Because rab6A but not A', binds rabkinesin6, this motor protein is proposed to mediate COPI-independent recycling. We show here that both rab6A and rab6A' GTP-restricted mutants promote, with similar efficiency, a microtubule-dependent recycling of Golgi resident glycosylation enzymes upon overexpression. Moreover, we used small interfering RNA mediated down-regulation of rab6A and A' expression and found that reduced levels of rab6 perturbs organization of the Golgi apparatus and delays Golgi-to-ER recycling. Rab6-directed Golgi-to-ER recycling seems to require functional dynactin, as overexpression of p50/dynamitin, or a C-terminal fragment of Bicaudal-D, both known to interact with dynactin inhibit recycling. We further present evidence that rab6-mediated recycling seems to be initiated from the trans-Golgi network. Together, this suggests that a recycling pathway operates at the level of the trans-Golgi linking directly to the ER. This pathway would be the preferred route for both toxins and resident Golgi proteins. 相似文献
47.
Ascorbic acid (vitamin C) induced hydrogen peroxide (H2O2) formation was measured in household drinking water and metal supplemented Milli-Q water by using the FOX assay. Here we show that ascorbic acid readily induces H2O2 formation in Cu(II) supplemented Milli-Q water and poorly buffered household drinking water. In contrast to Cu(II), iron was not capable to support ascorbic acid induced H2O2 formation during acidic conditions (pH: 3.5-5). In 12 out of the 48 drinking water samples incubated with 2 mM ascorbic acid, the H2O2 concentration exceeded 400 μM. However, when trace amounts of Fe(III) (0.2 mg/l) was present during incubation, the ascorbic acid/Cu(II)-induced H2O2 accumulation was totally blocked. Of the other common divalent or trivalent metal ions tested, that are normally present in drinking water (calcium, magnesium, zinc, cobalt, manganese or aluminum), only calcium and magnesium displayed a modest inhibitory activity on the ascorbic acid/Cu(II)-induced H2O2 formation. Oxalic acid, one of the degradation products from ascorbic acid, was confirmed to actively participate in the iron induced degradation of H2O2. Ascorbic acid/Cu(II)-induced H2O2 formation during acidic conditions, as demonstrated here in poorly buffered drinking water, could be of importance in host defense against bacterial infections. In addition, our findings might explain the mechanism for the protective effect of iron against vitamin C induced cell toxicity. 相似文献
48.
Franciskovich JB Masters JJ Tinsley JM Craft TJ Froelich LL Gifford-Moore DS Klimkowski VJ Smallwood JK Smith GF Smith T Towner RR Weir LC Wiley MR 《Bioorganic & medicinal chemistry letters》2005,15(21):4838-4841
Several non-amidino S1 derivatives of the 1,2-diaminobenzene-based scaffold (4) were synthesized and evaluated for their ability to bind to the active site and inhibit the human protease factor Xa. A subset of these compounds were also evaluated for their anticoagulant effects in human plasma as measured by prothrombin time (PT). 相似文献
49.
The interaction of DNA with amino-functionalized polystyrene particles has been studied by using a dynamic light scattering (DLS) technique. In 10 mM NaBr solution the particles have a hydrodynamic radius of 76 nm and the DNA macromolecule investigated (double stranded) has a hydrodynamic radius of 107 nm. At very low DNA concentrations, DNA adopts a flat conformation on the particle surface. If the DNA concentration is increased above 0.1 microg/mL, the thickness of the DNA layer increases, suggesting the presence of large loops and tails. Although the particles contain primary amino groups, they have a negative net charge under the conditions used in this work. Thus, the driving force for DNA adsorption is not of electrostatic origin but rather due to a hydrophobic effect. Addition of cationic surfactant to the DNA-precoated amino-functionalized particles induces changes in the adsorbed layer conformation, in agreement with the coadsorption of cationic surfactant. 相似文献
50.