1,721,019 research outputs found
A different involvement of polyamines in the induction of tyrosine aminotransferase by glucagon, isoproterenol or serum in cultured heart cells
No full textCrosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer
Full text linkAbstract
The introduction of therapeutics targeting specific tumor-promoting oncogenic or non-oncogenic signaling pathways has revolutionized cancer treatment. Mechanistic (previously mammalian) target of rapamycin (mTOR), a highly conserved Ser/Thr kinase, is a central hub of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR network, one of the most frequently deregulated signaling pathways in cancer, that makes it an attractive target for therapy. Numerous mTOR inhibitors have progressed to clinical trials and two of them have been officially approved as anticancer therapeutics. However, mTOR-targeting drugs have met with a very limited success in cancer patients. Frequently, the primary impediment to a successful targeted therapy in cancer is drug-resistance, either from the very beginning of the therapy (innate resistance) or after an initial response and upon repeated drug treatment (evasive or acquired resistance). Drug-resistance leads to treatment failure and relapse/progression of the disease. Resistance to mTOR inhibitors depends, among other reasons, on activation/deactivation of several signaling pathways, included those regulated by glycogen synthase kinase-3 (GSK3), a protein that targets a vast number of substrates in its repertoire, thereby orchestrating many processes that include cell proliferation and survival, metabolism, differentiation, and stemness. A detailed knowledge of the rewiring of signaling pathways triggered by exposure to mTOR inhibitors is critical to our understanding of the consequences such perturbations cause in tumors, including the emergence of drug-resistant cells. Here, we provide the reader with an updated overview of intricate circuitries that connect mTOR and GSK3 and we relate them to the efficacy (or lack of efficacy) of mTOR inhibitors in cancer cells
Effect of sodium arsentie on the induction and turnover of ornithine decarboxylase activity in erythroleukemia cells
No full textSodium arsenite proved effective in preventing the induction of ornithine decarboxylase (ODC) activity elicited by dilution of Friend erythroleukemia cells in fresh medium. A 50 per cent inhibition was produced at approximately 1 μM arsenite and complete inhibition was obtained at concentrations above 10 μM. However, addition of arsenite 5 h after cell dilution, i.e. when ODC was already induced, appeared to stabilize the enzyme. The half‐life of ODC activity, measured after cycloheximide treatment, increased almost six‐fold after addition of sodium arsenite. Agents known to provoke oxidative alteration of the thiol‐redox status in cells, also caused a similar effect on the induction and stability of ODC. Copyright © 1989 John Wiley & Sons Ltd
Inositol lipid phosphorylation and breakdown in rat liver nuclei is affected by hydrocortisone blood levels
No full textThe possibility that inositol lipid metabolism is related to nuclear events accompanying steroid hormone action has been investigated by comparing lipid phosphorylation and breakdown in normal rat liver nuclei and in hypo‐ and hypercortisolemic conditions. Lipid phosphorylation in vitro showed the presence of diacylglycerol (DAG)‐, phosphatidylinositol (PI)‐ and phosphatidylinositol‐4‐phosphate (PIP)‐kinase activity, with differences between total tissue homogenates and isolated nuclei, relevant to the treatment in vivo. Administration of hydrocortisone (HC) produced a marked decrease in the phosphorylated nuclear products without influencing the homogenate kinase activity. Under conditions which were optimal for the kinase activities, nuclear PIP‐kinase was strongly increased in presence of a high blood level of HC whereas PI‐kinase activity was reduced. From these observations it appears that the observed differences were due to specific modulation of kinase activities rather than to changes in the availability of substrates. The phosphoinositide‐specific phospholipase C (PLC) activity was also investigated. In the presence of a high HC blood level, the phosphodiesteratic cleavage of PIP strongly increased, while that of phosphatidylinositol bisphosphate (PIP2) was similar in normal and hypercortisolemic conditions. Nuclear phosphoinositide hydrolysis was affected by PLC, β and γ isoforms, which were equally represented in all the conditions investigated, indicating that the observed changes of activity were due to a modulation rather than to a change in the amount of enzyme. These results suggest that inositol lipid metabolism plays a role in the nuclear modifications accompanying steroid hormone induction of transcriptional activity. Copyright © 1994 John Wiley & Sons Ltd
Stabilization of ornithine decarboxylase in erythroleukemia cells depleted of ATP
No full textOrnithine decarboxylase activity in Friend erythroleukemia cells decayed with a half-life of 50 minutes after addition of cycloheximide and at a faster rate after addition of spermidine. Incubation with a medium containing dinitrophenol and 2-deoxyglucose in place of glucose caused ATP depletion and blocked the turnover of ornithine decarboxylase, even after addition of spermidine. Dinitrophenol in the presence of glucose was able to provoke only a slight increase of the half-life of the enzyme. These results suggest that degradation of ornithine decarboxylase in erythroleukemia cells is ATP-dependent. © 1989
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Involvement of thiol transferase- and thioredoxin-dependent systems in the protection of 'essential' thiol groups of ornithine decarboxylase
No full textOrnithine decarboxylase (ODC), an enzyme with 'essential' thiol group(s), may be inactivated in vitro by removal of thiol reducing agents and re-activated by soluble factors from rat liver in the presence of NADPH or GSH. The NADPH- and GSH-dependent reducing systems were sepated and resolved into three components, called factors A, B1 and B2, by chromatographic techniques. Factor B1 (M(r) 12000) could reactivate ODC in the presence of GSH of co-purified with thiol transferase activity. Factor B2 (M(r) 12000) and factor A (M(r) approx. 110000) were both needed to re-activate ODC in the presence of NADPH, and co-purified with thioredoxin and thioredoxin reductase activity respectively. In an attempt to investigate the physiological role of the 'essential' thiol group(s) of ODC, erythroleukemia cells were incubated with NN-bis-(2-chloroethyl)-N'-nitrosourea, t-butyl hydroperoxide and vinblastine, which are known to increase the cellular GSSG/GSH ratio, azelaic acid, an inhibitor of thioredoxin reductase, and sodium arsenite, a strong inhibitor of the ODC-re-activating factors. All these compounds were able to decrease significantly the ODC activity induced in these cells. These results suggest that the thiol transferase- and thioredoxin-dependent systems may be physiologically relevant in maintaining ODC in the active, reduced, state
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