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 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

Many chemopreventive agents have been shown to modulate gene expression including induction of phase II detoxifying enzymes, such as glutathione S-transferases (GST) and quinone reductases (QR). Induction of phase II enzymes in general leads to protection of cells/tissues against exogenous and/or endogenous carcinogenic intermediates. The antioxidant or electrophile response element (ARE/EpRE) found at the 5'-flanking region of these phase II genes may play important role in mediating their induction by xenobiotics including chemopreventive agents. Members of the basic leucine zipper (bZIP) transcription factor, Nrf2 which heterodimerizes with Maf G/K, are found to bind to the ARE, and transcriptionally-activated ARE. Recently, we showed that the mitogen-activated protein kinases (MAPK) were activated by phase II gene inducers such as phenolic antioxidant butylated hydroxyanisol (BHA) and isothiocyanate sulforaphane (SUL), and involved in the transcription activation of ARE-mediated reporter gene. Transfection studies with wild-type and dominant negative mutants of Nrf2 and MAPK showed synergistic response during co-transfection as well as to phase II gene inducers. However, increasing the concentrations of these compounds such as BHA, the activities of cell death signaling molecules, caspases, were stimulated and resulted in apoptotic cell death. At these concentrations, BHA stimulated loss of mitochondrial membrane potential, cytochrome c release, and activation of caspase 3, 8 and 9 preceding apoptosis. Further increase in concentrations led to rapid cell necrosis. A model is proposed for BHA and SUL, in that at low concentrations, these potential chemopreventive agents may modulate MAPK pathway leading to transcription activation of Nrf2 and ARE with subsequent induction of cellular defensive enzymes including phase II detoxifying enzymes as well as other defensive genes, which may protect the cells against cellular injury, which is a homeostatic response. At higher concentrations, these agents may activate the caspase pathways, leading to apoptosis, a potential beneficial effect if occurs at preneoplastic/neoplastic tissues, but a potential cytotoxic response if occurs in normal tissues. On the other hand, some phenolic compounds such as resveratrol inhibits TPA- or UV-induced AP-1-mediated activity through the inhibition of c-Src non-receptor tyrosine kinase and MAPK pathways. It is possible that in proliferating or stimulated cells, these chemopreventive compounds may block proliferation by inhibiting these signaling kinases, whereas in non-proliferating or quiescent cells, some of these compounds may activate these signaling kinases leading to gene expression of cellular defensive enzymes such as phase II detoxifying enzymes. The studies of these and other signaling pathways may yield insights into the development of potential chemopreventive compounds.
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PMID:Signal transduction events elicited by cancer prevention compounds. 1150 17

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

Mortal human fibroblasts can be partially transformed by the bovine papillomavirus E5 oncoprotein through activation of the platelet-derived growth factor beta receptor. Here, we report that these cells undergo massive apoptosis 2 weeks after confluence. Although activation of caspase 3 was observed in the apoptotic cells, it was not required for apoptosis. The appearance of the mitochondrial proteins cytochrome c and apoptosis-inducing factor in cytosolic and nuclear compartments, respectively, provided a basis for mitochondrial dysfunction and a caspase-independent mechanism of apoptosis in these cells. Although an activating conformational change in Bax also was evident in the apoptotic cells, enforced overexpression of Bcl-2 was insufficient to prevent apoptosis. Finally, a small peptide present in the conditioned medium from dying transformed cells appeared responsible for inducing apoptosis through affecting a conformational change in Bax and eventual relocalization of apoptosis-inducing factor to the nucleus. Thus, an atypical apoptotic pathway is activated in mortal human fibroblasts in response to transformation induced by sustained receptor tyrosine kinase activation.
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PMID:Apoptosis of mortal human fibroblasts transformed by the bovine papillomavirus E5 oncoprotein. 1249 59

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

The Met receptor tyrosine kinase has been shown to be overexpressed or mutated in a variety of solid tumors and has, therefore, been identified as a good candidate for molecularly targeted therapy. Activation of the Met tyrosine kinase by the TPR gene was originally described in vitro through carcinogen-induced rearrangement. The TPR-MET fusion protein contains constitutively elevated Met tyrosine kinase activity and constitutes an ideal model to study the transforming activity of the Met kinase. We found, when introduced into an interleukin 3-dependent cell line, TPR-MET induces factor independence and constitutive tyrosine phosphorylation of several cellular proteins. One major tyrosine phosphorylated protein was identified as the TPR-MET oncoprotein itself. Inhibition of the Met kinase activity by the novel small molecule drug SU11274 [(3Z)-N-(3-chlorophenyl)-3-([3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl]methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide] led to time- and dose-dependent reduced cell growth. The inhibitor did not affect other tyrosine kinase oncoproteins, including BCR-ABL, TEL-JAK2, TEL-PDGFbetaR, or TEL-ABL. The Met inhibitor induced G(1) cell cycle arrest and apoptosis with increased Annexin V staining and caspase 3 activity. The autophosphorylation of the Met kinase was reduced on sites that have been shown previously to be important for activation of pathways involved in cell growth and survival, especially the phosphatidylinositol-3'-kinase and the Ras pathway. In particular, we found that the inhibitor blocked phosphorylation of AKT, GSK-3beta, and the pro-apoptotic transcription factor FKHR. The characterization of SU11274 as an effective inhibitor of Met tyrosine kinase activity illustrates the potential of targeting for Met therapeutic use in cancers associated with activated forms of this kinase.
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PMID:A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. 1450 Mar 82


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