UNIPROT:P10415 - FACTA Search

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer is one of the most common cancers in men and it is the second leading cause of cancer related death in men in the United States. Recent dietary and epidemiological studies have suggested the benefit of dietary intake of fruits and vegetables in lowering the incidence of prostate cancer. A diet rich in fruits and vegetables provides phytochemicals, particularly indole-3-carbinol (I3C), which may be responsible for the prevention of many types of cancer, including hormone-related cancers such as prostate. Studies to elucidate the role and the molecular mechanism(s) of action of I3C in prostate cancer, however, have not been conducted. In the current study, we investigated whether I3C had any effect against prostate cancer cells and, if so, attempts were made to identify the potential molecular mechanism(s) by which I3C elicits its biological effects on prostate cancer cells. Here we report for the first time that I3C inhibits the growth of PC-3 prostate cancer cells. Induction of G1 cell cycle arrest was also observed in PC-3 cells treated with I3C, which may be due to the observed effects of I3C in the up-regulation of p21(WAF1) and p27(Kip1) CDK inhibitors, followed by their association with cyclin D1 and E and down-regulation of CDK6 protein kinase levels and activity. The induction of p21(WAF1) appears to be transcriptionally upregulated and independent of the p53 responsive element. In addition, I3C inhibited the hyperpohosphorylation of the Retinoblastoma (Rb) protein in PC-3 cells. Induction of apoptosis was also observed in this cell line when treated with I3C, as measured by DNA laddering and poly (ADP-ribose) polymersae (PARP) cleavage. We also found an up-regulation of Bax, and down-regulation of Bcl-2 in I3C-treated cells. These effects may also be mediated by the down-regulation of NF-kappaB observed in I3C treated PC-3 cells. From these results, we conclude that I3C inhibits the growth of PC-3 prostate cancer cells by inducing G1 cell cycle arrest leading to apoptosis, and regulates the expression of apoptosis-related genes. These findings suggest that I3C may be an effective chemopreventive or therapeutic agent against prostate cancer.
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PMID:Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. 1142 Jul 5

A novel reagent, FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride), has been shown to induce a significant decrease of lymphocytes and lymphoma cells and is expected to be a potent immunosuppressant and anti-tumor drug. The decrease in lymphocytes and lymphoma cells is mainly the result of FTY720-induced apoptosis. FTY720 directly affects mitochondria and induces cell death. Moreover, FTY720 activates protein phosphatase (PP) 2A and affects anti-apoptotic intracellular signal transduction proteins to attenuate the anti-apoptotic effect. In this study, we examined the relationship between FTY720-induced apoptosis and cell cycle regulation. FTY720 induced apoptosis significantly at the G0 / G1 phase and caused G0 / G1 cell cycle arrest of the human lymphoma cell lines HL-60RG and Jurkat. Simultaneously, retinoblastoma protein (pRB) was dephosphorylated, suggesting that dephosphorylation of pRB was related to FTY720-induced G0 / G1 cell cycle arrest. Because this dephosphorylation was completely blocked by a specific PP1 / 2A inhibitor, okadaic acid, it appears that FTY720-activated PP2A is essential for FTY720-induced cell cycle arrest. FTY720-induced apoptosis was inhibited by Bcl-2 overexpression in Jurkat cells, but this did not prevent FTY720-induced cell cycle arrest, suggesting that the mechanism of FTY720-induced cell cycle arrest is independent of the mechanism of FTY720-induced apoptosis. These two independent pathways strengthen the effect of FTY720.
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PMID:Coordinate involvement of cell cycle arrest and apoptosis strengthen the effect of FTY720. 1142 58

Apoptosis is an integral part of neural development. To elucidate the importance of programmed cell death on cell lineage determination we utilized murine PCC7-Mzl cells, a model system for neural differentiation. Treatment of pluripotent PCC7-Mzl stem cells with 0.1 microM all-trans retinoic acid (RA) causes a cease of proliferation and an initiation of differentiation into neurons, glial cells and fibroblasts. Simultaneously, a fraction of the cell culture (ca. 25%) dies within 24 h by apoptosis. We transfected PCC7-Mzl cells with the human bcl-2 cDNA and generated PCC7-Mz-Bcl-2 cell lines expressing two- to tenfold higher levels of Bcl-2 than parental cells. Overexpression of Bcl-2 resulted in hypophosphorylation of the retinoblastoma (Rb) protein and consequently prolonged the doubling time of the culture from 18 h to 23 h. RA-induced apoptosis was drastically reduced to 3 to 15% depending on the level of Bcl-2 expression. RA-induced caspase activation, cytochrome c release from the mitochondria to the cytosol and DNA fragmentation was completely blocked. Furthermore, treating Bcl-2 cultures with ceramide (10 microM), a second messenger mediating the RA-initiated death signal in parental cells, no longer caused DNA laddering. Bcl-2 overexpression did not interfere with the potential of PCC7-Mz cells to develop into neurons, glial cells and fibroblasts. However, the relative distribution of cell types in the culture was shifted such that the fraction of neurons was reduced to half (from 60 to 30%) with a concomitant increase in the number of glial and fibroblastoid cells. Furthermore, Bcl-2-overexpressing neurons, but not neurons of parental or mock-transfected PCC7-Mzl cultures, were able to grow as single cells.
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PMID:Differentiation-associated apoptosis of neural stem cells is effected by Bcl-2 overexpression: impact on cell lineage determination. 1156 5

We have used a combination of vitamin A (all-trans-retinyl palmitate), 5-fluorouracil (5-FU) and radiation to treat human head and neck squamous cell carcinoma (HNSCC). This chemoradiotherapy is called "FAR therapy." In this study we examined the effects of all-trans-retinoic acid (ATRA), the active metabolite of vitamin A, and ATRA plus 5-FU on two HNSCC cell lines (YCU-N861 and YCU-H891) to gain insight into the molecular mechanisms of FAR therapy. ATRA at 1 mM (the order of concentration found in HNSCC tumors treated with FAR therapy) inhibited cell proliferation and caused G1 cell cycle arrest in both cell lines. This was associated with a decrease in cyclin D1, an increase in p27(Kip1) and a reduction in the hyperphosphorylated form of retinoblastoma protein (pRB). With YCU-N861 cells, ATRA also caused a decrease in Bcl-2 and Bcl-X(L) and an increase in Bax. Both ATRA and 5-FU activated c-Jun N-terminal kinase (JNK) 1 and the combination of both agents resulted in additive or synergistic activation of JNK1, and also enhanced the induction of apoptosis. The YCU-H891 cells, in which the epidermal growth factor receptor (EGFR)-signal transducer and activator of transcription 3 (Stat3) pathway is constitutively activated, were more resistant to treatments with ATRA, 5-FU and the combination of both agents than YCU-N861 cells. A dominant negative Stat3 construct strongly enhanced the cellular sensitivity of this cell line to 5-FU but not to ATRA. In addition there is evidence that activation of Stat3 is associated with cellular resistance to radiation in HNSCC. Therefore, the addition to FAR therapy of agents that inhibit activation of the Stat3 pathway may enhance the clinical response of patients with HNSCC to FAR therapy.
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PMID:The roles of JNK1 and Stat3 in the response of head and neck cancer cell lines to combined treatment with all-trans-retinoic acid and 5-fluorouracil. 1192 16

Extensive studies have implicated the role of dietary fatty acids in prostatecancer progression. Platelet-type 12-Lipoxygenase (12-LOX) has beenshown to regulate growth, metastasis, and angiogenesis of prostate cancer. The effect of two 12-LOX inhibitors, Baicalein and N-benzyl-N-hydroxy-5-phenylpentamide (BHPP), on the mechanisms controlling cell cycle progression and apoptosis were examined in two prostate cancer cell lines, PC3 and DU-145. Treatment with Baicalein or BHPP resulted in a dose-dependent decrease in cell proliferation, as measured by BrdUrd incorporation. This growth arrest was shown to be because of cell cycle inhibition at G0/G1, and was associated with suppression of cyclin D1 and D3 protein levels. PC3 cells also showed a strong decrease in phosphorylated retinoblastoma (pRB) protein, whereas the other retinoblastoma-associated proteins, p107 and p130, were inhibited in DU-145 cells. Treatment with 12-hydroxyeicosatetraenoic acid in the presence of Baicalein blocked loss of pRB, whereas 12(S)-HETE alone induced pRB expression. Treatment with either Baicalein or BHPP resulted in significant apoptosis in both cell lines as measured by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling. DU-145 cells underwent apoptosis more rapidly than PC-3 cells. The mechanisms involved were decreased phosphorylation of Akt, loss of survivin and subsequent activation of caspase-3 and caspase-7 in each cell line, decreased Bcl-2 and Bcl-X(L) expression in DU-145, and a shift in Bcl-2/Bax levels favoring apoptosis in PC-3 cells. Addition of 12(S)-HETE protected both cell lines from Baicalein-induced apoptosis, whereas other LOX metabolites, 5(S)-HETE, or 15(S)-HETE did not. These results show that the 12-LOX pathway is a critical regulator of prostate cancer progression and apoptosis, by affecting various proteins regulating these processes. Therefore, inhibition of 12-LOX is a potential therapeutic agent in the treatment of prostate cancer.
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PMID:Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells. 1198 Jun 74

A clinically relevant dose (2.0 Gy) of ionizing radiation (IR) was employed to determine if subsequent exposure to the protein kinase C (PKC) and Chk 1 inhibitor UCN-01 for 24 h could abrogate IR-induced G2/M arrest and promote apoptosis in U937 leukemic cells ectopically expressing Bcl-2 (U937/Bcl-2). To this end, empty-vector control (U937/pCEP4) and U937/Bcl-2 cells were exposed to two UCN-01 concentrations following IR: i) a 50 nM concentration, which by itself was minimally toxic to both cell lines, and ii) a 150 nM concentration, which modestly induced apoptosis (e.g., ~19%) in control cells after 24 h. The effects of UCN-01 on IR responses were examined in relation to apoptosis induction, suspension culture growth inhibition, loss of clonogenic survival, and cell cycle perturbations. IR (2 Gy) alone minimally induced apoptosis in both U937 transfectant cell lines (e.g., <5% at 24 h in each case). Although UCN-01 failed to potentiate IR-mediated apoptosis at either early (e.g., 24 h) or late (e.g., 72 h) intervals, exposure to 50 or 150 nM UCN-01 resulted in a significant, albeit modest, reduction in proliferation and colony formation in irradiated U937/pCEP4 and U937/Bcl-2 cells. Despite failing to enhance apoptosis, UCN-01 treatment abrogated IR-induced G2/M arrest in both cell lines, an event associated with enhanced activation of cyclin-dependent kinase 1 (cdk1), promotion of G0/G1 arrest, and dephosphorylation of the retinoblastoma protein (pRb). Together, these findings indicate that exposure of U937 cells ectopically-expressing Bcl-2 to the combination of UCN-01 + IR leads to a further reduction in cell proliferation, and that this phenomenon appears to involve a non-apoptotic mechanism.
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PMID:7-hydroxystaurosporine (UCN-01) and ionizing radiation combine to inhibit the growth of Bcl-2-overexpressing U937 leukemia cells through a non-apoptotic mechanism. 1211 31

We show that mitogenic cells expressing T-type Ca(2+) channels (T-channels) are more sensitive to the antiproliferative effects of the drugs pimozide and mibefradil than cells without significant T-channel expression. The growth of Y79 and WERI-Rb1 retinoblastoma cells, as well as MCF7 breast cancer epithelial cells, all of which express T-channel current and mRNA for T-channel subunits, is inhibited by pimozide and mibefradil with IC(50) values between 0.6 and 1.5 microM. Proliferation of glioma C6 cells, which show little T-channel expression, is less sensitive to these drugs (IC(50) = 8 and 5 microM for pimozide and mibefradil, respectively). Neither drug seems to alter cell cycle or the expression of cyclins. Although this strong correlation between T-channel expression and growth inhibition exists, the following results suggest that the drugs inhibit cell growth via different cytotoxic pathways: 1) pimozide and mibefradil have additive effects on T-channel current inhibition, whereas the antiproliferative activity of the drugs together is synergistic; 2) an increase in the number of apoptotic Y79 and MCF7 cells and a decrease in the mRNA for the antiapoptotic gene Bcl-2 is detected only in pimozide-treated cells, whereas in mibefradil-treated cells, the toxicity is primarily necrotic; and 3) growth inhibition by mibefradil is reduced in Y79 cells transfected with T-channel antisense and in differentiated Y79 cells (which have decreased T-channel expression), but growth inhibition by pimozide is affected to a lesser extent. These results suggest that pimozide and mibefradil inhibit cell proliferation via different cytotoxic pathways and that in the case of pimozide, it is unlikely that this effect is mediated solely by T-channel inhibition.
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PMID:The Ca(2+) channel antagonists mibefradil and pimozide inhibit cell growth via different cytotoxic mechanisms. 1213 Jun 71

The simian virus 40 (SV40) large tumor (T) antigen is sufficient to transform cells in cultures and induce tumors in experimental animals. Transformation of primary cells in cultures requires both overcoming growth arrest by stimulating the cell cycle and blocking cell death activities presumably activated by oncogene-mediated hyperproliferation signals. The study presented here examined the ability of specific regions and activities of T antigen to modulate apoptosis in cells treated with the genotoxic agent 5-fluorouracil (5-FU). The results showed that the expression of full-length T antigen rendered rat embryo fibroblasts (REF) sensitive to 5-FU-induced apoptosis. Thus, neither the p53-binding region nor the Bcl-2 homology region of T antigen was sufficient to prevent cell death induced by the DNA-damaging agent. T-antigen-mediated sensitization occurred independently of retinoblastoma protein or p53 and p300 binding. An N-terminal segment containing the first 127 T-antigen amino acids (T1-127) was sufficient to sensitize cells. A C-terminal segment consisting of T-antigen amino acids 251 to 708 (T251-708) also sensitized cells to 5-FU-induced apoptosis. This sensitization did not occur when T251-708 was targeted to the nucleus by inclusion of the SV40 nuclear localization signal. The introduction of mutations into the T-antigen J domain resulted in mutation-specific and variable inhibition of apoptosis. This result suggested that either the structural or the functional integrity of the J domain is required to sensitize cells to apoptosis. Treatment of REF or REF expressing full-length T antigen, an N-terminal segment, or T251-708 resulted in increased expression of the p53-responsive MDM2 gene; apoptosis occurred through a p53-dependent pathway, as p53-null cells expressing these T antigens were resistant to 5-FU-induced apoptosis. Possible mechanisms involved in sensitizing cells to a p53-dependent apoptosis pathway in spite of the ability of T antigen to bind and inactivate the transcriptional transactivating activity of p53 are discussed.
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PMID:Simian virus 40 large T antigen and two independent T-antigen segments sensitize cells to apoptosis following genotoxic damage. 1213 45

This study shows that in the glioblastoma hamster cell line HJC12 the retinoblastoma family member pRb2/p130 enhances gamma-radiation-induced cell death. In HJC12 cells the tetracycline-regulated expression of pRb2/p130 increased the percentage of gamma-radiation-induced apoptotic cells from 27 to 47%. pRb2/p130 overexpression was associated with the downregulation of the anti-apoptotic factor Bcl-2 and the upregulation of the steady-state protein levels of the pro-apoptotic transcription factor p73. In particular, RT-PCR showed a significant increase in the expression of the p73delta isoform when pRb2/p130 was overexpressed. The ability of pRb2/p130 to modulate apoptosis was not associated with its role in mediating G0/G1 arrest during cell cycle progression. Our data suggest a role for pRb2/p130 in glioblastoma gamma-radiation-induced cell death, indicating that the antitumoral action of pRb2/p130 can regulate both inhibition of cell cycle progression and induction of cell death.
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PMID:pRb2/p130 promotes radiation-induced cell death in the glioblastoma cell line HJC12 by p73 upregulation and Bcl-2 downregulation. 1218 89

Cross-linking of the B cell antigen receptor (BCR) on germinal center B cells can induce growth arrest and apoptosis, thereby eliminating potentially autoreactive B cells. Using the Burkitt lymphoma cell line Ramos as a model, we studied the commitment to apoptosis following growth arrest, as well as how triggering of CD40 or addition of tumor necrosis factor (TNF)-alpha can interfere to block cell death. Both BCR triggering and direct induction of growth arrest by sodium butyrate (n-But) caused hypophosphorylation of the retinoblastoma protein (pRb), followed by apoptosis. Interestingly, although CD40 ligation or TNF-alpha efficiently prevented BCR-induced and n-But-induced apoptosis, these co-stimuli did not inhibit, but rather augmented, growth arrest. Analysis of cell cycle regulators showed that each apoptotic and T(h) stimulus distinctly affected cyclins or cyclin-dependent kinase inhibitors, indicating that growth arrest can be uncoupled from apoptosis. BCR ligation and growth arrest activated the intrinsic or mitochondrial route of apoptosis. CD40 ligation and TNF-alpha prevented release of cytochrome c and activation of caspase-3, which could not be explained by effects on the expression of Bcl-2, Bcl-x(L) or Bax. Finally, the onset of BCR-induced apoptosis occurred after 10-12 h and addition of CD40 mAb or TNF-alpha at that point still prevented further execution of apoptosis. We conclude that in mature B cells apoptosis is not an obligatory event following growth arrest. Instead, commitment to apoptosis can be rapidly controlled by T cells via CD40 ligand and TNF-alpha, downstream of the pRb-regulated restriction point of the cell cycle, but prior to mitochondrial cytochrome c release.
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PMID:Prevention of B cell antigen receptor-induced apoptosis by ligation of CD40 occurs downstream of cell cycle regulation. 1220 95

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