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 development and progression of epithelial cancers are the result of an imbalance in signals promoting and inhibiting cellular proliferation and apoptosis. The aim of this study is to evaluate the expression of cell-cycle and apoptosis regulators and correlate them with clinical outcome in the most frequent carcinomas, in order to establish common prognostic biomarkers independent of cancer origin. Using tissue microarrays (TMAs), we have analysed the immuno-expression of Ki-67, Bcl-2, Bax, cyclin D1, cyclin D3, CDK1, CDK2, CDK6, p16, p21, and p27 in a series of 205 carcinomas of the large bowel, breast, lung and prostate (80, 73, 37 and 15 cases, respectively). By univariate analysis, positivity for p27, p16 and Bcl-2 was associated with better overall survival (P<0.0135, P<0.0442 and P<0.0001, respectively). The risk of mortality was 2.3-fold greater in patients without Bcl-2 expression. TMA immunohistochemical analysis identified a subset of epithelial cancers with overlapping alterations in cell-cycle checkpoints, apoptosis regulators and tumour suppressor pathways. We found that in most common epithelial cancers, regardless of origin, Bcl-2 appears to be the key biological factor influencing clinical behaviour.
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PMID:Cell-cycle-associated markers and clinical outcome in human epithelial cancers: a tissue microarray study. 1627 50

Peptidylarginine deiminases (PADIs) convert peptidylarginine into citrulline via posttranslational modification. One member of the family, PADI4, plays an important role in immune cell differentiation and cell death. To elucidate the participation of PADI4 in haematopoietic cell death, we examine whether inducible overexpression of PADI4 enhances the apoptotic cell death. PADI4 reduced the viability in a dose- and time-dependent manner of human leukemia HL-60 cells and human acute T leukemia Jurkat cells. The apoptosis-inducing activities were determined by nuclear condensation, DNA fragmentation, sub-G1 appearance, loss of mitochondrial membrane potential (delta psi(m)), release of mitochondrial cytochrome c into cytoplasm and proteolytic activation of caspase 9 and 3. Following PADI4 overexpression, cells arrest in G1 phase significantly before their entrance into apoptotic cell death. PADI4 increases tumor suppressor p53 and its downstream p21 to control cell cycle. In the detections of protein expression and kinase activity, all protein levels of cyclin-dependent kinases (CDKs) and cyclins are not reduced except cyclin D, however, CDK2 (G1 entry S phase) and CDK1 (G2 entry M phase) enzyme activities are inhibited by conditionally inducible PADI4. p53 also expands its other downstream Bax to induce cytochrome c release from mitochondria. According to these data, we suggest that PADI4 induces apoptosis mainly through cell cycle arrest and mitochondria-mediated pathway. Furthermore, p53 features in PADI4-induced apoptosis by increasing intracellular p21 to control cell cycle and by Bax accumulation to decline Bcl-2 function, destroy delta psi(m), release cytochrome c to cytoplasm and activate the caspase cascade.
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PMID:Overexpression of peptidylarginine deiminase IV features in apoptosis of haematopoietic cells. 1650 57

Cyclin-dependent kinase 1 (CDK1) is a major component of the cell cycle progression engine. Recently, several investigations provided evidence demonstrating that unscheduled CDK1 activation may also be involved in apoptosis in cancerous cells. In this article, we demonstrate that X-ray irradiation induced G1 arrest in MOLT-4 lymphocytic leukemia cells, the arrest being accompanied by reduction in the activity of CDK2, but increased CDK1 activity and cell apoptosis in the G1 phase. Interestingly, this increase in CDK1 and apoptosis by ionizing radiation was prevented by pretreatment with the CDK1 inhibitor, roscovitine, suggesting that CDK1 kinase activity is required for radiation-induced apoptotic cell death in this model system. Furthermore, cyclin B1 and CDK1 were detected co-localizing and associating in G1 phase MOLT-4 cells, with the cellular lysates from these cells revealing a genotoxic stress-induced increase in CDK1 phosphorylation (Thr-161) and dephosphorylation (Tyr-15), as analyzed by postsorting immunoprecipitation and immunoblotting. Finally, X-irradiation was found to increase Bcl-2 phosphorylation in G1 phase cells. Taken together, these novel findings suggest that CDK1 is activated by unscheduled accumulation of cyclin B1 in G1 phase cells exposed to X-ray, and that CDK1 activation, at the wrong time and in the wrong phase, may directly or indirectly trigger a Bcl-2-dependent signaling pathway leading to apoptotic cell death in MOLT-4 cells.
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PMID:Unscheduled CDK1 activity in G1 phase of the cell cycle triggers apoptosis in X-irradiated lymphocytic leukemia cells. 1701 63

We have previously shown that the leukotriene B4 receptor antagonist, LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells both in vitro and in vivo. In the current study, we investigated the molecular mechanisms of LY293111-induced apoptosis and cell cycle arrest. Two human pancreatic cancer cell lines were used in this study, MiaPaCa-2 and AsPC-1. Cell cycle analysis by flow cytometry showed a dramatic increase in the percentage of apoptotic cells as well as S-phase arrest after treatment with 250 nmol/l LY293111 for up to 48 h. Western blotting indicated that LY293111 treatment induced cytochrome c release from the mitochondria into the cytosol, accompanied by caspase-9, caspase-7 and caspase-3 activation, and cleavage of poly ADP-ribose polymerase. Caspase-8 was not activated by LY293111. A decrease was found in the expression of the antiapoptotic proteins, Bcl-2 and Mcl-1, and an increase in the proapoptotic protein, Bax. LY293111 reduced the expression of CDK2, cyclin A and cyclin E, consistent with the S-phase arrest observed in these cells. The expression of cyclin-dependent kinase inhibitors, p21 and p27 was not affected by LY293111 treatment. In conclusion, LY293111 induces apoptosis in human pancreatic cancer cells through the mitochondria-mediated pathway. LY293111 also induces S-phase arrest with downregulation of CDK2, cyclin A and cyclin E. Blockade of leukotriene B4 metabolic pathway may provide a novel treatment for human pancreatic cancer.
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PMID:Leukotriene B4 receptor antagonist LY293111 induces S-phase cell cycle arrest and apoptosis in human pancreatic cancer cells. 1741 22

Mcl-1 is an antiapoptotic Bcl-2 family member that is highly regulated and when dysregulated contributes to cancer. The Mcl-1 protein is phosphorylated at multiple sites in response to different signaling events. Phosphorylations at Thr163 (by ERK) and Ser159 (by glycogen-synthase kinase 3beta) have recently been shown to slow and enhance, respectively, Mcl-1 protein turnover. Phosphorylation is also known to be stimulated at other, as-yet uncharacterized sites in the G2/M phase of the cell cycle. Using an S peptide-tagged Mcl-1 T163A mutant, Ser64 was identified as a novel Mcl-1 phosphorylation site by mass spectrometry. Immunoblotting demonstrated that phosphorylation at this site was maximal in cells in G2/M phase, was enhanced by tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) treatment, was blocked by inhibitors of CDK (but not ERK or glycogen-synthase kinase 3beta), and was stimulated in vitro by CDK 1, CDK2, and JNK1. The half-life of a nonphosphorylatable S64A Mcl-1 mutant was indistinguishable from that of the wild type polypeptide. In contrast, this mutant failed to protect cells from TRAIL-mediated apoptosis, whereas reconstitution with the phosphomimetic S64E Mcl-1 mutant rendered cells TRAIL-resistant. This anti-apoptotic phenotype of the S64E Mcl-1 mutant was also associated with enhanced binding to the proapoptotic proteins Bim, Noxa, and Bak. A pharmacological CDK inhibitor that reduced Ser64 phosphorylation also sensitized cells to TRAIL cytotoxicity. Collectively, these observations not only identify G2/M-associated phosphorylation at Ser64 as a critical determinant of the antiapoptotic activity of Mcl-1 but also elucidate a novel mechanism by which CDK1/2 inhibitors can enhance the effectiveness of the cytotoxic cytokine TRAIL.
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PMID:Serine 64 phosphorylation enhances the antiapoptotic function of Mcl-1. 1746 1

ZD6474 is a vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The present study was undertaken to investigate the direct antiproliferative effect of ZD6474 on human nasopharyngeal carcinoma (NPC) in vitro and the antitumor activity on NPC xenografts in vivo. Results indicated that ZD6474 treatment inhibited EGFR phosphorylation and led to a dose- and time-dependent decrease in NPC cell (CNE-1, CNE-2 and C666-1) proliferation. Further investigation demonstrated G0/G1 cell cycle arrest in all 3 cell lines, which was associated with an upregulation of p21 and/or p27, and downregulation of CDK4, CDK6 and CDK2. ZD6474 treatment also induced apoptosis in CNE-1 and CNE-2 cells. The apoptosis mechanisms involved reduction of Bcl-2 and/or Bcl-XL, induction of Bak and/or Bax, and activation of caspases-3, -9 and/or -8. The in vivo antitumor activity was evaluated in CNE-2 and C666-1 xenografted nude mice. Administration of ZD6474 (25-100 mg/kg/day, once-daily, p.o.) produced a dose-dependent inhibition of tumor growth and prolonged survival in both models. This study suggests that ZD6474 exerts direct antiproliferative effects on NPC cell lines in vitro by inducing G0/G1 arrest and apoptosis, and potent antitumor effects on NPC xenografts in vivo. It indicates that ZD6474 may offer a new and effective treatment for human NPC.
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PMID:Induction of cell cycle arrest and apoptosis in human nasopharyngeal carcinoma cells by ZD6474, an inhibitor of VEGFR tyrosine kinase with additional activity against EGFR tyrosine kinase. 1763 46

The effect of Bcl-2 on oncogenesis is complex and expression may either delay or accelerate oncogenesis. The pro-oncogenic activity is attributed to its well characterized anti-apoptotic function while the anti-oncogenic function has been attributed to its inhibition of cellular proliferation. Recent studies demonstrate that p27 may mediate the effects of Bcl-2 on cellular proliferation. We hypothesized that p27 may suppress tumor formation by Bcl-2 family members. To test this hypothesis, cell cycle inhibition and lymphoma development were examined in Lck-Bcl-2 and Lck-Bax38/1 transgenic mice deficient in p27. Strikingly, p27 deficiency synergistically cooperates with Bcl-2 to increase T cell hyperplasia and development of spontaneous T cell lymphomas. Within 1 year, >90% of these mice had developed thymic T cell lymphomas. This high penetrance contrasts with a one year incidence of <5% of thymic lymphoma in Lck-Bcl-2 or p27 -/- mice alone. In contrast, p27 deficiency had no effect on tumor formation in Lck-Bax38/1 transgenic mice, another model of T cell lymphoma. Histologically the lymphomas in p27 -/- Lck-Bcl-2 mice are lymphoblastic and frequently involve multiple organs suggesting an aggressive phenotype. Interestingly, in mature splenic T cells, Bcl-2 largely retains its anti-proliferative function even in the absence of p27. T cells from p27 -/- Lck-Bcl-2 mice show delayed kinetics of CDK2 Thr-160 phosphorylation. This delay is associated with a delay in the up regulation of both Cyclin D2 and D3. These data demonstrate a complex relationship between the Bcl-2 family, cellular proliferation, and oncogenesis and demonstrate that p27 up-regulation is not singularly important in the proliferative delay observed in T cells expressing Bcl-2 family members. Nonetheless, the results indicate that p27 is a critical tumor suppressor in the context of Bcl-2 expression.
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PMID:p27 deficiency cooperates with Bcl-2 but not Bax to promote T-cell lymphoma. 1838 84

Humic acid (HA) in well water used by the inhabitants for drinking is one of the possible etiological factors for Blackfoot disease (BFD). In this study, the ability of HA to inhibit cell cycle progression and induce apoptosis in cultured smooth muscle cells (SMCs; A7r5) was investigated. Treatment of the SMCs at various HA concentrations (25-200 microg/mL) resulted in sequences of events marked by apoptosis, as shown by loss of cell viability, morphology change, and internucleosomal DNA fragmentation. HA-induced apoptotic cell death that is associated with loss of mitochondrial membrane potential (Delta Psi m), cytochrome c translocation, caspase-3, -8, and -9 activation, poly ADP-ribose polymerase (PARP) degradation, dysregulation of Bcl-2 and Bax, and upregulation of p53 and phospholyrated p53 (p-p53) in SMCs. Flow cytometry analysis demonstrated that HA blocked cell cycle progress in the G1 phase in SMCs. This blockade of cell cycle was associated with reduced amounts of cyclin D1, CDK4, cyclin E, CDK2, and hyperphosphorylated retinoblastoma protein (pRb) in a time-dependent manner. Apparent DNA strand breaks (DNA damage) were also detected in a dose-dependent manner using Single-cell gel electrophoresis assay (comet assay). Furthermore, HA induced dose-dependent elevation of reactive oxygen species (ROS) level in SMCs, and antioxidant vitamin C and Trolox effectively suppressed HA-induced DNA damage and dysregulation of Bcl-2/Bax. Our findings suggest that HA-induced DNA damage, cell cycle arrest, and apoptosis in SMCs may be an underlying mechanisms for the atherosclerosis and thrombosis observed in the BFD endemic region.
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PMID:Humic acid induces G1 phase arrest and apoptosis in cultured vascular smooth muscle cells. 1868 88

We examined the effects of rapamycin on activation, proliferation, and expression of cytotoxic effector molecules in Molt-4 human T lymphocytes. We investigated the effects of rapamycin on cell viability, caspase family protein activities. Western blots of Bcl-2, Bak, p53, p21, p27, Rb, CDK2, and cyclin B1, as well as measurement of reactive oxygen species (ROS) generation and mitochondrial membrane potential transition. Cells were cultured in the presence or absence of rapamycin. Flow cytometric analysis was performed using propidium iodide stain. Viability of Molt-4 cells was decreased by the addition of rapamycin in dose- and time-dependent manners. Rapamycin induced no nuclear fragmentation in Molt-4 cells. Generation of H2O2 in rapamycin-treated Molt-4 cells increased in a time-dependent manner. There were no changes among catalytic activities of caspase proteases. And there was no evidence of expression of Bcl-2, p53, p21, p27, or Rb proteins. G2/M phase cell cycle arrest was identified by flow cytometry. We noted decreased expressions of CDK2 and cyclin B1. We also noted increased Bak protein expression and change in mitochondrial membrane potential transition. In conclusion, rapamycin-induced cytotoxicity was characterized by generation of ROS, which modulated Bak protein expression and mitochondrial dysfunction. G2/M phase cell cycle arrest was achieved by decreased expressions of CDK2 and cyclin B1.
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PMID:Rapamycin-induced cytotoxic signal transduction pathway. 1892 49

Honokiol is a naturally occurring neolignan abundant in Magnoliae Cortex and has showed anti-proliferative and pro-apoptotic effects in a wide range of human cancer cells. However, the molecular mechanisms on the anti-proliferative activity in cancer cells have been poorly elucidated. In this study, we evaluated the growth inhibitory activity of honokiol in cultured estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. Honokiol exerted anti-proliferative activity with the cell cycle arrest at the G0/G1 phase and sequential induction of apoptotic cell death in a concentration-dependent manner. The honokiol-induced cell cycle arrest was well correlated with the suppressive expression of CDK4, cyclin D1, CDK2, cyclin E, c-Myc, and phosphorylated retinoblastoma protein (pRb) at Ser780. Apoptosis caused by honokiol was also concomitant with the cleavage of caspases (caspase-3, -8, and -9) and Bid along with the suppressive expression of Bcl-2, but it was independent on the expression of Bax and p53. In addition, honokiol-treated cells exhibited the cleavage of poly (ADP-ribose) polymerase (PARP) and DNA fragmentation. In the analysis of signal transduction pathway, honokiol down-regulated the expression and phosphorylation of c-Src, epidermal growth factor receptor (EGFR), and Akt, and consequently led to the inactivation of mTOR and its downstream signal molecules including 4E-binding protein (4E-BP) and p70 S6 kinase. These findings suggest that honokiol-mediated inhibitory activity of cancer cell growth might be related with the cell cycle arrest and induction of apoptosis via modulating signal transduction pathways.
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PMID:Down-regulation of c-Src/EGFR-mediated signaling activation is involved in the honokiol-induced cell cycle arrest and apoptosis in MDA-MB-231 human breast cancer cells. 1913 78


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