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)

Synucleins are a family of highly conserved small proteins predominantly expressed in neurons. Recently we and others have found that gamma-synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and that gamma-synuclein over-expression can enhance tumorigenicity. In the current study, we have found that gamma-synuclein is associated with two major mitogen-activated kinases (MAPKs), i.e. extracellular signal-regulated protein kinases (ERK1/2) and c-Jun N-terminal kinase 1 (JNK1), and have shown that over-expression of gamma-synuclein leads to constitutive activation of ERK1/2 and down-regulation of JNK1 in response to a host of environmental stress signals, including UV, arsenate, and heat shock. We also tested the effects of gamma-synuclein on apoptosis and activation of JNK and ERK in response to several chemotherapy drugs. We have found that gamma-synuclein-expressing cells are significantly more resistant to the chemotherapeutic drugs paclitaxel and vinblastine as compared with the parental cells. The resistance to paclitaxel can be partially obliterated when ERK activity is inhibited using a MEK1/2 inhibitor. Activation of JNK and its downstream caspase-3 by paclitaxel or vinblastine is significantly down-regulated in gamma-synuclein-expressing cells, indicating that the paclitaxel- or vinblastine-activated apoptosis pathway is blocked by gamma-synuclein. In contrast to paclitaxel and vinblastine, etoposide does not activate JNK, and gamma-synuclein over-expression has no apparent effect on this drug-induced apoptosis. Taken together, our data indicate that oncogenic activation of gamma-synuclein contributes to the development of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain chemotherapeutic drugs.
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PMID:Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways. 1212 74

Hepatic myofibroblasts (hMFs) are central in the development of liver fibrosis during chronic liver diseases, and their removal by apoptosis contributes to the resolution of liver fibrosis. We previously identified Edg receptors for sphingosine 1-phosphate (S1P) in human hMFs. Here, we investigated the effects of S1P on hMF apoptosis. S1P reduced viability of serum-deprived hMFs by an apoptotic process that was unrelated to the conversion of S1P into sphingosine and ceramide. The apoptotic effects of S1P were receptor-independent because dihydro-S1P, an Edg agonist, had no effect. S1P also stimulated a receptor-dependent survival pathway, revealed by enhanced activation of caspase-3 by S1P in the presence of pertussis toxin. Cell survival relied on two pertussis toxin-sensitive events, activation of ERK and activation of phosphatidylinositol 3-kinase (PI3K)/Akt by S1P. Both pathways were also activated by dihydro-S1P. Blunting either ERK or PI3K enhanced caspase-3 stimulation by S1P, and simultaneous inhibition of both pathways resulted in additive effects on caspase-3 activation. In conclusion, S1P induces apoptosis of human hMFs via a receptor-independent mechanism and stimulates a survival pathway following activation of Edg receptors. The survival pathway arises from the sequential activation of G(i)/G(o) proteins and independent stimulations of ERK and PI3K/Akt. Therefore, blocking Edg receptors may sensitize hepatic myofibroblasts to apoptosis by S1P.
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PMID:Sphingosine 1-phosphate triggers both apoptotic and survival signals for human hepatic myofibroblasts. 1213 95

Oxidative stress in the human brain has been strongly implicated as the cause of neuronal cell losses in Alzheimer's disease patients, but the exact mechanism still remains unknown. In this report several oxidative stress parameters and an associated signalling transduction cascade predating neuronal cell death in cultures treated with the oxidative stressors Fe(2+) (5 microm) and the amyloid beta (A beta(1-40)) peptide (5 microm) were studied. Production of reactive oxygen species as detected by dichlorofluorescein staining was apparent within 5 min in the presence of both agents. Lipid peroxide content increased by approximately 10-fold after 2 h, while mitochondrial activity was impaired by 40% after 6 h. Caspase-3 activity was elevated 5-6 fold, all indicative of oxidative cell stress. The combined presence of A beta(1-40) and Fe(2+) resulted in a rapid (5 min) ERK activation followed by a decline by 30 min and a second activation that continued up to 24 h when nuclear translocation was noticed. Neither treatment with Fe(2+) nor that with A beta(1-40) alone caused similar changes. Addition of either deferroxamine (DFe, 25 microm), catalase (0.4 mg/mL) or N-acetyl cysteine (0.5 mm) - the last two known as suppressants of oxidative stress - attenuated ERK activation and nuclear translocation. The mitogen-activated protein/ERK kinase (MEK) inhibitor U0126 blocked ERK and caspase 3 activation, suppressed ERK translocation and reduced the number of apoptotic cells, suggesting a central role for the ERK signalling cascade in A beta(1-40) plus Fe(2+) (A beta(1-40)/Fe(2+)) -induced apoptotic death. The full peptide A beta(1-42) was very effective at 0.5 microm while the inverse peptide A beta(40-1) at 5 microm was ineffective. The acetyl-amyloid-beta protein amide fragment 15-20 (V-pep) known to be an A beta aggregation inhibitor, prevented A beta(1-40)/Fe(2+)-induced toxicity. These findings indicate that metal ions chelators and antioxidants suppress the A beta(1-40)/Fe(2+)-induced oxidative stress cascade and may be beneficial in reducing the severity of Alzheimer's disease.
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PMID:ERK activation and nuclear translocation in amyloid-beta peptide- and iron-stressed neuronal cell cultures. 1215 30

Vascular endothelial growth factor (VEGF) is an angiogenic protein with neurotrophic and neuroprotective effects. Because VEGF promotes the proliferation of vascular endothelial cells, we examined the possibility that it also stimulates the proliferation of neuronal precursors in murine cerebral cortical cultures and in adult rat brain in vivo. VEGF (>10 ng/ml) stimulated 5-bromo-2'-deoxyuridine (BrdUrd) incorporation into cells that expressed immature neuronal marker proteins and increased cell number in cultures by 20-30%. Cultured cells labeled by BrdUrd expressed VEGFR2/Flk-1, but not VEGFR1/Flt-1 receptors, and the effect of VEGF was blocked by the VEGFR2/Flk-1 receptor tyrosine kinase inhibitor SU1498. Intracerebroventricular administration of VEGF into rat brain increased BrdUrd labeling of cells in the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), where VEGFR2/Flk-1 was colocalized with the immature neuronal marker, doublecortin (Dcx). The increase in BrdUrd labeling after the administration of VEGF was caused by an increase in cell proliferation, rather than a decrease in cell death, because VEGF did not reduce caspase-3 cleavage in SVZ or SGZ. Cells labeled with BrdUrd after VEGF treatment in vivo include immature and mature neurons, astroglia, and endothelial cells. These findings implicate the angiogenesis factor VEGF in neurogenesis as well.
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PMID:Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. 1218 92

The purpose of this investigation was to evaluate firstly whether different protein expression patterns exist in primary squamous cell lung carcinomas of patients with and without lymph node involvement and secondly, whether or not different patterns exist in tumours with positive lymph nodes. For this reason, formalin-fixed, paraffin-embedded specimens from 130 patients with squamous cell lung carcinomas were analyzed by immunohistochemistry. In a first step, proteins were selected which showed a relationship to lymph node involvement. The expression of JUN, ERBB2, MYC, cyclin D, PCNA, bFGF, VEGF and Hsp70 proteins revealed a positive correlation to lymph node involvement. In contrast, caspase-3, Fas ligand, Fas/CD95, and PAI showed an inverse correlation to lymph node involvement. In a second step, these parameters were further analyzed by hierarchical cluster analyses. The resulting clusters were correlated to patients with or without lymph node involvement. The data show that different protein expression patterns exist between primary squamous cell lung carcinomas with and without lymph node involvement and within carcinomas with lymph node involvement. The data suggest that various metastasis profiles exist.
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PMID:Protein expression profile of primary human squamous cell lung carcinomas indicative of the incidence of metastases. 1219 66

Arsenic trioxide (As(2)O(3)) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) as well as in patients with APL in whom all-trans-retinoic acid and conventional chemotherapy failed. Chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs. To determine if As(2)O(3) might be useful for the treatment of chronic myelogenous leukemia, we examined the ability of As(2)O(3) to induce apoptosis in K562 cells. In vitro cytotoxicity of As(2)O(3) was evaluated in K562 cells by a MTT assay; the IC(50) value for As(2)O(3) was determined to be 10 microM. When analyzed by agarose gel electrophoresis, the DNA fragments became evident after incubation of the cells with 20 microM As(2)O(3) for 24 h. We also found morphological changes and chromatin condensation of the cells undergoing apoptosis. Activation of caspase-3 was observed 6 h after treatment with 20 microM As(2)O(3) by a Western blot analysis. Next, we examined the MAP kinase-signaling pathway of As(2)O(3)-induced apoptosis in K562 cells. As(2)O(3) at 10 microM strongly induced the activation of p38 and JNK 1/2, while ERK 1/2 was inhibited. In addition, pretreatment of SB203580, a specific inhibitor of p38, inhibited As(2)O(3) induced apoptotic cell death. These results suggest that As(2)O(3) is able to induce the apoptotic activity in K562 cells, and its apoptotic mechanism may be associated with the activation of p38.
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PMID:Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase. 1229 96

Studies in vitro have shown that phosphorylated translation initiation factor 2 alpha (TIF 2 alpha) may have several functions, including regulation of protein synthesis, control of cell death and procurement of resistance to oxidative stress in nerve cells. These properties may have implications in certain human neurodegenerative diseases, such as Alzheimer's disease (AD) and Creutzfeldt-Jakob's disease (CJD), in which oxidative stress appears to be involved in the process of neurodegeneration and neurone death. Single and double-labelling immunohistochemistry to phosphorylated TIF 2 alpha, phosphorylated SAPK/JNK, phosphorylated p38, tau, Cu/Zn superoxide dismutase 1 (SOD 1) and cleaved caspase-3 (17 kDa), and in situ end-labelling of nuclear DNA fragmentation, was carried out in postmortem samples of 10 patients with AD (stages III and VI of Braak and Braak), seven patients with CJD (five cases with methionine/methionine and two cases with methionine/valine at the codon 129 of the PrP gene) and eight age-matched controls. No phosphorylated TIF 2 alpha immunoreactivity was found in control brains, but strong phosphorylated TIF 2 alpha expression was observed in subpopulations of neurones bearing neurofibrillary tangles (NFTs) or pretangles in the hippocampus, entorhinal cortex and isocortex in AD. Phosphorylated TIF 2 alpha is restricted to neurones with abnormal tau deposition, but only approximately 80% of neurones with NFTs in the hippocampus and 60% in the isocortex colocalize phosphorylated TIF 2 alpha, thus indicating that not all neurones with NFTs over-express phosphorylated TIF 2 alpha. Moreover, phosphorylated TIF 2 alpha immunoreactivity was found in a percentage of neurones expressing phosphorylated SAPK/JNK and p38, which, in turn, are involved in tau phosphorylation in AD. However, dystrophic neurites of senile plaques that contain abnormal tau and express SOD 1 are negative to antiphosphorylated TIF 2 alpha antibodies. Smooth muscle cells in blood vessels affected by amyloid angiopathy, which are putative targets of beta A 4 amyloid-derived oxidative stress, are not associated with phosphorylated TIF 2 alpha immunoreactivity. Double-staining with the method of in situ end-labelling of nuclear DNA fragmentation demonstrated no relationship between phosphorylated TIF 2 alpha expression and increased nuclear DNA vulnerability in individual cells. Moreover, no single caspase-3-immunoreactive cell in AD expressed phosphorylated TIF 2 alpha. Oxidative stress response, manifested as positive SOD 1 expression in Bergmann glia and in a few reactive astrocytes, has been demonstrated in CJD. No phosphorylated SAPK/JNK or phosphorylated p38 kinase immunoreactivity was observed in these cases. Moreover, neurones and glial cells do not over-express phosphorylated TIF 2 alpha in CJD. The present results demonstrate selective expression of phosphorylated TIF 2 alpha in subpopulations of nerve cells with abnormal tau deposition, and suggest that factors linked with tau deposition regulate protein synthesis throughout TIF 2 alpha phosphorylation in certain neurones sensitive to oxidative stress in AD.
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PMID:Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer's disease and Creutzfeldt-Jakob's disease. 1244 60

Evidence from live cell bioassays shows that the flat mucosa from patients with colon cancer exhibits resistance to bile salt-induced apoptosis. Three independent cell lines derived from the colonic epithelial cell line HCT-116 were selected for resistance to bile salt-induced apoptosis. These cell lines were developed as tissue culture models of apoptosis resistance. Selection was carried out for resistance to apoptosis induced by sodium deoxycholate (NaDOC), the bile salt found in highest concentrations in human fecal water. Cultures of HCT-116 cells were serially passaged in the presence of increasing concentrations of NaDOC. The resulting apoptosis resistant cells were able to grow at concentrations of NaDOC (0.5 mM) that cause apoptosis in a few hours in unselected HCT-116 cells. These cells were then analyzed for changes in gene expression. Observations from cDNA microarray, 2-D gel electrophoresis/MALDI-mass spectroscopy, and confocal microscopy of immunofluorescently stained preparations indicated underexpression or overexpression of numerous genes at either the protein or mRNA level. Genes that may play a role in apoptosis and early stage carcinogenesis have been identified as upregulated in these cell lines, including Grp78, Bcl-2, NF-kappaB(p50), NF-kappaB(p65), thioredoxin peroxidase (peroxiredoxin) 2, peroxiredoxin 4, maspin, guanylate cyclase activating protein-1, PKCzeta, EGFR, Ras family members, PKA, PI(4,5)K, TRAF2 and BIRC1 (IAP protein). Under-expressed mRNAs included BNIP3, caspase-6, caspase-3 and serine protease 11. NF-kappaB was constitutively activated in all three resistant cell lines, and was responsible, in part, for the observed apoptosis resistance, determined using antisense oligonucleotide strategies. Molecular and cellular analyses of these resistant cell lines has suggested potential mechanisms by which apoptosis resistance may develop in the colonic epithelium in response to high concentrations of hydrophobic bile acids that are associated with a Western-style diet. These analyses provide the rationale for the development of hypothesis-driven intermediate biomarkers to assess colon cancer risk on an individual basis.
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PMID:Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. 1250 30

1 Magnolol, an active component isolated from the root and stem bark of Magnolia officinalis, has been reported to exhibit antitumour effects, but little is known about its molecular mechanisms of action. 2 Magnolol inhibited proliferation of human lung squamous carcinoma CH27 cells at low concentrations (10-40 microM), and induced apoptosis at high concentrations (80-100 microM). 3 Treatment with 80 microM magnolol significantly increased the expression of Bad and Bcl-X(S) proteins, whereas it decreased the expression of Bcl-X(L). Overexpression of Bcl-2 protected CH27 cells against magnolol-triggered apoptosis. 4 Magnolol treatment resulted in accumulation of cytosolic cytochrome c and activation of caspase-9 and downstream caspases (caspase-3 and -6). Pretreatment with z-VAD-fmk markedly inhibited magnolol-induced cell death, but did not prevent cytosolic cytochrome c accumulation. 5 Magnolol induced a modest and persistent JNK activation and ERK inactivation in CH27 cells without evident changes in the protein levels. The responsiveness of JNK and ERK to magnolol suggests the involvement of these kinases in the initiation of the apoptosis process. 6 These results indicate that regulation of the Bcl-2 family, accumulation of cytosolic cytochrome c, and activation of caspase-9 and caspase-3 may be the effector mechanisms of magnolol-induced apoptosis.
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PMID:Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells. 1252 90

Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family (also known as FGF-7), is an important protective factor for epithelial cells. The receptor for KGF (also called FGFR2-IIIb), which has intrinsic tyrosine kinase activity, is expressed specifically on epithelial cells and in the lung epithelium. Administration of KGF has been shown to protect the lung from various insults, but the mechanism of protection is not well understood. To understand the mechanism by which KGF exerts protective functions on epithelial cells, we used the yeast two-hybrid assay to identify proteins that interact with the KGF receptor (KGFR). Here we show that the cytoplasmic domain of KGFR interacts with p21-activated protein kinase (PAK) 4, which is a new member of the PAK family. The PAKs are regulated by the Rho-family GTPases Rac and Cdc42. PAK4 is the most divergent member of the PAK family of proteins and may have distinct functions. However, stimuli that regulate PAK4 activity are not known. Our data show that PAK4 can associate with the KGFR, which is dependent on KGFR tyrosine kinase activity. We show that a dominant negative mutant of PAK4 blocks KGF-mediated inhibition of caspase-3 activation in epithelial cells subjected to oxidant stress. Our data demonstrate that PAK4 is an important mediator of the anti-apoptotic effects of KGF on epithelial cells.
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PMID:p21-activated protein kinase 4 (PAK4) interacts with the keratinocyte growth factor receptor and participates in keratinocyte growth factor-mediated inhibition of oxidant-induced cell death. 1252 71


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