Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The erbB-2/neu oncogene is frequently over-expressed in many different tumors in humans, including those of breast and ovary. The oncogene encodes a receptor tyrosine kinase closely related to the epidermal-growth-factor receptor. We studied effects on differentiation and cell death of erbB-2/neu during mammary-gland development in transgenic mice expressing an activated, oncogenic rat erbB-2/neu gene controlled by the mammary-gland-specific promoter from mouse-mammary-tumor virus (MMTV-LTR). Transgenic animals develop mammary cancer after repeated pregnancies and lactation. We present evidence that over-expression of erbB-2/neu in these mice is restricted to tumor cells. Tumor cells fail to differentiate and express milk proteins such as beta-casein and whey acidic protein (WAP) during lactation. Epithelial-cell apoptosis during normal involution is characterized by non-random DNA degradation into oligonucleosomal fragments. Tumor cells were mostly refractory to this developmentally controlled programmed cell death. Distinct areas within tumors, however, showed spontaneous cell death as measured by in situ TUNEL staining that co-localized with caspase-3-like activity. Our results indicate that the control of developmental cell death during involution is disturbed in erbB-2/neu-induced tumors although cell death and caspase activation can take place.
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PMID:Over-expression of erbB-2/neu is paralleled by inhibition of mouse-mammary-epithelial-cell differentiation and developmental apoptosis. 1069 33

Low oxygen and nutrient depletion play critical roles in tumorigenesis, but little is known about how they interact to produce tumor survival and tumor malignancy. In the present study, we investigated the mechanism underlying hypoxia-modulated apoptosis of serum-deprived HepG2 cells. Our results showed that hypoxia blocked the apoptosis, which was accompanied with decreased Bax/Bcl-2 ratio, inhibited cytochrome c release, and reduced caspase-3 activity. More importantly, increased expressions of VEGF and its receptor-2 (KDR) under hypoxic/serum-deprived condition suggest that VEGF may act as a survival factor in a self-promoting manner. Data were further supported by results that recombinant human VEGF (rhVEGF) suppressed the serum deprivation-induced apoptosis, and anti-VEGF neutralizing antibody block anti-apoptotic activity of hypoxia. In addition, inhibitors of receptor tyrosine kinase blocked antiapoptosis of hypoxia. Our study further showed that rhVEGF or hypoxia induced ERK phosphorylation in serum-deprived cells, and that a specific inhibitor of MAPK/ERK, PD98059 eliminated the anti-apoptotic activity of rhVEGF or hypoxia by increasing Bax/Bcl-2 ratio and caspase-3 activity. Our data led us to conclude that induction of ERK phosphorylation and decrease of Bax/Bcl-2 ratio by rhVEGF implies that hypoxia-induced VEGF prevents apoptosis of serum-deprived cells by activating the MAPK/ERK pathway. Taken together, we propose that hypoxia enhances survival of nutrient-depleted tumor cells by reducing susceptibility to apoptosis, which consequently leads to tumor malignancy.
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PMID:Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. 1103 Jan 51

Nerve growth factor (NGF) mediates a variety of nerve cell actions through receptor tyrosine kinase TrkA. It has been revealed that the Akt pathway contributes to the prevention of apoptosis. It is thought that Parkinson's disease involves apoptosis, and NGF prevents apoptosis in an in vivo model system. However, there is no evidence that the Akt pathway helps to prevent parkinsonism. Here, we report that NGF prevents apoptosis induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in PC12 cells as an in vitro model system of parkinsonism and that this survival effect diminishes on addition of LY294002, a specific inhibitor of phosphatidylinositol 3-kinase. Immunocytochemical analysis revealed that 1 mM MPTP-treated cells or dominant negative Akt-expressing cells, to which were added NGF and MPTP, undergo apoptosis. Moreover, the caspase-3-like activity is increased by addition of MPTP or MPTP with NGF and LY294002. The importance of another signal pathway is shown by PD98059, a specific inhibitor of MAP kinase (MAPK) kinase, but PD98059 does not alter the survival effect in this model system. These results indicate that the Akt pathway helps to prevent parkinsonism by suppressing caspase-3-like activity, but the MAPK pathway is not involved in the NGF-dependent survival enhancing effect in this model system.
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PMID:Nerve growth factor prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced cell death via the Akt pathway by suppressing caspase-3-like activity using PC12 cells: relevance to therapeutical application for Parkinson's disease. 1122 15

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

Cholangiocarcinoma is a rare but highly malignant primary hepatobiliary cancer with a high rate of mortality. Early diagnosis is difficult and current therapies are ineffective for the advanced disease. Although the molecular pathogenesis of cholangiocarcinoma is still poorly understood, there is increasing evidence to suggest that overexpression of the proto-oncogene-encoded receptor tyrosine kinase ERBB-2 together with upregulation of cyclooxygenase-2 (COX-2) may be an important feature of cholangiocarcinogenesis in both the human and the experimental rodent models. Evidence presented supports a strong positive correlation between ERBB-2 overexpression and cyclooxygenase upregulation in human cholangiocarcinogenesis. Combination drug targeting of ERBB-2 and of COX-2 was also found to act synergistically to suppress anchorage-independent growth and activate caspase-3 in cultured rat cholangiocarcinoma cells overexpressing both proteins. These findings suggest that aberrant expression of ERBB-2 and COX-2 is a common feature of human and rat cholangiocarcinomas and that targeting of both proteins may prove useful as a therapeutic strategy for this lethal cancer.
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PMID:Cyclooxygenase-2 and ERBB-2 in cholangiocarcinoma: potential therapeutic targets. 1236 Apr 23

Nitric oxide (NO) generated by either endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS) may be involved in prostate tumorigenesis through the inhibition of reactive oxygen species (ROS)-induced apoptosis. Multicellular DU-145 prostate tumor spheroids endogenously generated NO that paralleled the production of ROS. With increasing spheroid size, eNOS expression was downregulated, whereas an upregulation of iNOS expression was observed. In parallel, NO generation declined, as evaluated by the NO indicator diaminofluorescein-2 diacetate (DAF-2DA), suggesting that NO generation in DU-145 tumor spheroids is mainly mediated by eNOS. Elevation of ROS by treatment of tumor spheroids with either buthionine sulfoximine (BSO) or hydrogen peroxide resulted in upregulation of eNOS, whereas iNOS was downregulated. Furthermore, eNOS expression was increased by epidermal growth factor (EGF) in a redox-sensitive manner. Upregulation of eNOS after treatment with hydrogen peroxide was apparently transduced through receptor tyrosine kinase signaling pathways since it was abolished by the protein kinase C (PKC) inhibitor bisindolylmaleimide-1 (BIM-1), the p21(ras) inhibitor S-trans-trans-farnesylthiosalicylic acid (FTS), the c-Raf inhibitor ZM 336372 and PD98059, which inhibits ERK1/2 activation. Endogenous NO may serve to escape from oxidative stress-induced apoptosis since treatment of tumor spheroids with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide (carboxy-PTIO) as well as the NO synthase inhibitor N-omega-amino-L-arginine (L-NAA) increased cleaved caspase-3. Consequently, lowering intracellular NO levels with either L-NAA or PTIO significantly raised ROS levels, indicating that endogenously generated NO may play a role as a ROS scavenger, thereby protecting exponentially growing tumor spheroids from ROS-induced apoptosis.
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PMID:Reactive oxygen species-mediated regulation of eNOS and iNOS expression in multicellular prostate tumor spheroids. 1256 50

c-Abl, a non-receptor tyrosine kinase, is found in both nucleus and cytoplasm of proliferating fibroblasts. RB negatively regulates the kinase activity of c-Abl. Overexpression of kinase active c-Abl can overcome RB-induced growth arrest in Saos-2 cells. However, we previously reported that disruption of the RB matchmaker function leads to delayed cell cycle progression in the presence of p53. In this study, we investigated whether overexpression of mutant c-Abl (AS2, RB-resistant Abl kinase) not only lead to delayed cell cycle progression but also make cells susceptible to apoptosis under coexpression with a fragment of RB C pocket in human skin fibroblast. AS2 expressing cells showed delayed cell growth rate in normal growth condition. After genotoxic stress such as etoposide treatment, AS2 expressing cells readily progressed into apoptosis through p53 and caspase-3 activations. Our results suggest that expression of AS2 not only induces delayed cell cycle progression but also results in increased sensitivity to apoptosis in the presence of p53.
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PMID:RB-resistant Abl kinase induces delayed cell cycle progression and increases susceptibility to apoptosis upon cellular stresses through interaction with p53. 1273 83

Several pieces of evidence have demonstrated the importance of reduction/oxidation (redox) signaling in biological processes, including sensitivity toward apoptosis. In parallel, it was recently reported that growth factors induce the generation of reactive oxygen species (ROS). Therefore, we tested the hypothesis that the anti-apoptotic effect of epidermal growth factor (EGF) was mediated by changes in the redox state of hepatocytes through changes in GSH stocks. Isolated mouse hepatocytes were cultured and exposed to anti-Fas stimulation in order to induce apoptosis. Cell death by apoptosis was assessed by Hoechst 33258 staining and by measuring caspase-3 proteolysis activity. Cell treatment with EGF significantly decreased total (GSx) and reduced (GSH) glutathione levels in the presence and the absence of anti-Fas. Furthermore, glutathione reductase activity was lower in EGF-treated cultures (by 28%) as compared to untreated cultures which lead to a significant decline in GSH/GSx ratio. These effects were found to be EGF-receptor tyrosine kinase activity dependent. Co-stimulation of cells with anti-Fas and EGF attenuated caspase-3 activation and cell death by apoptosis by 70%. GSH monoethylester (GSHmee) significantly attenuated the effect of EGF on GSH and GSH/GSx ratio. It caused an increase in caspase-3 activation and in the percentage of apoptotic cells in anti-Fas + EGF-treated cells, thus resulting in a 53% decline in the protective effect of EGF. In conclusion, EGF induces a significant and specific depletion and oxidization of intracellular GSH, paralleled by a protection against Fas-induced apoptosis. GSH repenishment partly counteracted these effects suggesting that GSH depletion contributed to the protective effect of EGF against caspase-3 activation and cell death by apoptosis.
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PMID:EGF mediates protection against Fas-induced apoptosis by depleting and oxidizing intracellular GSH stocks. 1458 45

Overexpression of the receptor tyrosine kinase HER-2/neu is associated with poor prognosis in patients with breast and ovarian cancer. Recent excitement has surrounded the therapeutic effects of HER-2-blocking therapy strategies and has rekindled interest on the molecular mechanisms of HER-2/neu in tumor biology. To study the role of HER-2/neu overexpression in vivo, we used a murine fibroblast cell line (NIH3T3-her2) conditionally expressing human HER-2/neu under control of a tetracycline-responsive promoter. Expression of HER-2 could be down-regulated below detection limit (>625-fold dilution) by exposure of NIH3T3-her2 cells to anhydrotetracycline (ATc). Subcutaneous injection of NIH3T3-her2 cells into nude mice resulted in rapid tumor growth. Mice with mean tumor volumes of 0.2, 0.8, 1.9, and 14.9 cm(3) were treated daily with 10 mg/kg ATc to switch off HER-2/neu expression, producing reductions in tumor size of 100, 98.1, 81.4, and 74.2%, respectively, by 7 days after onset of ATc administration (P = 0.005, Kruskal-Wallis test). Different long-term effects of HER-2 down-regulation were observed when mice with small (0.2 cm(3); n = 7), intermediate (0.8-1.2 cm(3); n = 10) and large (> or =1.9 cm(3); n = 11) tumors received ATc for up to 40 days. Complete remission was observed for 100, 40, and 18% of the small-, intermediate-, and large-sized tumors, respectively (P = 0.003). However, after 20-45 days of ATc administration, recurrent tumor growth was observed for all mice, even in those with previous complete remissions. The time periods for which mean tumor volume could be suppressed to volumes <0.1 cm(3) under ATc administration were 34, 22, 8, and 0 days for tumors with initial volumes of 0.2, 0.8, 1.9 and 14.9 cm(3), respectively (P = 0.005, Kruskal-Wallis test). Interestingly, HER-2 remained below the detection limit in recurrent tumor tissue, suggesting that initially HER-2-dependent tumors switched to HER-2 independence. The "second hits" leading to HER-2-independent tumor growth have not yet been identified. The rapid regression of tumors after down-regulation of HER-2 was explained by two independent mechanisms: (a) a block in cell cycle progression, as evidenced by a decrease in Ki-67 antigen expression from 40% before ATc treatment to 8.3% after 7 days of ATc treatment; and (b) induction of apoptosis as demonstrated by caspase-3 activation and by the terminal deoxynucleotidyltransferase (Tdt)-mediated nick end labeling assay (TUNEL). In conclusion, we have shown that switching off HER-2 may disturb the sensitive balance between cell proliferation and cell death, leading to apoptosis and tumor remission. Tumor remission was dependent on the volume of the tumors before down-regulation of HER-2/neu.
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PMID:Switching off HER-2/neu in a tetracycline-controlled mouse tumor model leads to apoptosis and tumor-size-dependent remission. 1461 17

Axl is a receptor tyrosine kinase that is activated by Gas6, a growth factor that belongs to the vitamin K-dependent protein family. Although Gas6 binding to Axl has been shown to transmit mitogenic and/or antiapoptotic signals to a variety of cell types, the role of the Axl-Gas6 system in normal and pathological lens biology is not known. We demonstrate for the first time that Axl protein is expressed in normal rat and bovine lens and that its ligand, Gas6, is present in bovine aqueous humor. In addition, we have detected tyrosine-phosphorylated Axl in normal rat and bovine lens epithelial tissues. We further show that human recombinant Gas6 is able to act as a growth factor in cultured human lens epithelial cells by activating Axl and then the AKT signaling pathway. Gas6 mediates a survival and anti-apoptotic response in cultured human lens epithelial cells subjected to serum-starvation (48-72hr), or treated with transforming growth factor beta1 (5 ng ml(-1), 48hr) or tumor necrosis alpha (100 ng ml(-1), 48hr), as demonstrated by increased number of viable cells, and decreased DNA condensation or caspase-3 activity. In contrast, Gas6 is not able to block apoptosis induced by staurosporin (1microM, 5-24hr) in human lens epithelial cells. Taken together, these data suggest that the Gas6/Axl signaling plays an important role in the control of lens epithelial cell growth and survival and hence in the maintenance of lens homeostasis.
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PMID:Role of Gas6/Axl signaling in lens epithelial cell proliferation and survival. 1466 25


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