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 PTEN tumor suppressor gene modulates cell growth and survival known to be regulated by the activation of the transcription factor NFkappaB, suggesting PTEN might affect the NFkappaB activation pathway. We found that PTEN inhibited NFkappaB activation induced by TNF. The suppression of NFkappaB activation correlated with sequential inhibition of the tumor necrosis factor-induced expression of NFkappaB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin) gene products. Downregulation of the antiapoptotic genes by PTEN increased TNF-induced apoptosis, as indicated by caspase activation, TUNEL, annexin staining, and esterase assay. We conclude that the ectopic expression of PTEN enhances TNF-induced apoptosis and downregulates the proliferation of glioma cells through the suppression of various molecules including NFkappaB, and various mediators of cellular survival and proliferation, and that this targets might be essential for its central role in the growth and survival of glioma cancer cells.
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PMID:PTEN enhances TNF-induced apoptosis through modulation of nuclear factor-kappaB signaling pathway in human glioma cells. 1701 14

Preeclampsia is often accompanied by hypoxia of the placenta and this condition induces apoptosis in trophoblastic cells. The aim of this study was to characterize global changes of apoptosis-related proteins induced by hypoxia in trophoblastic cells so as to clarify the mechanism of hypoxia-induced apoptosis by using the PoweBlot, an antibody-based Western array. Human choriocarcinoma cell line JAR was cultured for 24 hours under aerobic and hypoxic conditions. Hypoxia induced apoptosis accompanied by increased expression of Bcl-x, Caspase-3 and -9, Hsp70, PTEN, and Bag-1. Bad, pan-JNK/SAPK-1, Bcl-2, Bid, and Caspase-8 showed decreased expression. Hypoxia-induced apoptosis was increased with the transfection of a bag-1 antisense oligonucleotide. The bag-1 antisense oligonucleotide affected the expression of Bid, Bad, Bcl-2, JNK, and phosphorylated JNK, although expression of PTEN and Bcl-X did not change. Bag-1 may inhibit apoptosis by suppressing the expression of Bid and Bad. It may also enhance apoptosis by inhibiting the expression of Bcl-2 and by modulating phosphorylation of JNK. Both mitochondrial and stress-activated apoptosis pathways played important roles in the hypoxia induced cell death of trophoblastic cells. These findings will contribute to establish new approach to detect hypoxic stress of the placenta, which leads to preeclampsia and other hypoxia-related obstetrics complications.
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PMID:Proteomic analysis of mechanisms of hypoxia-induced apoptosis in trophoblastic cells. 1729 80

Phosphatidylinositol 3-kinase/AKT1 pathway was an important intracellular pathway that was frequently activated in cancer cells. In the present study, we constructed the siRNA eukaryotic expression vectors of AKT1 and transfected them into AGS cells to examine whether the down-regulation of AKT1 increased cell sensitivity towards chemotherapeutic drugs. After transfection, the expression of AKT1 was dramatically decreased in AKT1 siRNA transfectants compared with that in parental cells and empty vector control cells. The down-regulation of AKT1 could significantly enhance the sensitivity of AGS cells to vincristine, adriamycin, 5-fludrouracil and cisplatin. AKT1 siRNA could significantly down-regulate the expression of Bcl-2, and up-regulate the expression of Bax, but not alter the expression of PTEN in gastric cancer cells. These observations suggested that the siRNA constructs of AKT1 we obtained could effectively down-regulate the expression of AKT1 and reverse the resistant phenotype of gastric cancer cells. The further study of the biological functions of AKT1 may be helpful for understanding the mechanisms of multidrug resistance of gastric cancer and developing possible strategies to treat gastric cancer.
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PMID:Reversal of multidrug resistance of gastric cancer cells by downregulation of Akt1 with Akt1 siRNA. 1731 Aug 52

A survival kinase, Akt, is a downstream factor in the phosphatidylinositide-3'-kinase-dependent pathway, which mediates many biological responses including glucose uptake, protein synthesis and the regulation of proliferation and apoptosis, which is assumed to contribute to acquisition of malignant properties of human cancers. Here we find that an anti-tumor antibiotic, tetrocarcin A, directly induces apoptosis of human breast cancer cells. The apoptosis is accompanied by the activation of a proteolytic cascade of caspases including caspase-3 and -9, and concomitantly decreases phosphorylation of Akt, PDK1, and PTEN, a tumor suppressor that regulates the activity of Akt through the dephosphorylation of polyphosphoinositides. Tetrocarcin A affected neither expression of Akt, PDK1, or PTEN, nor did it affect the expression of Bcl family members including Bcl-2, Bcl-X(L), and Bax. These results suggest that tetrocarcin A could be a potent chemotherapeutic agent for human breast cancer targeting the phosphatidylinositide-3'-kinase/Akt signaling pathway.
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PMID:Apoptosis and inactivation of the PI3-kinase pathway by tetrocarcin A in breast cancers. 1735 May 98

To investigate whether PTEN can augment doxorubicin-induced apoptosis in PTEN-null Ishikawa cells. We previously demonstrated that Ishikawa cells do not possess functional PTEN protein because of protein truncations. Clones expressing the steady-state level of the PTEN protein from PTEN-null Ishikawa cells have been established and were used in this study. Doxorubicin is a commonly used anticancer drug in endometrial carcinoma. The cytotoxic effect of doxorubicin was evaluated using the methyl thiazoleterazolium (MTT) assay. We used the Hoechst 33258 staining to confirm the induction of apoptosis. Immunoprecipitation and Western blot analysis were performed to evaluate the effects of doxorubicin on phosphorylation of Bcl-2 antagonist of cell death (Bad) and protein kinase B (Akt/PKB). Doxorubicin induced death of all cell lines in a dose-dependent manner, but the death was more significant in PTEN-expressing clones than in parent Ishikawa cells. A low concentration of doxorubicin (0.1 muM) did not affect apoptosis in PTEN-null Ishikawa cells, but it induced apoptosis in PTEN-expressing clones. A high concentration (1 microM) induced apoptosis in all cell lines, but the percentages of apoptotic cells were higher in PTEN-expressing clones than in parent Ishikawa cells. In the clones, phospho-Akt/PKB and phospho-Bad (Ser-136) were downregulated. Doxorubicin reduced the levels of phospho-Akt/PKB and phospho-Bad (Ser-136) in all the cell lines, but the reduction was most significant in the PTEN-expressing clones. Our present results indicate that PTEN transfection significantly enhances doxorubicin chemosensitivity through effective induction of apoptosis by downregulation of the PI3K/Akt/PKB signaling pathway in Ishikawa cells.
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PMID:PTEN augments doxorubicin-induced apoptosis in PTEN-null Ishikawa cells. 1735 93

MicroRNAs (miRNAs) are a recently discovered class of endogenous, small, noncoding RNAs that regulate about 30% of the encoding genes of the human genome. However, the role of miRNAs in vascular disease is currently completely unknown. Using microarray analysis, we demonstrated for the first time that miRNAs are aberrantly expressed in the vascular walls after balloon injury. The aberrantly expressed miRNAs were further confirmed by Northern blot and quantitative real-time polymerase chain reaction. Modulating an aberrantly overexpressed miRNA, miR-21, via antisense-mediated depletion (knock-down) had a significant negative effect on neointimal lesion formation. In vitro, the expression level of miR-21 in dedifferentiated vascular smooth muscle cells was significantly higher than that in fresh isolated differentiated cells. Depletion of miR-21 resulted in decreased cell proliferation and increased cell apoptosis in a dose-dependent manner. MiR-21-mediated cellular effects were further confirmed in vivo in balloon-injured rat carotid arteries. Western blot analysis demonstrated that PTEN and Bcl-2 were involved in miR-21-mediated cellular effects. The results suggest that miRNAs are novel regulatory RNAs for neointimal lesion formation. MiRNAs may be a new therapeutic target for proliferative vascular diseases such as atherosclerosis, postangioplasty restenosis, transplantation arteriopathy, and stroke.
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PMID:MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. 1846 32

Phosphatidylinositol 3-kinase/Akt pathway is an important intracellular pathway that is frequently activated in cancer cells. The role of P-AKT in multidrug resistance of gastric cancer cells and the possible underlying mechanisms are here investigated. Up-regulation of P-AKT expression could confer resistance to both P-glycoprotein-related and P-glycoprotein-non-related drugs on AGS cells, and suppress adriamycin-induced apoptosis, along with decreased accumulation and increased releasing amount of adriamycin. P-AKT could significantly up-regulate the expression of Bcl-2, and down-regulate the expression of Bax, but not alter the expression of PTEN in gastric cancer cells. Inhibition of P-AKT expression could partially reverse P-AKT-mediated multidrug resistance and significantly up-regulate P53 expression, and down-regulate the expression of P-glycoprotein and the transcription of the multidrug resistance gene 1. Further studies of the biological functions of P-AKT may be helpful for understanding the mechanisms of multidrug resistance of gastric cancer and developing possible therapeutical strategies.
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PMID:Phospho Akt mediates multidrug resistance of gastric cancer cells through regulation of P-gp, Bcl-2 and Bax. 1772 7

Notch signalling plays an important role in hematopoiesis and in the pathogenesis of T-ALL. Notch is known to interact with Ras and PTEN/PI3K (phosphoinositide-3 kinase)/Akt pathways. We investigated the interaction of Notch with these pathways and the possible reciprocal regulation of these signalling systems in T-ALL cells in vitro. Our analyses indicate that the PI3K/Akt pathway is constitutively active in the four T-ALL cell lines tested. Akt phosphorylation was not altered by the sequestration of growth factors, that is, Akt activation seems to be less dependent on but not completely independent of growth factors, possibly being not subject to negative feedback regulation. PTEN expression was not detected in 3/4 cell lines tested, suggesting the loss of PTEN-mediated Akt activation. Inhibition of the PI3K/Akt pathway arrests growth and enhances apoptosis, but with no modulation of expression of Bax-alpha and Bcl-2 proteins. We analysed the relationship between Notch-1 and the PI3K/Akt signalling and show that inhibition of the Akt pathway changes Notch expression; Notch-1 protein decreased in all the cell lines upon treatment with the inhibitor. Our studies strongly suggest that Notch signalling interacts with PI3K/Akt signalling and further that this occurs in the absence of PTEN expression. The consequences of this to the signalling outcome are yet unclear, but we have uncovered a significant inverse relationship between Notch and PI3K/Akt pathway, which leads us to postulate the operation of a reciprocal regulatory loop between Notch and Ras-PI3K/Akt in the pathogenesis of T-ALL.
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PMID:Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells in vitro. 1784 43

PTEN is a tumor suppressor gene mutated in many human cancers. We generated a bronchioalveolar epithelium-specific null mutation of Pten in mice [SP-C-rtTA/(tetO)(7)-Cre/Pten(flox/flox) (SOPten(flox/flox)) mice] that was under the control of doxycycline. Ninety percent of SOPten(flox/flox) mice that received doxycycline in utero [SOPten(flox/flox)(E10-16) mice] died of hypoxia soon after birth. Surviving SOPten(flox/flox)(E10-16) mice and mice that received doxycycline postnatally [SOPten(flox/flox)(P21-27) mice] developed spontaneous lung adenocarcinomas. Urethane treatment accelerated number and size of lung tumors developing in SOPten(flox/flox) mice of both ages. Histological and biochemical examinations of the lungs of SOPten(flox/flox)(E10-16) mice revealed hyperplasia of bronchioalveolar epithelial cells and myofibroblast precursors, enlarged alveolar epithelial cells, and impaired production of surfactant proteins. Numbers of bronchioalveolar stem cells (BASCs), putative initiators of lung adenocarcinomas, were increased. Lungs of SOPten(flox/flox)(E10-16) mice showed increased expression of Spry2, which inhibits the maturation of alveolar epithelial cells. Levels of Akt, c-Myc, Bcl-2, and Shh were also elevated in SOPten(flox/flox)(E10-16) and SOPten(flox/flox)(P21-27) lungs. Furthermore, K-ras was frequently mutated in adenocarcinomas observed in SOPten(flox/flox)(P21-27) lungs. These results indicate that Pten is essential for both normal lung morphogenesis and the prevention of lung carcinogenesis, possibly because this tumor suppressor is required for BASC homeostasis.
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PMID:Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice. 1790 29

The Akt pathway is one of the most common molecular alterations in various human malignancies. However, its involvement in nasopharyngeal carcinoma (NPC) tumorigenesis has not been well established. In this study, the status of Akt activation and expression of its upstream and downstream molecules was investigated in 64 NPC and 38 non-malignant nasopharyngeal tissues by immunohistochemistry. The hotspot mutations of PIK3CA, encoding the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), were also determined in 25 of these NPC tissues. No hotspot mutations were found in any of the samples tested. Akt was activated in 27 (42.2%) and 23 (35.9%) NPCs, as indicated by p-Akt (Thr308) and p-Akt (Ser473) immunoreactivity, respectively. PTEN loss did not correlate statistically with activated Akt. However, a positive correlation was observed between activated Akt and phospho-epidermal growth factor receptor (p-EGFR), suggesting that the EGFR signaling might be one of the upstream regulators of the Akt pathway. The phosphorylation of forkhead (FKHR) and Bcl-2 associated death domain (BAD), but not mammalian target of rapamycin and glycogen synthase kinase-3beta, was significantly correlated with Akt activation. This implies that Akt promotes cell proliferation (as estimated by Ki-67) and survival, at least, through the inactivation of FKHR and BAD in NPC. Our data revealed that the EGFR/PI3K/Akt signaling pathway is important in NPC pathogenesis and that PIK3CA hotspot mutations are rare in NPC.
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PMID:Overexpression of phospho-Akt correlates with phosphorylation of EGF receptor, FKHR and BAD in nasopharyngeal carcinoma. 1820 77


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