Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which nitric oxide (NO) protects from apoptosis is a matter of debate. We have shown previously that phosphorylation of tyrosine residues participates in the protection from apoptosis in insulin-producing RINm5F cells (Inorg. Chem. Commun. 3 (2000) 32). Since NO has been reported to activate the tyrosine kinase c-Src and this kinase is involved in the activation of protein kinase G (PKG) in some cell systems, we aimed at studying the contribution of c-Src and PKG systems in anti-apoptotic actions of NO in serum-deprived RINm5F cells. Here we report that exposure of serum-deprived cells to 10 microM DETA/NO results in protection from degradation of the anti-apoptotic protein Bcl-2, together with a reduction of cytochrome c release from mitochondria and caspase-3 inhibition. Studies with the inhibitors ODQ and KT-5823 revealed that these actions are dependent on both activation of guanylate cyclase and PKG. DETA/NO was also able to induce autophosphorylation and activation c-Src protein both in vivo and in vitro and active c-Src was able to induce tyrosine phosphorylation of Bcl-2 in vitro. The c-Src kinase inhibitor PP1 abrogated the actions of DETA/NO on cGMP formation, PKG activation, caspase activation, cytochrome c release from mitochondria, and Bcl-2 phosphorylation and degradation in serum-deprived cells. We thus propose that activation of c-Src is an early step in the chain of events that signal cGMP-dependent anti-apoptotic actions of NO in mitocohondria.
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PMID:Evidence for involvement of c-Src in the anti-apoptotic action of nitric oxide in serum-deprived RINm5F cells. 1158 16

Chromosomal translocations involving the platelet-derived growth factor beta receptor (PDGFbetaR) gene have been reported in some patients with chronic myelomonocytic leukemia (CMML). The resultant fusion proteins have constitutive PDGFbetaR tyrosine kinase activity, but the partner genes previously reported (tel, Huntingtin interacting protein 1 [HIP-1], H4/D10S170) have poorly understood roles in the oncogenic activity of the fusion proteins. A novel PDGFbetaR fusion protein has been characterized in a patient with CMML and an acquired t(5;17)(q33;p13). Southern blot analysis on patient leukemia cells demonstrated involvement of the PDGFbetaR gene. Using 5' rapid amplification of complementary DNA ends-polymerase chain reaction (RACE-PCR) on patient RNA, rabaptin-5 was identified as a novel partner fused in-frame to the PDGFbetaR gene. The new fusion protein includes more than 85% of the native Rabaptin-5 fused to the transmembrane and intracellular tyrosine kinase domains of the PDGFbetaR. Transduction with a retroviral vector expressing rabaptin-5/PDGFbetaR transformed the hematopoietic cell line Ba/F3 to growth factor independence and caused a fatal myeloproliferative disease in mice. Rabaptin-5 is a well-studied protein shown to be an essential and rate-limiting component of early endosomal fusion through interaction with the Ras family GTPases Rab5 and Rab4. The fusion protein includes 3 of 4 coiled-coil domains (involved in homodimerization of native rabaptin-5), 2 caspase-3 cleavage sites, and a binding site for the tumor suppressor gene tuberin (tuberous sclerosis complex-2). Early endosomal transport is critical in regulation of various growth factor receptors, through ligand-induced clathrin-mediated endocytosis, and thus this new fusion protein links together 2 important pathways of growth regulation.
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PMID:Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia. 1158 50

RAD51 is one of six mitotic human homologs of the E. coli RecA protein (RAD51-Paralogs) that play a central role in homologous recombination and repair of DNA double-strand breaks (DSBs). Here we demonstrate that RAD51 is important for resistance to cisplatin and mitomycin C in cells expressing the BCR/ABL oncogenic tyrosine kinase. BCR/ABL significantly enhances the expression of RAD51 and several RAD51-Paralogs. RAD51 overexpression is mediated by a STAT5-dependent transcription as well as by inhibition of caspase-3-dependent cleavage. Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance. Induction of the mammalian RecA homologs establishes a unique mechanism for DNA damage resistance in mammalian cells transformed by an oncogenic tyrosine kinase.
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PMID:BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance. 1168 15

The present study examined the effect of ambroxol on free radical production, granule enzyme release, and cell death in silica-activated rat alveolar macrophages. The action of ambroxol was assayed by measuring changes in the activities of protein kinase C (PKC) and tyrosine kinase (PTK) and in the intracellular calcium level. Ambroxol attenuated the production of superoxide, hydrogen peroxide, and nitric oxide and the release of acid phosphatase and lysozyme in macrophages activated by silica. Staurosporine, genistein, EGTA, and trifluoperazine inhibited the silica-induced free radical production and granule enzyme release. Silica induced the increase in PKC and PTK activities and the elevation of intracellular calcium level in macrophages, which was decreased by ambroxol. Silica induced a cell death and increased the caspase-3 activity in macrophages in a concentration-dependent manner. Ambroxol decreased the silica-induced cell viability loss in macrophages. The results show that ambroxol decreases the stimulated responses and cell death in rat alveolar macrophages exposed to silica, which may be accomplished by inhibition of activation processes, protein kinases, and calcium transport. The inhibitory effect of ambroxol on silica-induced cell death appears to provide the protective effect on pulmonary tissues against the toxic action of silica.
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PMID:Depressant effect of ambroxol on stimulated functional responses and cell death in rat alveolar macrophages exposed to silica in vitro. 1180 26

Phospholipase C-gamma1, a tyrosine kinase substrate, hydrolyses phosphatidylinositol 4,5-bisphosphate to produce inositol 1,4,5-trisphosphate and diacylglycerol, which act as second messenger moleculesto mobilize intracellular calcium and activate protein kinase C, respectively. We have investigated the role of phospholipase C-gamma1 in anoikis, or cell death, induced by the loss of extracellular matrix adhesion. Spontaneously immortalized mouse embryonic fibroblasts nullizygous at the Plcg1 locus (Plcg1(-/-)), referred to as Null cells, were derived from targeted gene disruption experiments. Subsequently, phospholipase C-gamma1 was re-expressed in these cells to derive Null+ cells. The Null and Null+ cells were then placed in suspension to induce cell death, which was measured directly as well as by the induction of caspase 3, as an index of programmed cell death or apoptosis. The results demonstrate that insulin-like growth factor can rescue Null+ cells but not Null cells from suspension-induced cell death. This demonstrates that phospholipase C-gamma1 is required for insulin-like growth factor dependent cell survival under these conditions. Lastly, the data demonstrate that insulinlike growth factor stimulated tyrosine phosphorylation of phospholipase C-gamma1 in both adherent and suspension cells.
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PMID:PLC-gamma1 is required for IGF-I protection from cell death induced by loss of extracellular matrix adhesion. 1197 63

BCR/ABL oncogenic tyrosine kinase activates STAT5, which plays an important role in leukemogenesis. The downstream effectors of the BCR/ABL-->STAT5 pathway remain poorly defined. We show here that expression of the antiapoptotic protein A1, a member of the Bcl-2 family, and the serine/threonine kinase pim-1 are enhanced by BCR/ABL. This up-regulation requires activation of STAT5 by the signaling from SH3+SH2 domains of BCR/ABL. Enhanced expression of A1 and pim-1 played a key role in the BCR/ABL-mediated cell protection from apoptosis. In addition, pim-1 promoted proliferation of the BCR/ABL-transformed cells. Both A1 and pim-1 were required to induce interleukin 3-independent cell growth, inhibit activation of caspase 3, and stimulate cell cycle progression. Moreover, simultaneous up-regulation of both A1 and pim-1 was essential for in vitro transformation and in vivo leukemogenesis mediated by BCR/ABL. These data indicate that induction of A1 and pim-1 expression may play a critical role in the BCR/ABL-dependent transformation.
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PMID:Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis. 1203 85

BCR/ABL fusion tyrosine kinase is responsible for the initiation and maintenance of the Philadelphia chromosome (Ph(1))-positive chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemias (ALL). STI571 (Gleevec), a novel anti-leukemia drug targeting BCR/ABL kinase can induce remissions of the Ph(1)-positive leukemias. STI571 was recently combined with the standard cytostatic drugs to achieve better therapeutic results and to overcome emerging drug resistance mechanisms. We decided to search for a more specific partner compound for STI571. Our previous studies showed that a signaling protein phosphatidylinositol-3 kinase (PI-3k) is essential for the growth of CML cells, but not of normal hematopoietic cells (Blood, 86:726,1995). Therefore the anti- Ph(1)-leukemia effect of the combination of BCR/ABL kinase inhibitor STI571 and PI-3k inhibitor wortmannin (WT) or LY294002 (LY) was tested. We showed that STI571+WT exerted a synergistic effect against the Ph(1)-positive cell lines, but did not affect the growth of Ph(1)-negative cell line. Moreover, the combinations of STI571+WT or STI571+LY were effective in the inhibition of clonogenic growth of CML-chronic phase and CML-blast crisis patient cells, while sparing normal bone marrow cells. Single colony RT-PCR assay showed that colonies arising from the mixture of CML cells and normal bone marrow cells after treatment with STI571+WT were selectively depleted of BCR/ABL-positive cells. Biochemical analysis of the CML cells after the treatment revealed that combination of STI571+WT caused a more pronounced activation of caspase-3 and induced massive apoptosis, in comparison to STI571 and WT alone. In conclusion, combination of STI571+WT or STI571+LY may represent a novel approach against the Ph(1)-positive leukemias.
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PMID:Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. 1218 86

Cultured human cytotrophoblasts are more susceptible than syncytiotrophoblasts to hypoxia-induced apoptosis. Caspases are cysteine proteases that cleave cellular components to effect the apoptotic cascade. We hypothesized that cultured cytotrophoblasts exhibit a higher activity of caspases when compared with syncytiotrophoblasts. Using western analysis, we demonstrated that the pro-caspases 3, 6, 8, and 9 are expressed in cytotrophoblasts cultured for 24 h, and also, in trophoblasts cultured 72 h when syncytiotrophoblasts have formed. Importantly, we found significantly higher activity of all four caspases in trophoblasts cultured 24 h compared with cells cultured 72 h. Colchicine and DMSO, which hinder trophoblast differentiation, enhanced the activity of all four caspases in cells cultured 72 h. Conversely, caspase activity was reduced in trophoblasts cultured for 24 h in the presence of epidermal growth factor, which enhances differentiation. This effect was most pronounced on caspase 3 and was attenuated by addition of the tyrosine kinase inhibitor AG1478. We conclude that cytotrophoblasts exhibit a higher activity of caspases 3, 6, 8, and 9 when compared with the more differentiated syncytium. This may account for the higher susceptibility of cytotrophoblasts to hypoxia-induced apoptosis.
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PMID:Trophoblast differentiation modulates the activity of caspases in primary cultures of term human trophoblasts. 1219 77

Interleukin-12 (IL-12) is an immunoregulatory cytokine that plays an essential role in cell-mediated immunity. It is known to induce T cell apoptosis in in vivo systems such as graft-versus-host disease (GVHD) and experimental autoimmune uveitis (EAU). However, the role of IL-12 in T cell apoptosis in the absence of antigenic stimulation has not been clearly defined. This study was conducted to investigate whether IL-12, in the absence of an antigen, is able to induce T cell apoptosis, and also, which signalling pathways utilized by IL-12 are involved in this process. Our data clearly showed that IL-12 in the absence of an antigen induces apoptosis in T cells. Flow cytometry and ELISA showed FasL up-regulation and increased IFN-gamma synthesis in IL-12 treated T cells, while Fas and TNF-R1 showed little change. Semi-quantitative RT-PCR demonstrated that IL-12 was able to up-regulate TNF-alpha and FasL mRNA expression. Furthermore, IL-12 induced apoptosis was associated with caspase-3, caspase-2, caspase-7, DNA fragmentation factor 45 (DFF45) and Fas associated death domain (FADD) whereas TNF receptor associated death domain (TRADD) and receptor interacting protein (RIP) were not. Inhibition of Janus tyrosine kinase (JAK) was able to suppress IL-12 induced T cell apoptosis. Anti-FasL antibody was able to block IL-12 induced T cell apoptosis. In conclusion, our findings suggest that IL-12 is able to induce T cell apoptosis in the absence of an antigen. In addition, the present data suggest that this process is FasL mediated and caspase-3 dependent. Furthermore, JAK was shown to be involved in this process. These results may have significant implications in the understanding of IL-12 mediated T cell apoptosis.
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PMID:IL-12 plays a significant role in the apoptosis of human T cells in the absence of antigenic stimulation. 1224 79

Elevated expression of phospholipase D (PLD) in rat fibroblasts overexpressing a tyrosine kinase leads to cell transformation. However, it has been difficult to get elevated expression of PLD in normal rat fibroblasts. Using transient transfection and an inducible expression system, we were able to get elevated expression of PLD1 and PLD2 in 3Y1 rat fibroblasts. Elevated expression of either PLD1 or PLD2 in 3Y1 cells led to apoptosis in the absence of serum. Elevated PLD expression resulted in reduced cell viability and the cleavage of the caspase 3 substrates poly-ADP-ribose polymerase (PARP) and protein kinase C delta. Elevated PLD expression also stimulated cytochrome c release, indicating that the mitochondrial apoptosis pathway was activated. Thus, while elevated PLD expression can transform cells with elevated tyrosine kinase expression, elevated expression of PLD activity in normal cells renders cells sensitive to apoptotic insult.
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PMID:Elevated phospholipase D activity induces apoptosis in normal rat fibroblasts. 1240 76


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