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)

The signaling enzyme phosphoinositide 3-kinase (PI3K) is activated following B cell receptor (BCR) engagement and by many other receptors on B lymphocytes. Mice lacking p85alpha, the predominant PI3K regulatory isoform, exhibit defects in B cell development and activation that are grossly similar to those found in mice lacking Bruton's tyrosine kinase (Btk) and other critical signaling molecules. However, a detailed analysis of splenic B cell subsets in p85alpha-deficient mice has not been reported. Here we show that these mice are deficient in four major B cell subsets: transitional-1, transitional-2, follicular and marginal zone. These defects are distinct from those observed in Xid mice that express a mutant Btk unable to interact with PI3K lipid products. Moreover, mice with both genetic lesions exhibit even greater impairment in B cell development. Finally, we show that transgenic expression of the anti-apoptotic protein Bcl-2 in p85alpha-deficient mice restores the transitional B cell subsets but not the marginal zone subset, and produces a follicular population with an aberrant phenotype. These findings establish a role for PI3K-p85alpha in differentiation of both follicular and marginal zone B cells, and suggest that these functions are required not solely for the propagation of anti-apoptotic signals.
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PMID:Altered splenic B cell subset development in mice lacking phosphoinositide 3-kinase p85alpha. 1552 44

Cross-linking FcepsilonRI on mast cells by immunoglobulin E (IgE) and antigen (Ag) initiates cascades leading to antiparasitic or allergic responses. It was recently reported that IgE without antigen, IgE(-Ag), actively promotes mast cell survival. Although we have demonstrated that the immunoreceptor tyrosine-based activation motif within FcRgamma is essential for IgE(-Ag)-induced mast cell survival, the underlying mechanism remains still unclear. Here, we investigated the mechanism of IgE(-Ag)-induced survival using mast cells lacking several downstream molecules. Lyn and Syk were essential, whereas Fyn, Gab2, and the phosphoinositide 3-kinase-Akt pathway were not critical for survival. Failure of survival in FcRgamma-/- bone marrow mast cells (BMMCs) was rescued by coculture with IgE-treated wild-type BMMCs, suggesting that survival is induced not directly through FcepsilonRI signals. We found that the survival is predominantly mediated by high production of interleukin 3 (IL-3), evidenced by severe impairment of survival by anti-IL-3 and in IL-3-/- BMMCs. The up-regulation of Bcl-xL/Bcl-2 by IgE was abrogated in IL-3-/- BMMCs, whereas the expression of histidine decarboxylase was normally induced. These results indicate that IL-3 plays a crucial role for IgE(-Ag)-induced mast cell survival, functioning in an autocrine manner by inducing the Bcl-xL/Bcl-2 via signal transducer and activator of transduction 5. We further suggest that IgE(-Ag)-mediated gene expression in mast cells is regulated at least 2 mechanisms: autocrine IL-3 dependent and independent.
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PMID:Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen. 1554 85

Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERaalpha)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kappaB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kappaB, were both inhibited by RES. The patterns for NF-kappaB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kappaB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kappaB and calpain protease activity. Therefore, Bcl-2 and NF-kappaB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells.
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PMID:Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB. 1568 15

Radiotherapy is one of the most widely used cancer treatments, but it is often unsuccessful due to the development of radioresistance by tumor cells and endothelial cells (ECs) lining the tumor blood vessels. We have previously shown that ECs are protected against ionizing irradiation primarily via the activation of the phosphoinositide 3-kinase (PI3 K)-Akt-Bcl-2 survival pathway. Here we report that combination treatment with low doses of PI3 K inhibitor (LY294002), cisplatin and gamma-irradiation resulted in significantly higher (61%) EC death as compared to each agent used alone (17, 17 and 11%, respectively). This combination treatment was equally effective in inducing tumor cell death (72%). Combination treatment also significantly inhibited EC tube formation in Matrigel (75%) as compared to each of the agents used alone (8, 8 and 18% for LY294002, cisplatin and gamma-irradiation, respectively). In our in vivo severe combined immunodeficient mouse model of human tumor growth and angiogenesis, combination treatment with low doses of LY294002, cisplatin and irradiation significantly inhibited the growth of human oral squamous carcinoma (OSCC-3) as well as prostate cancer (LnCap). The combination therapy was also very effective in inhibiting tumor angiogenesis where it showed a greater than 90% decrease in neovascularization. In contrast, combination treatment showed only a 29% inhibition of physiological angiogenesis. Taken together, these results suggest a potentially novel strategy to overcome the resistance in ECs lining tumor blood vessels, thereby enhancing the effectiveness of the radiation and chemotherapy. Moreover, this strategy of using a combination of low doses of PI3K/Akt inhibitor, cisplatin and radiation has the potential of significantly decreasing untoward side effects associated with the maximum tolerated doses of radiation and chemotherapy while maintaining their therapeutic efficacy.
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PMID:Combination treatment significantly enhances the efficacy of antitumor therapy by preferentially targeting angiogenesis. 1586 18

Signaling pathways underlying transition of cardiomyocyte growth from hyperplasia in fetal/newborn to hypertrophy in postnatal/adult hearts are not well understood. We have shown that beta-adrenergic receptor (beta-AR)-mediated regulation of neonatal cardiomyocyte proliferation involves p70 ribosomal protein S6 kinase (p70S6K). Here we examined the ontogeny of phosphoinositide 3-kinase (PI3K)/p70S6K signaling pathway in rat hearts and investigated the influence of beta-AR on this pathway during development. Cardiac PI3K and p70S6K1 activities were high in the embryonic day 20 fetus, decreased gradually postnatally, and were low in the adult. In contrast, p70S6K2 was barely detectable. Phosphorylation of p70S6K1, Akt, and phosphoinositide-dependent protein kinase 1 were markedly increased in late gestation and early postnatal life but not in adult hearts. Phosphatase and tensin homolog on chromosome 10 (PTEN), a negative regulator of PI3K, was highly expressed in adult hearts but only at low levels and mostly in the phosphorylated (inactivated) form in the fetus. Beta-AR stimulation resulted in increased cardiac p70S6K1 activity only in animals > or = 2 wk old, whereas Akt level was increased in all developmental stages tested. These increases were accompanied by increased Bcl-2 associated death promoter (Ser136) phosphorylation without changes in PTEN level. Thus there is globally high input of cardiac PI3K signaling during the fetal-neonatal transition period. Inactivation of PTEN may in part contribute to the high activity of PI3K signaling, which coincides with the period of high cardiomyocyte proliferation. Beta-AR stimulation activates cardiac p70S6K1 and Akt in postnatal animals and may activate cardiac survival signals. These data provide further evidence for the importance of beta-AR and PI3K signaling in the regulation of cardiac growth during development.
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PMID:Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute beta-adrenergic stimulation. 1600 45

Programmed cell death is vital for a number of pathophysiologic settings. Apoptotic cells are rapidly engulfed by phagocytes (ie, macrophages), which in turn acquire an anti-inflammatory phenotype known as alternative activation or the M2-type. Here we show that interaction of apoptotic cells with macrophages attenuates cell death pathways in the latter. Protection of human macrophages required phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinase 1/2 (ERK1/2), and Ca2+ signaling, and correlated with Bcl-X(L) and Bcl-2 up-regulation as well as Ser136-Bad phosphorylation. Unexpectedly, neither phagocytosis nor binding of apoptotic debris to the phagocyte was necessary to induce protection. Surprisingly, apoptotic cells released sphingosine-1-phosphate (S1P), mainly derived from sphingosine kinase 2, as a survival messenger. This points to an active role of apoptotic cells in preventing cell destruction in their neighborhood, with implications for innate immunity and inflammation.
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PMID:Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate. 1669 Sep 65

Given a previous report that Bcl-w is expressed in gastric cancer cells, particularly in those of an infiltrative morphology, we investigated whether Bcl-w expression influences the invasiveness of gastric cancer cells. To accomplish this, Bcl-w was overexpressed in adherent types of gastric adenocarcinoma cell lines, and this was found to result in an increase in their migratory and invasive potentials. These effects were not induced when Bcl-2 was overexpressed in the same cell types. Consistently, Bcl-w, but not Bcl-2, overexpression increased matrix metalloproteinase-2 (MMP-2) expression, and synthetic or natural inhibitors of MMP-2 abolished Bcl-w-induced cell invasion. Bcl-w overexpression also activated phosphoinositide 3-kinase (PI3K), Akt, and Sp1, and the blocking effects of each of these components using pharmacologic inhibitors, dominant-negative mutants, or small interfering RNA abolished the ability of Bcl-w to induce MMP-2 and cell invasion. The inhibition of PI3K/Akt signaling also prevented Sp1 activation. Overall, our data suggest that Bcl-w, which was previously shown to enhance gastric cancer cell survivability, also promotes their invasiveness by inducing MMP-2 expression via the sequential actions of PI3K, Akt, and Sp1.
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PMID:Bcl-w promotes gastric cancer cell invasion by inducing matrix metalloproteinase-2 expression via phosphoinositide 3-kinase, Akt, and Sp1. 1670 18

Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. We have previously reported that glucan phosphate (GP) significantly increased survival in a murine model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we examined the effect of GP on cardiac dysfunction in CLP-induced septic mice. GP was administered to ICR/HSD mice 1 h before induction of CLP. Sham surgically operated mice served as control. Cardiac function was significantly decreased 6 h after CLP-induced sepsis compared with sham control. In contrast, GP administration prevented CLP-induced cardiac dysfunction. Macrophage migration inhibitory factor (MIF) has been implicated as a major factor in cardiomyocyte apoptosis and cardiac dysfunction during septic shock. CLP increased myocardial MIF expression by 88.3% (P < 0.05) and cardiomyocyte apoptosis by 7.8-fold (P < 0.05) compared with sham control. GP administration, however, prevented CLP-increased MIF expression and decreased cardiomyocyte apoptosis by 51.2% (P < 0.05) compared with untreated CLP mice. GP also prevented sepsis-caused decreases in phospho-Akt, phospho-GSK-3beta, and Bcl-2 levels in the myocardium of septic mice. These data suggest that GP treatment attenuates cardiovascular dysfunction in fulminating sepsis. GP administration also activates the phosphoinositide 3-kinase/Akt pathway, decreases myocardial MIF expression, and reduces cardiomyocyte apoptosis.
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PMID:Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice. 1676 37

Our previous studies showed that oridonin could induce apoptosis in HeLa cells; and in this study, we further investigated autophagy induced by oridonin in HeLa cells and the relationship between apoptosis and autophagy. HeLa cells were exposed with oridonin after 3-methyladenine (3-MA) pre-culture, and we evaluated the growth inhibitory ratio, morphologic changes, DNA fragmentation, proteins expression as well as autophagic and apoptotic levels. Oridonin inhibited the proliferation of HeLa cells in vitro and induced autophagy. Oligonucleosomal fragementation of DNA as well as increased activities of Bax proteins were induced by oridonin, but the expression of p-Bcl-2 protein was reduced. In the condition of oridonin-treatment, when the inhibitor of phosphoinositide 3-kinase (PI3K), wortmannin, was applied, the autophagic level was significantly decreased, while the apoptotic level was increased, indicating that PI3K is a key regulator of both autophagy and apoptosis. Akt, down-stream factor of PI3K, was activated in autophagic process but suppressed in apoptosis in this study. In addition, when autophagy was blocked by 3-MA, the expression of SIRT-1 was decreased, indicating SIRT-1 contributed to autophagy. Taken together, oridonin simultaneously induced HeLa cell both apoptosis and autophagy in HeLa cells, and inhibition of autophagy contributes to upregulation of apoptosis.
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PMID:Augmentation of oridonin-induced apoptosis observed with reduced autophagy. 1686 22

Numerous studies have demonstrated the neuroprotective effects of estrogen in experimental cerebral ischemia. To investigate molecular mechanisms of estrogen neuroprotection in global ischemia, immunoblotting, immunohistochemistry and Nissel-staining analysis were used. Our results showed that chronic pretreatment with beta-estradiol 3-benzoate (E2) enhanced Akt1 activation and reduced the activation of mixed-lineage kinase 3 (MLK3), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase 1/2 (JNK1/2) in the hippocampal CA1 subfield during reperfusion after 15 min of global ischemia. In addition, E2 reduced downstream JNK nuclear and non-nuclear components, c-Jun and Bcl-2 phosphorylation and Fas ligand protein expression induced by ischemia/reperfusion. Administration of phosphoinositide 3-kinase (PI3K) inhibitor LY 294,002 prevented both activation of Akt1 and inhibition of MLK3, MKK4/7 and JNK1/2. The interaction between ERalpha and the p85 subunit of PI3K was also examined. E2 and antiestrogen ICI 182,780 promoted and prevented this interaction, respectively. Furthermore, ICI 182,780 blocked both the activation of Akt1 and the inhibition of MLK3, MKK4/7 and JNK1/2. Photomicrographs of cresyl violet-stained brain sections showed that E2 reduced CA1 neuron loss after 5 days of reperfusion, which was abolished by ICI 182,780 and LY 294,002. Our data indicate that in response to estrogen, ERalpha interacts with PI3K to activate Akt1, which may inhibit the MLK3-MKK4/7-JNK1/2 pathway to protect hippocampal CA1 neurons against global cerebral ischemia in male rats.
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PMID:Inhibition of MLK3-MKK4/7-JNK1/2 pathway by Akt1 in exogenous estrogen-induced neuroprotection against transient global cerebral ischemia by a non-genomic mechanism in male rats. 1706 55


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