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 3-phosphoinositide-dependent kinase-1 (PDK1) plays an important role in the regulation of cellular responses in multiple organs by mediating the phosphoinositide 3-kinase (PI3-K) signaling pathway through activating AGC kinases. Here we defined the role of PDK1 in controlling cardiac homeostasis. Cardiac expression of PDK1 was significantly decreased in murine models of heart failure. Tamoxifen-inducible and heart-specific disruption of Pdk1 in adult mice caused severe and lethal heart failure, which was associated with apoptotic death of cardiomyocytes and beta(1)-adrenergic receptor (AR) down-regulation. Overexpression of Bcl-2 protein prevented cardiomyocyte apoptosis and improved cardiac function. In addition, PDK1-deficient hearts showed enhanced activity of PI3-Kgamma, leading to robust beta(1)-AR internalization by forming complex with beta-AR kinase 1 (betaARK1). Interference of betaARK1/PI3-Kgamma complex formation by transgenic overexpression of phosphoinositide kinase domain normalized beta(1)-AR trafficking and improved cardiac function. Taken together, these results suggest that PDK1 plays a critical role in cardiac homeostasis in vivo by serving as a dual effector for cell survival and beta-adrenergic response.
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PMID:PDK1 coordinates survival pathways and beta-adrenergic response in the heart. 1942 9

Mesothelin, a secreted protein, is overexpressed in some cancers, but its exact function remains unclear. The aim of the present study was to evaluate the possible function of mesothelin. Real-time PCR, RT (reverse transcription)-PCR, cytotoxicity assays, proliferative assays, apoptotic assays by Hoechst staining, detection of active caspases 3 and 7 by flow cytometric analysis, and immunoprecipitation and immunoblotting were performed. Cancer tissues in paclitaxel-resistant ovarian cancer patients expressed higher levels of mesothelin as assessed using real-time PCR than paclitaxel-sensitive ovarian cancer patients (the mean crossing point value change of mesothelin was 26.9+/-0.4 in the resistant group and 34.3+/-0.7 for the sensitive group; P<0.001). Mesothelin also protected cells from paclitaxel-induced apoptosis. The protein expression of Bcl-2 family members, such as Bcl-2 and Mcl-1, was significantly increased regardless of whether cells were treated with exogenous mesothelin or were mesothelin-transfectants. Furthermore, mesothelin-treated cells revealed rapid tyrosine phosphorylation of the p85 subunit of PI3K (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) 1/2 for enhancing MAPK (mitogen-activated protein kinase) activity. The anti-apoptotic ability was suppressed and the expression of Bcl-2 family in response to mesothelin was altered by inhibiting PI3K activity, but not by inhibiting MAPK activity. Thus mesothelin can inhibit paclitaxel-induced cell death mainly by involving PI3K signalling in the regulation of Bcl-2 family expression. Mesothelin is a potential target in reducing resistance to cytotoxic drugs.
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PMID:Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway. 1974 65

Topical used glucocorticoids (GC) represent an important class of steroid hormones for the treatment of a broad range of acute or chronic inflammatory diseases. Most interestingly, GC exert a pronounced anti-apoptotic effect in primary human fibroblasts whereas in variety of hematopoietic cells a pro-apoptotic effect is visible. Recently, it has been discovered that in human fibroblasts the GC dexamethasone (Dex) exerts its protection from programmed cell death via the formation of the lipid mediator sphingosine 1-phosphate (S1P) followed by an activation of the S1P(3)-receptor subtype. In the present study, the molecular mechanism of Dex to protect human fibroblasts from apoptosis was elucidated. Thereupon, Dex not only mediates its anti-apoptotic effect via activation of phosphoinositide 3-kinase (PI3K)/Akt signalling but also includes an involvement of the Bcl-2 family protein Bcl(XL). Most interestingly, the use of S1P(3)-knockout fibroblasts revealed that the S1P(3)-receptor subtype is crucial for activation of PKB/Akt as well as Bcl(XL) by Dex.
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PMID:Dexamethasone protects human fibroblasts from apoptosis via an S1P3-receptor subtype dependent activation of PKB/Akt and Bcl XL. 2000 55

Although thiazolidinediones (TZDs) are potent promoters of adipogenesis in the preadipocyte, they induce apoptosis in several other cell types, such as cancer cells, endothelial cells and T-lymphocytes. In this study, we investigated the proapoptotic effect of TZDs in mature 3T3-L1 adipocytes, which express high levels of the peroxisome proliferator-activated receptor-gamma (PPARgamma) protein. Apoptosis was induced in mature 3T3-L1 adipocytes by treatment with troglitazone, pioglitazone or prostaglandin J2, and could be blocked by the PPARgamma antagonist GW9662. Treatment with PPARgamma agonists also decreased Akt-1 protein and phosphorylation levels without affecting phosphoinositide 3-kinase and PTEN. Further analysis indicated that in troglitazone-treated 3T3-L1 adipocytes, Bad phosphorylation and Bcl-2 protein levels were reduced, and Bax translocation to the mitochondria was increased. Subsequently, cytochrome c release and caspase-3 cleavage were observed. TZD-induced adipocyte apoptosis could be blocked by the caspase-3 inhibitor Ac-DEVD-CHO or by overexpression of Bcl2. In cultured rat primary adipocytes, similar apoptosis-inducing effects of troglitazone were also observed. Thus, TZDs promote apoptosis in adipocytes through a PPARgamma-dependent pathway. This apoptosis is mediated by the inhibition of Akt-1, which decreases Bad phosphorylation and activates the mitochondrial apoptotic pathway.
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PMID:3T3-L1 adipocyte apoptosis induced by thiazolidinediones is peroxisome proliferator-activated receptor-gamma-dependent and mediated by the caspase-3-dependent apoptotic pathway. 2005 Sep 18

Previous reports suggest that, in addition to its therapeutic effects, ionizing radiation (IR) increases the invasiveness of surviving cancer cells. Here, we demonstrate that this activity of IR in lung cancer cells is mediated by a signaling pathway involving p38 kinase, phosphoinositide 3-kinase, Akt, and matrix metalloproteinase (MMP-2). The invasion-promoting doses of IR also increased and reduced the levels of vimentin and E-cadherin, respectively, both of which are markers for the epithelial-mesenchymal transition (EMT). Interestingly, all of these malignant actions of IR were mimicked by the overexpression of Bcl-X(L), a pro-survival member of the Bcl-2 family, in lung cancer cells. Moreover, both RNA and protein levels of Bcl-X(L) were elevated upon irradiation of the cells, and the prevention of this event using small-interfering RNAs of Bcl-X(L) reduced the ability of IR to promote invasion signals and EMT-associated events. This suggests that Bcl-X(L) functions as a signaling mediator of the malignant effects of IR. It was also demonstrated that IR enhances signal transducer and activator of transcription 3 (STAT3) phosphorylation, and the reduction of STAT3 levels via RNA interference prevented IR-induced Bcl-X(L) accumulation, and thus all the tested Bcl-X(L)-dependent events. Overall, the data suggest that IR induces Bcl-X(L) accumulation via STAT3, which then promotes cancer cell invasion and EMT-associated markers. Our findings demonstrate a novel function of Bcl-X(L) in cancer, and also advance our understanding of the malignant actions of IR significantly.
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PMID:Bcl-XL and STAT3 mediate malignant actions of gamma-irradiation in lung cancer cells. 2033 35

Toxigenic Pasteurella multocida strains produce a 146 kDa protein toxin (PMT) that due to its high mitogenic activity is thought to possess carcinogenic properties. PMT affects several signal transduction pathways related to cancer by constitutively stimulating heterotrimeric G proteins. Downstream of Galpha(q), Galpha(13) and Galpha(i), the toxin activates the small GTPase RhoA, MAP kinases and signal transducer and activator of transcription (STAT) proteins. PMT also stimulates Gbetagamma signalling and activates phosphoinositide 3-kinase (PI3K)-related pathways, which play a crucial role in proliferation and apoptosis. We show that treatment of HEK293 cells with PMT inhibits staurosporine-mediated apoptosis through PI3K-dependent phosphorylation of Akt and constitutive expression of Pim-1 kinase. Simultaneous activation of these survival kinases allows the activation of pro-survival pathways, such as GSK3beta, Mcl-1, Bcl-xL and Bcl-2, as well as the downregulation of apoptotic signals by Bax or Puma. Only the combined inhibition of Akt and Pim reverses the PMT-induced protection from staurosporine-induced apoptosis. In addition, we show that apoptosis induced by tumour chemotherapeutic agents is blocked by PMT in human cancer cell lines. Our data indicate that PMT is a highly potent anti-apoptotic agent, which supports the view of a carcinogenic potential of the toxin.
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PMID:Pasteurella multocida toxin is a potent activator of anti-apoptotic signalling pathways. 2033 38

Increasing evidence suggests that glucagon-like peptide-1 (GLP-1), an incretin hormone of current interest in type 2 diabetes, is neuroprotective in both cell culture and animal models. To characterize the neuroprotective properties of GLP-1 and associated underlying mechanisms, we over-expressed the GLP-1 receptor (GLP-1R) on human neuroblastoma SH-SY5Y cells to generate a neuronal culture system featuring enhanced GLP-1R signaling. In GLP-1R over-expressing SH-SY5Y (SH-hGLP-1R#9) cells, GLP-1 and the long-acting agonist exendin-4 stimulated cell proliferation and increased cell viability by 2-fold at 24 h at physiologically relevant concentrations. This GLP-1R-dependent action was mediated via the protein kinase A and phosphoinositide 3-kinase signaling pathways, with the MAPK pathway playing a minor role. GLP-1 and exendin-4 pretreatment dose-dependently protected SH-hGLP-1R#9 cells from hydrogen peroxide (H(2)O(2))- and 6-hydroxydopamine-induced cell death. This involved amelioration of elevated caspase 3 activity, down-regulation of pro-apoptotic Bax and up-regulation of anti-apoptotic Bcl-2 protein. In the presence of 6-hydroxydopamine, GLP-1's ability to lower caspase-3 activity was abolished with the phosphoinositide 3-kinase inhibitor, LY2940002, and partly reduced with the protein kinase A inhibitor, H89. Hence, GLP-1R mediated neurotrophic and anti-apoptotic actions co-contribute to the neuroprotective property of GLP-1 in neuronal cell cultures, and reinforce the potential therapeutic value of GLP-1R agonists in neurodegenerative disorders involving oxidative stress.
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PMID:Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells. 2037 30

The insulin-like growth factor I receptor (IGFIR) has emerged as a key therapeutic target in many human malignancies, including childhood cancers such as Ewing family tumors (EFT). In this study, we show that IGFIR is constitutively activated in EFTs and that the major catechin derivative found in green tea, (-)-epigallocatechin gallate (EGCG), can inhibit cell proliferation and survival of EFT cells through the inhibition of IGFIR activity. Treatment of EFT cell lines with EGCG blocked the autophosphorylation of IGFIR tyrosine residues and inhibited its downstream pathways including phosphoinositide 3-kinase-Akt, Ras-Erk, and Jak-Stat cascades. EGCG treatment was associated with dose- and time-dependent inhibition of cellular proliferation, viability, and anchorage-independent growth, as well as with the induction of cell cycle arrest and apoptosis. Apoptosis in EFT cells by EGCG correlated with altered expression of Bcl-2 family proteins, including increased expression of proapoptotic Bax and decreased expression of prosurvival Bcl2, Bcl-XL, and Mcl-1 proteins. Our results provide further evidence that IGFIR is an attractive therapeutic target in EFTs and that EGCG is an effective inhibitor of this receptor tyrosine kinase. EGCG may be a useful agent for targeting IGFIR, either alone or in combination, with other potentially more toxic IGFIR inhibitors for the management of EFTs.
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PMID:Inhibition of the insulin-like growth factor I receptor by epigallocatechin gallate blocks proliferation and induces the death of Ewing tumor cells. 2042 94

Autophagy is a regulated catabolic process triggered in cells deprived of nutrients or growth factors that govern nutrient uptake. Here, we report that autophagy is induced by cetuximab, a therapeutic antibody that blocks epidermal growth factor receptor function. Cancer cell treatment with cetuximab triggered autophagosome formation, conversion of microtubule-associated protein 1 light chain 3 from its cytoplasmic to membrane-associated form, and increased acidic vesicular organelle formation. Autophagy occurred when cetuximab inhibited the class I phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, but not when it inhibited only the mitogen-activated protein/extracellular signal-regulated kinase kinase/Erk pathway, and it was accompanied by decreased levels of hypoxia inducible factor-1 alpha (HIF-1alpha) and Bcl-2. Stable overexpression of a HIF-1alpha mutant prevented cetuximab-induced autophagy and decrease in Bcl-2 levels. Knockdown of autophagy regulator beclin 1 or cell treatment with autophagy inhibitor 3-methyladenine, a class III PI3K (hVps34) inhibitor, also inhibited cetuximab-induced autophagy. Furthermore, knockdown of beclin 1 or Atg7 or treatment with the lysosome inhibitor chloroquine sensitized cancer cells to cetuximab-induced apoptosis. Mechanistic analysis argued that cetuximab acted by promoting an association between beclin 1 and hVps34, which was inhibited by overexpression of Bcl-2. Our findings suggest that the autophagy protects cancer cells from the proapoptotic effects of cetuximab.
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PMID:The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex. 2063 5

Promoting human embryonic stem cell (hESC)-derived-neural progenitor survival in the pro-apoptotic niche is pivotal for stem cell replacement therapy. The present study was designed to investigate the protective effect of hepatocyte growth factor (HGF) on hESC-derived neural progenitor injured by hydrogen peroxide (H(2)O(2)) exposure. Treatment of hESC-derived neural progenitor cells with HGF prior to H(2)O(2) exposure conferred protective effect against oxidative stress-induced apoptosis. HGF treatment increased both phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation. However, selective inhibition of each pathway supported that the activation of PI3K/AKT, but not ERK1/2, provides survival advantage to the neural progenitor cells. Further investigation indicated that HGF pretreatment could attenuate the decrease of the expression of Bcl-2 protein induced by H(2)O(2), whereas the level of Bax was not affected. Additionally, we observed that H(2)O(2)-induced decrease of mitochondrial transmembrane potential, release of cytochrome c and increase of caspase-3 activation were alleviated by HGF pretreatment. These effects of HGF could be reversed by inhibition of the PI3K/Akt and ERKs pathways, indicating PI3K/Akt and ERKs signaling might be involved in HGF-mediated regulation of mitochondrial apoptotic pathway mediated by H(2)O(2). The neuroprotective effect of HGF might potentially be useful in stem cell-based therapies for neurodegenerative disorders.
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PMID:Hepatocyte growth factor protects human embryonic stem cell derived-neural progenitors from hydrogen peroxide-induced apoptosis. 2065 99


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