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Of a number of factors involved in apoptosis, protease activity may play a crucial role. We show that N-benzyloxycarbonyl-Ile-Glu(O-t-butyl)-Ala-leucinal (PSI), a selective inhibitor of the chymotrypsin-like activity of the proteasome, induces massive apoptosis in murine leukaemia L1210 cells. At 50 nM concentration, PSI induces a block of cytokinesis, while higher concentrations (500 nM) cause S...
Multicellular organisms have evolved elaborate signal transduction pathways for maintaining homeostasis through the control of cell proliferation and death. The recent surge of interest in the regulation of programmed cell death has led to the rapid identification of many proteins involved in controlling and executing apoptosis. The inhibitors of apoptosis proteins (IAPs) constitute a family of highly...
The TNF ligand family member termed TRAIL has been shown to induce apoptosis in a wide variety of transformed cell lines. The normal functions of this cytokine in vivo remain, however, relatively unknown. The complexity of this biological system has now increased unexpectedly with the identification of four distinct receptors for TRAIL, two of which have cytoplasmic death domains. This review will...
Transgenic mice have proved to be a valuable tool in various aspects of apoptosis research. They are particularly useful for studying apoptosis-related gene products in primary cells which may lead to different effects from similar experiments using immortalized cell lines. They allow the impact of these gene products on multi-faceted physiological processes to be identified. Transgenic mice have...
Tumor necrosis factor (TNF) is a pleiotropic cytokine that potentiates the cytotoxic effects of chemotherapeutic drugs. Although emergence of resistance to chemotherapeutic drugs is a major problem in cancer therapy, its mechanism is incompletely understood. Recently, activation of a nuclear transcription factor NF-κB has been reported to be a signal for anti-apoptosis. In this report, we investigated the effect of TNF on activation of NF-κB, c-Jun N-terminal kinase (JNK), and apoptosis in vincristine-resistant human histiocytic lymphoma U937-VR cells. Unlike the parent clone (U937-VS), no activation of caspase-3, known to be required for apoptosis, was found in vincristine-resistant cells on exposure to vincristine. These cells were also more resistant than U-937-VS cells to doxorubicin, daunomycin, and taxol. TNF-induced NF-κB activation, IκB α degradation, and nuclear translocation of p65 were all found to be highly suppressed in the U-937-VR cells. NF-κB activation by LPS, H...
The cytokine tumor necrosis factor (TNF)α induces caspase-dependent cell death in a subset of tumor cells. In this report, we show a novel suppressive effect of calpeptin, a calpain inhibitor, on TNFα-induced cell death and accumulation of p53 in L929 mouse fibrosarcoma. Exposure to 10 ng/ml TNFα induced cell death in >50% of L929 cells within 12 h and stimulated accumulation of p53 (8-fold). Preincubation...
LUCA-15/RBM5 is a putative tumour suppressor. The gene encodes a number of alternative RNA splice variants with differing abilities to either enhance or suppress apoptosis, and it is likely that this ability to modulate apoptosis is central to the putative tumour suppressor activity of LUCA-15. This report demonstrates for the first time that expression from the LUCA-15 locus modulates apoptosis triggered...
Rat hepatoma HTC cells are intrinsically resistant to various apoptosis-inducing agents. Strategies to induce death in hepatoma cells are needed and the present experimental study was aimed to investigate the sensitivity of HTC cells to TNF and to clarify the mechanisms of action of this cytokine. Cells were treated with TNF and death mechanisms characterized employing an integration of morphological...
Purpose: One of the most relevant aspects in cell death regulation is the signalling of apoptosis by the serine/threonine kinases MAPKs. The aim of this study was to investigate the effects of TNF-α stimulation on MAPK activation, and the pro- or anti-apoptotic role of these kinases in LNCaP and PC3 cells. Material and methods: Treatments were carried out using several TNF-α concentrations, as well...
We have previously shown that protein kinase Cε (PKCε) acts as an antiapoptotic protein and protects breast cancer MCF-7 cells from tumor necrosis factor-α (TNF)-mediated apoptosis. In the present study, we have investigated the mechanism by which PKCε inhibits TNF-induced cell death. Overexpression of wild-type PKCε (WT-PKCε) in MCF-7 cells decreased TNF-induced mitochondrial depolarization. Depletion...
Vascular endothelial growth inhibitor (VEGI) is an endogenous inhibitor of endothelial cell growth and a promising candidate for cancer therapy. VEGI is able to inhibit tumor growth by specifically targeting the tumor neovasculature. Increasing the anti-angiogenic potential of this cytokine is of great interest for its therapeutic potential. NF-κB is known to have an integral role in TNF superfamily...
Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in immune modulation, inflammatory reactions, and target cell death in many pathologic conditions. The cell death pathways triggered by TNF include the caspase-8/Bid-dependent apoptotic pathway and the caspase-independent necrosis pathway (necroptosis). While the signaling pathways activated after binding of TNF to the TNF receptor (TNFR)...
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