Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth effects of tyrphostins A25 and AG1478 on colorectal tumor cells were studied to explore therapeutic potential. Cell number, DNA synthesis and apoptotic index were measured as growth parameters and cell-death-associated proteins Bcl-2 and Bak and protein phosphorylation were analyzed. Both tyrphostins inhibited DNA synthesis and induced apoptosis in tumor cell cultures with different patterns of activity. A25 displayed strong selectivity for the cell lines expressing high levels of epidermal growth factor (EGF), HT29/HI1 and SW480. Inhibition of DNA synthesis was efficient in all cells except T84, and the apoptotic index increased two- to fivefold. By contrast, AG1478 was highly effective in all cell lines. In addition, it caused cell loss in VACO235 adenoma cells at concentrations lower than those necessary to inhibit BrdU incorporation, reflecting preferential retention of cells actively synthesizing DNA. Induction of apoptosis was more efficient with AG1478 than with A25 (tenfold in VACO235). Insulin-like growth factor (IGF1) did not rescue cells exposed to A25 or to high concentrations of AG1478, but was effective with suboptimal amounts of AG1478. Both compounds inhibited phosphorylation of the EGF receptor as well as additional proteins. AG1478 induced expression of Bak and down-regulated Bcl-2. In summary, tyrphostins may provide alternatives for colorectal tumor treatment. Their broader range of activities and the lower susceptibility to interactions with IGF1 can be an advantage over receptor antibodies.
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PMID:Inhibition of epidermal-growth-factor-receptor-dependent signalling by tyrphostins A25 and AG1478 blocks growth and induces apoptosis in colorectal tumor cells in vitro. 1039 57

The inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and immune interferon gamma (IFN-gamma) stimulate villous cytotrophoblast apoptosis while epidermal growth factor (EGF) protects. We hypothesize that TNF-alpha, IFN-gamma and EGF regulate apoptosis in part by modulating cellular expression levels of the anti-death gene bcl-2. While Bcl-2 is reported to be strongly expressed in villous syncytiotrophoblasts, it is not known whether the protein is expressed in cultured villous cytotrophoblasts (CT) and, if so, whether it is functional. We show by Northern blot analysis that bcl-2 mRNA is expressed in cultured CT and by immunoblot analysis that the protein is strongly expressed in highly purified first trimester and term villous cytotrophoblasts. The expression levels of Bcl-2 protein were the same in first trimester and term cytotrophoblasts. Culture with TNF-alpha/IFN-gamma and EGF did not alter expression of either Bcl-2 protein or of the pro-apoptotic Bcl-2 family member Bak. Double label flow cytometric analysis that measured apoptosis and Bcl-2 content simultaneously showed that cells expressing low levels of Bcl-2 underwent TNF-alpha/IFN-gamma-induced apoptosis at a higher frequency than cells expressing lower levels. We conclude that Bcl-2 is expressed in cytotrophoblasts, that its expression is constitutive and that modulation of its expression levels does not mediate cytokine and growth factor regulation of apoptosis in these cells.
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PMID:The role of Bcl-2 expression in EGF inhibition of TNF-alpha/IFN-gamma-induced villous trophoblast apoptosis. 1041 7

Transforming growth factor-beta1 (TGF-beta1) has been shown to induce apoptosis in normal or transformed hepatocytes. To elucidate the biochemical pathways leading to apoptosis induced by TGF-beta1 in human hepatoma cells (HuH-7), we examined the expression of Bcl-2-related proteins and X-chromosome-linked inhibitor of apoptosis (XIAP), and activation of the caspase cascade following TGF-beta1 treatment. Bcl-xL expression began to decline at 12 hours after TGF-beta1 treatment and progressively decreased to very low levels in a time-dependent manner. Bax expression showed a little change throughout the experiment. On the other hand, activation of caspase-8 was clearly observed at 36 hours after TGF-beta1 treatment, followed by activation of caspase-9, and caspase-3 was activated at 48 hours after treatment at which time apoptosis of HuH-7 cells was observed. TGF-beta1 significantly decreased XIAP expression in HuH-7 cells. Addition of an inhibitor of caspase-8 or caspase-3 (IETD-FMK or DEVD-CHO) markedly inhibited TGF-beta1-induced apoptosis of HuH-7 cells. Fas/Fas ligand (FasL) interactions in HuH-7 cells were not involved in the apoptotic process. Furthermore, epidermal growth factor (EGF) also completely inhibited TGF-beta1-induced apoptosis of HuH-7 cells by inhibiting activation of the caspase cascade. Our results suggested that activation of caspase-3 initiated through caspase-8 activation is involved in the apoptotic process induced by TGF-beta1 in HuH-7 cells. Our results also showed that down-regulation of the expression of Bcl-xL and XIAP by TGF-beta1 may facilitate activation of caspase-3 in these cells.
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PMID:Activation of caspase-8 in transforming growth factor-beta-induced apoptosis of human hepatoma cells. 1053 43

Uterine leiomyomas appear during the reproductive years and regress after menopause, indicating the ovarian steroid-dependent growth potential. In order to characterize the molecular mechanism of sex steroidal regulation of leiomyoma growth, we examined whether sex steroids could influence the proliferation of leiomyoma cells. As epidermal growth factor (EGF) has been shown to mediate estrogen action and play a crucial role in regulating leiomyoma growth, we also investigated the effects of sex steroids on EGF and EGF receptor (EGF-R) expression in leiomyoma cells. In cultures of leiomyoma cells, the addition of either estradiol (E(2); 10 ng/ml) or progesterone (P(4); 100 ng/ml) resulted in an increase in proliferating cell nuclear antigen (PCNA) expression in the cells, whereas in cultures of normal myometrial cells, the addition of E(2) augmented PCNA expression in the cells, but P(4) did not. Immunoblot analysis revealed that leiomyoma cells contained immunoreactive EGF and that P(4) treatment resulted in an increase in EGF expression in the cells, whereas E(2) treatment resulted in a lower EGF expression in the cells. By contrast, E(2) treatment augmented EGF-R expression in cultured leiomyoma cells, but P(4) did not. These results indicate that P(4) upregulates the expression of PCNA and EGF in leiomyoma cells, whereas E(2) upregulates the expression of PCNA and EGF-R in those cells. It is, therefore, conceivable that P(4) and E(2) act in combination to stimulate the proliferative potential of leiomyoma cells through the induction of EGF and EGF-R expression. We also found that Bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyoma relative to that in normal myometrium and that Bcl-2 protein expression in leiomyoma cells was upregulated by P(4), but downregulated by E(2). It seems, therefore, likely that P(4) may also participate in leiomyoma growth through the induction of Bcl-2 protein in leiomyoma cells. The abundant expression of Bcl-2 protein in leiomyoma cells may be one of the molecular bases for the enhanced growth of a leiomyoma relative to that of normal myometrium in the uterus.
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PMID:Molecular bases for the actions of ovarian sex steroids in the regulation of proliferation and apoptosis of human uterine leiomyoma. 1054 3

The promotion of cell survival and regeneration in acute renal failure (ARF) is important for restitution of renal function. This study analyzes the temporal and spatial relationship between expression of pro- and anti-apoptotic members of the Bcl-2 gene family (Bcl-2, Bcl-X(L), Bax) and epidermal growth factor (EGF), insulin-like growth factor- (IGF-1), and transforming growth factor-beta (TGF-beta), growth factors that are thought to be reparative in ARF. A rat model of ischemic ARF involving 30 min of bilateral renal artery occlusion followed by reperfusion for 0 to 14 d was used. Apoptosis and mitosis were quantified and qualitative assessment was made of other cellular damage including necrosis and loss of cellular adhesion. Locality and level of expression of the Bcl-2 and growth factor proteins were determined using immunohistochemistry. Apoptosis peaked between 4 and 14 d postischemia in both proximal and distal tubules. Mitosis peaked at 2 d in proximal tubules and 4 to 14 d in the distal tubules. A spatio-temporal relationship was observed between anti-apoptotic Bcl-2 gene family members and growth factors after ischemia-reperfusion. In control kidneys, expression of Bcl-2, Bcl-X(L) was low in epithelium of distal tubules, Bax had low-to-moderate expression in the proximal tubule and had low expression in the distal tubule, EGF and IGF-1 had low-to-moderate expression in the distal tubule, and TGF-beta had low expression in the proximal tubule. In contrast, within 24 h of reperfusion, distal tubules showed a marked increase in expression of Bcl-2 and a moderate increase in Bcl-X(L) and Bax. Proximal tubules showed a marked increase in Bax expression and a moderate increase in Bcl-X(L). Twenty-four hours after expression of the Bcl-2 proteins was increased, IGF-1 and EGF protein levels were increased in the distal tubule, similar to the Bcl-2 anti-apoptotic proteins, and were also detected in the adjacent proximal tubules, suggestive of paracrine action in these tubules. TGF-beta expression was moderately increased in regenerating proximal tubules, but no relationship was seen with the pattern of expression of the Bcl-2 genes. An explanation of these results is that the distal tubule is adaptively resistant to ischemic injury via promotion of survival by anti-apoptotic Bcl-2 genes, and its survival allows expression of growth factors critical not only to the maintenance and regeneration of its own cell population (autocrine action), but also to the adjacent ischemia-sensitive proximal tubular cells (paracrine action).
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PMID:Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat. 1070 69

Here we present the genomic sequence, with analysis, of a pathogenic fowlpox virus (FPV). The 288-kbp FPV genome consists of a central coding region bounded by identical 9.5-kbp inverted terminal repeats and contains 260 open reading frames, of which 101 exhibit similarity to genes of known function. Comparison of the FPV genome with those of other chordopoxviruses (ChPVs) revealed 65 conserved gene homologues, encoding proteins involved in transcription and mRNA biogenesis, nucleotide metabolism, DNA replication and repair, protein processing, and virion structure. Comparison of the FPV genome with those of other ChPVs revealed extensive genome colinearity which is interrupted in FPV by a translocation and a major inversion, the presence of multiple and in some cases large gene families, and novel cellular homologues. Large numbers of cellular homologues together with 10 multigene families largely account for the marked size difference between the FPV genome (260 to 309 kbp) and other known ChPV genomes (178 to 191 kbp). Predicted proteins with putative functions involving immune evasion included eight natural killer cell receptors, four CC chemokines, three G-protein-coupled receptors, two beta nerve growth factors, transforming growth factor beta, interleukin-18-binding protein, semaphorin, and five serine proteinase inhibitors (serpins). Other potential FPV host range proteins included homologues of those involved in apoptosis (e.g., Bcl-2 protein), cell growth (e.g., epidermal growth factor domain protein), tissue tropism (e.g., ankyrin repeat-containing gene family, N1R/p28 gene family, and a T10 homologue), and avian host range (e.g., a protein present in both fowl adenovirus and Marek's disease virus). The presence of homologues of genes encoding proteins involved in steroid biogenesis (e.g., hydroxysteroid dehydrogenase), antioxidant functions (e.g., glutathione peroxidase), vesicle trafficking (e.g., two alpha-type soluble NSF attachment proteins), and other, unknown conserved cellular processes (e.g., Hal3 domain protein and GSN1/SUR4) suggests that significant modification of host cell function occurs upon viral infection. The presence of a cyclobutane pyrimidine dimer photolyase homologue in FPV suggests the presence of a photoreactivation DNA repair pathway. This diverse complement of genes with likely host range functions in FPV suggests significant viral adaptation to the avian host.
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PMID:The genome of fowlpox virus. 1072 56

Preeclampsia and fetal growth restriction are associated with placental hypoperfusion and villous hypoxia. The villous response to this environment includes diminished trophoblast differentiation and enhanced apoptosis. We tested the hypothesis that hypoxia induces apoptosis in cultured trophoblasts, and that epidermal growth factor (EGF), an enhancer of trophoblast differentiation, diminishes hypoxia-induced apoptosis. Trophoblasts isolated from placentas of term-uncomplicated human pregnancies were cultured up to 72 h in standard (PO(2) = 120 mm Hg) or hypoxic (PO(2) <15 mm Hg) conditions. Exposure to hypoxia for 24 h markedly enhanced trophoblast apoptosis as determined by DNA laddering, internucleosomal in situ DNA fragmentation, and histomorphology, as well as by the reversibility of the apoptotic process with a caspase inhibitor. Apoptosis was accompanied by increased expression of p53 and Bax and decreased expression of Bcl-2. Addition of EGF to cultured trophoblasts or exposure of more differentiated trophoblasts to hypoxia significantly lowered the level of apoptosis. We conclude that hypoxia enhances apoptosis in cultured trophoblasts by a mechanism that involves an increase in p53 and Bax expression. EGF and enhancement of cell differentiation protect against hypoxic-induced apoptosis.
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PMID:Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor. 1079 72

A dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), can induce dopaminergic denervation and Parkinsonism in humans. The active metabolite of MPTP is the 1-methyl-4-phenylpyridinium ion (MPP(+)). Previously we reported that MPP(+) is incorporated via the dopamine transport system and causes delayed cell death in GH3 cells, a clonal strain from the rat anterior pituitary. In this study, we investigated whether MPP(+) induces apoptosis. GH3 cells cultured with MPP(+) exhibited DNA laddering and fragmentation in a time- and concentration-dependent manner. The effect of MPP(+) was inhibited in GH3 cells treated with a pan-caspase inhibitor (100 microM ZVAD-fmk), an antioxidant (25 mM N-acetyl-l-cysteine), or epidermal growth factor (EGF; 50 ng/mL). Because EGF stimulated tyrosine phosphorylation of the EGF receptor and tyrphostin AG1478 [4-(3-chloroanilino)-6,7-dimethoxyquinazoline; 5 microM, a specific inhibitor of EGF receptor kinase] abolished EGF inhibition, involvement of EGF receptor kinase is assumed. Protein kinase C-dependent processes and Bcl-2 protein expression were shown not to be involved in EGF inhibition. MPP(+) increased cytochrome c immunoreactivity in cytosolic fractions in GH3 cells. The addition of 200 microM MPP(+) to isolated mitochondrial fractions from GH3 cells stimulated the release of a 13-kDa protein that cross-reacted with anti-cytochrome c antibody. The release was inhibited in EGF-treated GH3 cells. Our findings demonstrated that (i) MPP(+) induces apoptosis of GH3 cells via cytochrome c release and caspase activation, and (ii) apoptosis by MPP(+) can be blocked by N-acetyl-l-cysteine or EGF treatment.
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PMID:Apoptosis induction by a dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)), and inhibition by epidermal growth factor in GH3 cells. 1080 52

Lack of selectivity in the killing of tumor and normal cells is a major obstacle in cancer therapy. By inhibiting normal but not autonomous cell growth, we exploited the differences in cell cycle regulation to achieve a selective protection of nonautonomous cells against paclitaxel and other microtubule-active drugs. Tubulin polymerization, a primary effect of paclitaxel, can be dissociated from Bcl-2 phosphorylation and cytotoxicity in HL-60 cells. Growth arrest prevented paclitaxel-induced Bcl-2 phosphorylation and apoptosis without affecting paclitaxel-induced tubulin polymerization. We abrogated the effects of paclitaxel on MCF-10A immortalized breast cells, while preserving its effects on MCF-7 cancer cells. Unlike MCF-7 cells, MCF-10A cells were arrested by epidermal growth factor withdrawal, precluding paclitaxel-induced Bcl-2 phosphorylation. Furthermore, the inhibition of the epidermal growth factor receptor kinase with low doses of AG1478 arrested growth of MCF-10A but not MCF-7 cells. Pretreatment with AG1478 did not affect paclitaxel-induced Bcl-2/Raf-1 phosphorylation in MCF-7 but abrogated such phosphorylation in MCF-10A. Exploitation of growth factor dependency may allow the protection of normal cells from microtubule-active drugs.
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PMID:Loss of cell cycle control allows selective microtubule-active drug-induced Bcl-2 phosphorylation and cytotoxicity in autonomous cancer cells. 1091 51

An understanding of the mechanisms underlying the formation of renal lesions is necessary for the development of strategies aiming to delay the progression of chronic renal failure. The generation of transgenic mice in the past 20 years has contributed significantly to the study of this phenomenon. Overexpression and/or inactivation of single factors in renal tissue demonstrated that molecules such as growth factors, proto-oncogenes, and renin-angiotensin system elements play major roles in renal deterioration. Several mouse models of renal injury have been developed in the past 10 yr. Transgenic mice that exhibit a normal phenotype under physiologic conditions allow analysis of the roles of single factors in the progression of chronic renal failure when renal injury models are used. Using this strategy, it was demonstrated that vascular adaptation, which is a process that involves the endothelin/nitric oxide balance, is essential for the survival of mice after nephron reduction and that the epidermal growth factor/activator protein-1/Bcl-2 pathway is involved in the development of renal lesions after renal injury, possibly via adjustment of the proliferation/apoptosis balance. Moreover, it was demonstrated that selective inhibition of epidermal growth factor signaling in the kidney successfully prevents the progression of chronic renal failure. These results indicate the power of transgenesis for elucidation of the pathogenesis of renal disease.
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PMID:Using transgenic mice to analyze the mechanisms of progression of chronic renal failure. 1106 47


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