1,721,079 research outputs found
INCREASED EXPRESSION OF THE RAS SUPPRESSOR, RSU-1, INCREASES ERK-2 ACTIVATION AND INHIBITS JUN KINASE ACTIVATION
No full textStudies were undertaken to determine the effect of the Ras suppressor Rsu-1 on Ras signal transduction pathways in two different cell backgrounds. An expression vector containing the mouse rsu-I cDNA under the control of a mouse mammary tumor virus promoter was introduced into NIH 3T3 cells and the pheochromocytoma cell line PC12. Cell lines developed in the NIH 3T3 background expressed p33(rsu-1) at approximately twice the normal endogenous level. However, PC12 cell clones which expressed p33(rsu-1) at an increased level in a regulatable fashion in response to dexamethasone were isolated. Analysis of proteins involved in regulation of Ras and responsive to Ras signal transduction revealed similar changes in the two cell backgrounds in the presence of elevated p33(rsu-1). There was an increase in the level of SOS, the guanine nucleotide exchange factor, and an increase in the percentage of GTP-bound Ras. In addition, there was an increase in the amount of p120 Ras-specific GTPase-activating protein (GAP) and GAP-associated p190. However, a decrease in Ras GTPase-activating activity was detected in lysates of the Rsu-1 transfectants, and immunoprecipitated p120 GAP from the Rsu-1 transfectants showed less Ras GTPase-activating activity than GAP from control cells. Activation of Erk-2 kinase by growth factor and tetradecanyol phorbol acetate was greater in the Rsu-1 transfectants than in control cells. However, c-Jun amino-terminal kinase activity (Jun kinase) was not activatable by epidermal growth factor in Rsu-1 PC12 cell transfectants, in contrast to the PC12 vector control cell line. Transient expression of p33(rsu-1) in Cos1 cells following cotransfection with either hemagglutinin- tagged Jun kinase or hemagglutinin-tagged Erk-2 revealed that Rsu-1 expression inhibited constitutive Jun kinase activity while enhancing Erk-2 activity. Detection of in vitro binding of Rsu-1 to Raf-1 suggested that in Rsu-1 transfectants, increased activation of the Raf-1 pathway occurred at the expense of activation of signal transduction leading to Jun kinase. These results indicate that inhibition of Jun kinase activation was sufficient to inhibit Ras transformation even in the presence of activated Erk-2
New Insights into the Potential Role of Chimeric Activating Receptors-Engineered Natural Killer Cells to Fight Cancer
No full textTopical treatment of chronic venous ulcers with sucralfate: A placebo controlled randomized study
No full textVenous leg ulcers are an important medical issue due to their high incidence in the elderly and the lack of a standard curative approach. Apart from surgical therapy, different medical treatments to effect ulcer wound repair and regeneration are currently being investigated. Sucralfate is a cytoprotective agent employed to prevent or treat several gastrointestinal diseases such as gastroesophageal reflux, gastritis, peptic ulcer, stress ulcer and dyspepsia. In this study we evaluated the efficacy, safety and tolerability of topical sucralfate (SUC-LIS 95) on the healing of chronic venous leg ulcers in 50 patients by a double-blind, placebo-controlled, randomized study. Our results indicated that the daily application of SUC-LIS 95 to non-infected post-phlebitis/vascular ulcers, for a median period of 42.0 days, led to complete healing in 95.6% of patients, against only 10.9% of cases with a matched placebo. A significant improvement was obtained in the SUC-LIS 95-treated patient group with regard to local tissue inflammation as well as pain and burning, and consequently, in ulcer size and the evolution of granulation tissue. Our findings were corroborated for selected patients by the morphological analysis of biopsies obtained before and after treatment. Using ultrastructural analysis we demonstrated that the topical use of SUC-LIS 95 was able to affect neoangiogenesis, increase wound contraction, promote re-epithelialization of the wound area and diminish the inflammatory reaction. Overall, our results indicated that patients with chronic venous ulcers show improvement after the use of topical sucralfate
Novel Therapeutic Targets for Tumor Microenvironment in Cancer
Full text linkThe various immune effector cells that infiltrate the tumor microenvironment (TME) play a key role in directing the outcome of tumor growth [...
Autoantibodies to extracellular matrix components as outcome of tissue chronic inflammation.
No full textSUPPRESSION OF SRC-INDUCED TRANSFORMED PHENOTYPE BY EXPRESSION OF TROPOMYOSIN-1
No full textSuppression of high M(r) tropomyosins (TMs) is a common feature of transformed cells. Previous work from this laboratory has demonstrated that the isoform 1 of TM, TM1, acts as an anti-oncogene in ras-transformed murine fibroblasts. In this study, we have investigated whether TM1 is a ras-specific suppressor, or a general suppressor protein of the cellular transformation. V-src transformed fibroblasts, which express decreased TM1, were transduced with a full-length cDNA to overexpress TM1. Both the control and the transduced cells expressed v-src kinase at comparable levels. TM1 expressing (src-T1) cells grew at a lower rate in monolayer, exhibited well spread, flat morphology than the control cells. Enhanced expression of TM1 resulted in improved microfilamental architecture. More significantly, src-T1 cells completely failed to grow under anchorage independent conditions. These data demonstrate that TM1 is as an anti-oncogene of functionally diverse oncogenes, and it is a class II tumor suppressor protein
The Ras suppressor RSU-1 localizes to 10p13 and its expression in the U251 glioblastoma cell line correlates with a decrease in growth rate and tumorigenic potential.
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Inhibition of nuclear accumulation of phosphorylated ERK by tropomyosin-1-mediated cytoskeletal reorganization
No full textAIM: Most neoplastic cells express diminished levels of tropomyosin (TM) family of actin-binding proteins, which leads to the formation of poorly organized cytoskeleton. The aberrant cytoskeleton is hypothesized to contribute to the neoplastic phenotype through deregulation of intracellular signaling. The aim of the study is to evaluate whether reorganization of cytoskeleton modulates signaling pathways. Methods: We have utilized ras-transformed NIH3T3 (DT) cells and those transduced with TM1 (DT/TM1) as a model system. DT cells are highly malignant whereas the DT/TM1 cells contain reorganized cytoskeleton and exhibit revertant phenotype. Activation status of ras oncogene in DT and DT/TM1 cells was measured by GTP loading. Activation status and subcellular localization of extracellular signal regulated kinase (ERK) was measured in total, cytoplasmic and nuclear compartments by immunoblotting and confocal microscopy. Results: Transduction of TM1 does not alter the activation status of oncogenic ras. Both parental DT and DT/TM1 cells exhibit similar levels of activated ERK in total cellular lysates, whereas DT/TM1 cells contain significantly less phosphorylated ERK pERK) in the nuclear fraction. Disruption of cytosekeletal integrity results in increased nuclear content of pERK, suggesting that tropomyosin-1-induced microfilaments are critical for curtailing the nuclear accumulation of activated ERK, and may contribute to the anti-oncogenic effects of TM1. Conclusion: Our data suggest that spatiotemporal regulation of ERK by cytoskeleton is an important mechanism. Furthermore, aberrant microfilaments, present in neoplastic cells, fail to restrict nuclear localization of ERK, and hence contribute to deregulated ERK signaling. © 2008 MedUnion Press
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