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)

Leukemias are a heterogenous group of diseases characterized by uncontrolled proliferation of abnormal blood cells of hematopoietic system. Evodiamine, a characteristic alkaloid extracted from Evodia fruits, has been reported to exhibit inhibitory effect on cell proliferation and migration in several types of cancer cells. However, there is no report elucidating the action target and anti-cancer mechanism of this potential natural compound. In this study, we have defined the anti-proliferative and apoptotic mechanisms of evodiamine in human acute leukemia CCRF-CEM cells. According to the MTT assay, the cell viability was inhibited by evodiamine in a concentration-dependent manner with an IC50 of 0.57 +/- 0.05 microM. Flow cytometry analysis showed that the apoptotic cell death proceeded by evodiamine was accompanied with a cell cycle arrest at the G2/M phase. Using Wright-Giemsa staining, we observed that evodiamine caused the cells to arrest in mitosis. It also profoundly caused an increase in polymerized tubulin levels and Bcl-2 phosphorylation on serine 70 in these cells. These data imply that the microtubular cytoskeleton appears to be one of the cellular targets in response to evodiamine. Moreover, treatment of CCRF-CEM cells with evodiamine was associated with increased levels of pro-apoptotic protein Bax, activation of caspase-3, and proteolytic cleavage of poly (ADP-ribose) polymerase, an endogenous caspase-3 substrate. Taken together, we demonstrate that evodiamine causes the mitotic arrest and a consequent apoptosis in CCRF-CEM cells through the enhancement of polymerized tubulin levels. Furthermore, several biological events including the Bcl-2 phosphorylation, Bax up-regulation and increase of caspase-3 activity could explain evodiamine-induced cell apoptosis.
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PMID:Induction of mitotic arrest and apoptosis by evodiamine in human leukemic T-lymphocytes. 1510 20

Neonangiogenesis represents an important step in tumor development and propagation. Statins may have anticancerogenic potential by blocking vascular endothelial cell growth. The antiproliferative effect of four statins on human endothelial cells was compared, concomitantly delineating a possible pro-apoptotic process. All four statins tested, i. e. atorvastatin, fluvastatin, lovastatin, and simvastatin inhibited cell proliferation. Nearly complete blocking of cell proliferation was achieved at a concentration of 10 microM. We were able to demonstrate that the antiproliferative effect of the statins is not due to cytotoxicity but rather to an apoptotic effect as demonstrated by comparison of cytotoxicity assay and apoptosis assay. The apoptotic mechanism seems to involve caspases, since the statins significantly enhanced caspase activity at dosages of 10 and 20 microM. Further experiments revealed a downregulation of the pro-apoptotic protein Bcl-2. Our data indicate that statins may class-specific inhibit angiogenesis at high dosages which can contribute to prevention of tumor development and progression.
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PMID:Class-specific pro-apoptotic effect of statins on human vascular endothelial cells. 1516 Feb 75

Our aim was to examine the effects of melatonin on the testicular tissue of adult rats with experimentally-induced left varicocele, and to determine the relationship between melatonin and apoptosis regular proteins in the anti-oxidant defence system. Forty adult male Wistar rats were divided equally into four groups. A sham operation was performed on the rats in group I, and experimental left varicocele was created in groups II, III and IV. Melatonin was administered intraperitoneally at doses of 5 mg/kg and 10 mg/kg to rats in groups III and IV, respectively. An immunohistochemical analysis of the left testicular tissue was performed to evaluate the expression of Bax and Bcl-2, while tissue malondialdehyde (MDA) and antioxidant enzyme activities were assessed in homogenates to determine the role of the oxygen defence system. The immunohistochemical analysis revealed an increased ratio of pro-apoptotic protein Bax in groups II and III, whereas no significant activity was observed in the sham operated rats ( P<0.05). Similarly, the tissue MDA level increased and a significantly decreased level of antioxidant enzymes was observed in these groups ( P<0.05). Although rats in group IV showed a slightly increased ratio of the pro-apoptotic marker Bax, there was no significant difference between groups I and IV. Similarly, group IV showed decreased levels of MDA and increased levels of anti-oxidant enzyme activity with decreased Bax expression. The close relationship between pro-apoptotic/anti-apoptotic markers, reactive oxygen species and antioxidant agents provided a useful in vivo model for studying the pathophysiology of varicocele and evaluating the role of antioxidants in the prevention testicular damage.
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PMID:The effects of melatonin and the antioxidant defence system on apoptosis regulator proteins (Bax and Bcl-2) in experimentally induced varicocele. 1520 54

Dracorhodin perchlorate inhibited proliferation of several tumor cell lines. The drug induced oligonucleosomal fragmentation of DNA in HeLa cells and increased caspase-3, -8, -9 activities followed by the degradation of caspase-3 substrates, inhibitor of caspase-dependent DNase, and poly-(ADP-ribose) polymerase. It also increased caspase-1 activity and a caspase-1 inhibitor, Ac-YVAD-cmk, and a caspase-10 inhibitor z-AEVD-fmk, also reduced dracorhodin-perchlorate-induced HeLa cell death. Dracorhodin perchlorate decreased the expression of anti-apoptotic mitochondrial protein, Bcl-X(L), but not Bcl-2; and it increased the expression of pro-apoptotic protein, Bax. Dracorhodin perchlorate induced a sustained generation of reactive oxygen species (ROS) in HeLa cells; caspase-1 inhibitor, Ac-YVAD-cmk, and caspase-3 inhibitor, z-DEVD-fmk, attenuated the generation of ROS. Taken together, our results indicate that dracorhodin perchlorate alters the intracellular redox status, changed the balance of Bcl-X(L) and Bax protein expression, and induces apoptosis through caspase pathways in HeLa cells.
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PMID:Dracorhodin perchlorate induces apoptosis via activation of caspases and generation of reactive oxygen species. 1521 53

A milestone in understanding the functioning of the antiapoptotic cytoplasmic protein Bcl-2 was the discovery that Bcl-2 was capable of heterodimerising with the pro-apoptotic protein Bax at the mitochondrial level, creating a delicate balance of cell death preventing and promoting regulators. In recent years we identified substantial pools of Bcl-2 and Bax in nucleoplasm as well. We demonstrated that nuclear Bcl-2 controls cellular proliferation and, in an indirect manner, apoptosis. Sound support for functional presence of nuclear Bcl-2 and Bax would be evidence of Bcl-2-Bax binding in this compartment. Here we show by immunoprecipitation-using a battery of commercially available, monoclonal antibodies-that Bcl-2 binds Bax in nuclei of human breast cancer cells. Interestingly, findings by others pointed at an interaction between the product of the promyelocytic leukemia gene, the PML protein, and Bax. PML plays a part in cell proliferation and apoptosis, a rather similar role we assigned to nuclear Bcl-2. Nuclear Bcl-2, but not Bax, was found to immunoprecipitate with nuclear PML. These data show that binding of Bcl-2 with structurally and functionally related proteins extends to the nucleus, emphasizing its pivotal role in Bcl-2-mediated actions.
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PMID:Nuclear partners of Bcl-2: Bax and PML. 1523 Oct 68

Lats2, also known as Kpm, is the second mammalian member of the novel Lats tumor suppressor gene family. Recent studies have demonstrated that Lats2 negatively regulates the cell cycle by controlling G1/S and/or G2/M transition. To further understand the role of Lats2 in the control of human cancer development, we have expressed the protein in human lung cancer cells by transduction of a replication-deficient adenovirus expressing human Lats2 (Ad-Lats2). Using a variety of techniques, including Annexin V uptake, cleavage of PARP, and DNA laddering, we have demonstrated that the ectopic expression of human Lats2 induced apoptosis in two lung cancer cell lines, A549 and H1299. Caspases-3, 7, 8, and 9 were processed in the Ad-Lats2-transduced cells; however, it was active caspase-9, not caspase-8, that initiated the caspase cascade. Inhibitors specific to caspase-3 and 9 delayed the onset of Lats2-mediated apoptosis. Western blot analysis revealed that anti-apoptotic proteins, BCL-2 and BCL-x(L), but not the pro-apoptotic protein, BAX, were downregulated in Ad-Lats2-transduced human lung cancer cells. Overexpression of either Bcl-2 or Bcl-x(L) in these cells lead to the suppression of Lats2-mediated caspase cleavage and apoptosis. These results show that Lats2 induces apoptosis through downregulating anti-apoptotic proteins, BCL-2 and BCL-x(L), in human lung cancer cells.
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PMID:Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-x(L). 1526 83

Exercise training could potentially exert beneficial effects on the signaling events associated with cardiac cell apoptosis. Spontaneously hypertensive rats (SHR) were trained 5 days/week on a treadmill (18 m/min for 120 min/day) between the ages of 4 weeks and 1 week, corresponding to the hypertensive accelerating phase. The effect of exercise training on the expression of anti-apoptotic proteins HSP-72, Bcl-2 and protein kinase B (PKB), and the apoptotic proteins Bax and glycogen synthase kinase-3 (GSK-3) was examined. Exercise had a significant acute lowering effect on blood pressure, but this decrease did not attenuate the progressive increase in blood pressure. In the left ventricles of exercised SHR, PKB phosphorylation of both Ser473 and Thr308 residues was significantly increased by 166% and 120%, respectively, compared to sedentary SHR. PKB phosphorylation significantly correlated with GSK-3beta phosphorylation. HSP-72 and Bcl-2 protein expression were increased in the left ventricle of exercised SHR, and associated with the concomitant increased expression of the protein Bax. Thus, the Bcl-2/Bax ratio was not changed by exercise training, suggesting that the anti-apoptotic mechanism was effective in compensating the increase in the expression of the pro-apoptotic protein Bax in the myocardium of the SHR.
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PMID:Exercise training enhanced the expression of myocardial proteins related to cell protection in spontaneously hypertensive rats. 1529 Mar

The proteins of the bcl-2 family play an important role during apoptosis and may also regulate cell death in response to oxidative stress, which has been implicated in Parkinson's disease. In this study we examined the localization of the pro-apoptotic protein bax, and the anti-apoptotic proteins bcl-2 and bcl-x(L) in the substantia nigra (SN) of the adult rat and their response to oxidative stress caused by striatal injections of 6-hydroxydopamine (6-OHDA). Our data show that bcl-2, bcl-x and bax proteins are present in the SN. Bcl-2 and bax are localized primarily in neurons including all those positive for tyrosine hydroxylase (TH). The intraneuronal distribution of bcl-2 and bax were different. Bcl-2 was diffuse throughout the cell while bax was localized in well-defined structures around the nucleus and within processes. Bcl-x staining in neurons was weak, though it was strongly expressed in GFAP-positive astrocytes. 6-OHDA injections, which resulted in loss of dopamine neurons between 7-14 days post-lesion, altered the distribution of bax, bcl-2 and bcl-x proteins in the SN. Bcl-2 and bax were decreased in the TH-positive cells of the SN from 3 to 14 days post-lesion and many TH-positive neurons were bcl-2 negative. Neuronal bcl-x was initially unchanged after lesion, but increased in astrocytes between 3-7 days post-lesion before the increase in GFAP immunoreactivity, which was detectable at days 10-14. While the neuronal distribution of bcl-2 and bcl-x does not change following lesion, bax became evenly distributed thought the soma. Morphological features of apoptosis, including TUNEL labeling and chromatin condensation was not observed. These data suggest that striatal 6-OHDA lesions do not result in classical apoptosis in the SN of the adult rat, even though there are changes in the content and distribution of members of the bcl-2 family of proteins.
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PMID:Alterations in the cellular distribution of bcl-2, bcl-x and bax in the adult rat substantia nigra following striatal 6-hydroxydopamine lesions. 1532 79

The anti-apoptotic proteins Bcl-w and Bcl-2 and the pro-apoptotic protein Bax may mediate cell death or survival via regulation of the mitochondria including second mitochondria-derived activator of caspase (Smac)/direct inhibitor of apoptosis protein (IAP)-binding protein with low pI (DIABLO) release. This study aimed to explore alterations in Bcl-w, Bcl-2, and Bax and the relationship between these proteins and Smac/DIABLO by means of in situ hybridization, immunohistochemical (IHC) staining, and Western blots after low- and high-intensity photothrombotic ring stroke. At 4 h after low-intensity irradiation, we found widespread bcl-w overexpression on both the mRNA and protein levels in the bilateral cortex except the ring lesion region and in subcortical regions. A prolonged elevation of Bcl-2 with relatively unchanged Bax in the mitochondrial fraction was demonstrated from 4 to 72 h. These upregulated anti-apoptotic proteins combined with little Smac/DIABLO release might be associated with increased cell survival and thereby remarkable morphological recovery after low-intensity irradiation. After high-intensity irradiation, we observed decreased bcl-w and bcl-2 mRNA with increased Bcl-2 protein in the cytosolic fraction, whereas the Bax protein remained in scattered ischaemic cells in the ring lesion and the region at risk that corresponded with release of Smac/DIABLO from mitochondria to the cytosol at 1-24 h. These changes might be related to the massive cell death observed after high-intensity irradiation. Taken together, the balance and the location of anti-apoptotic proteins vs. pro-apoptotic proteins could be associated with the translocation of Smac/DIABLO from the mitochondria to the cytosol and therefore closely related to cell death or survival after focal cerebral ischaemia.
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PMID:Dynamic changes of the anti- and pro-apoptotic proteins Bcl-w, Bcl-2, and Bax with Smac/Diablo mitochondrial release after photothrombotic ring stroke in rats. 1534 89

We studied the effect of 4-acetyl-12,13-epoxyl-9-trichothecene-3, 15-diol (AETD) isolated from Isaria japonica, one of the most popular Chinese fungal medicines, on the induction of apoptosis in rat bladder carcinoma NBT-II cells. AETD was cytotoxic to NBT-II cells, and this cytotoxic effect appears to be attributed to its induction of apoptotic cell death, as AETD induced nuclear morphological changes and internucleosomal DNA fragmentation, and increased the proportion of hypodiploid cells and activity of caspase-3. AETD treatment also decreased the expression of the anti-apoptotic protein Bcl-2 and increased the expression of the pro-apoptotic protein Bax. These results provide important information in understanding the mechanism(s) of AETD-induced apoptosis.
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PMID:4-Acetyl-12,13-epoxyl-9-trichothecene-3, 15-diol from Isaria japonica mediates apoptosis of rat bladder carcinoma NBT-II cells by decreasing anti-apoptotic Bcl-2 expression and increasing pro-apoptotic Bax expression. 1534 21


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