Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bcl-2 and Bax are homologous proteins which can heterodimerize with each other. These proteins have opposing effects on cell survival when overexpressed in cells, with Bcl-2 blocking and Bax promoting apoptosis. Here we demonstrate that gene transfer-mediated elevations in Bcl-2 protein levels result in a marked increase in the steady-state levels of endogenous p21Bax protein as determined by immunoblotting in the Jurkat T-cell and 697 pre-B-cell leukemia cell lines, but not in several other cell lines including CEM T-cell leukemia, 32D.3 myeloid progenitor, PC12 pheochromocytoma, and NIH-3T3 fibroblasts. Steady-state levels of p21Bax protein were also elevated in the lymph nodes of Bcl-2 transgenic mice in which a BCL-2 transgene is expressed at high levels in B-cells. Northern blot analysis of BCL-2-transfected and control-transfected Jurkat and 697 leukemia cells revealed no Bcl-2-induced alterations in the steady-state levels of BAX mRNAs. In contrast, L-[35S]methionine pulse-chase analysis indicated a marked increase in the half-life (t1/2) of the p21Bax protein in BCL-2-transfected 697 cells compared to control-transfected cells (t1/2 > 24 h versus approximately 4 h), whereas the rate of Bax degradation was unaltered in Bcl-2-transfected CEM cells. The results demonstrate that levels of the proapoptotic p21Bax protein can be post-translationally regulated by Bcl-2, probably in a tissue-specific fashion, and suggest the existence of a feedback mechanism that may help to maintain the ratio of Bcl-2 to Bax protein in physiologically appropriate ranges.
 ...
PMID:Overexpression of the Bcl-2 protein increases the half-life of p21Bax. 759 1

Rat pheochromocytoma PC12 cells die when cultured in serum-free medium. Neurotrophic factors can rescue PC12 cells from cell death, and induce neuronal differentiation. To further investigate the relationship among cell death, survival, and differentiation, the bcl-2 cDNA, which is known to prevent apoptosis in various types of cells, was transfected into PC12 cells. Six monoclonal bcl-2-transfected cell lines were isolated and confirmed to express mRNA and protein product of bcl-2. The wild-type and bcl-2-transfected PC12 cells were kept to adhere to collagen-coated dishes at the initiation of serum-free experiments to avoid cellular damage due to detachment of the cells by trituration. Even under the conditions, the control PC12 cells mostly died within 24 h, when cultured in serum-free medium, whereas those expressing Bcl-2 survived even for 7 days in serum-free medium. Moreover, outgrowth of long processes in the bcl-2-transfected cells was only observed under the condition to keep the cells attached to the dishes in serum-free medium without any additive neurotrophic or growth factors. Neurofilament medium protein, which is a neuron-specific cytoskeletal component, was also expressed in the differentiated cells, suggesting that the long processes in bcl-2-transfected PC12 cells are neurites. However, neuronal differentiation of PC12 cells expressing Bcl-2 was not observed when cultured in serum-containing medium. Accordingly, survival of PC12 cells expressing Bcl-2 under the condition which cells usually die may be accompanied with neuronal differentiation.
 ...
PMID:Neuronal differentiation of PC12 cells as a result of prevention of cell death by bcl-2. 781 55

Expression of the protooncogene bcl-2 inhibits both apoptotic and in some cases necrotic cell death in many cell types, including neural cells, and in response to a wide variety of inducers. The mechanism by which the Bcl-2 protein acts to prevent cell death remains elusive. One mechanism by which Bcl-2 has been proposed to act is by decreasing the net cellular generation of reactive oxygen species. To evaluate this proposal, we measured activities of antioxidant enzymes as well as levels of glutathione and pyridine nucleotides in control and bcl-2 transfectants in two different neural cell lines-rat pheochromocytoma PC12 and the hypothalamic GnRH cell line GT1-7. Both neural cell lines overexpressing bcl-2 had elevated total glutathione levels when compared with control transfectants. The ratios of oxidized glutathione to total glutathione in PC12 and GT1-7 cells overexpressing bcl-2 were significantly reduced. In addition, the NAD+/NADH ratio of bcl-2-expressing PC12 and GT1-7 cells was two- to threefold less than that of control cell lines. GT1-7 cells overexpressing bcl-2 had the same level of glutathione peroxidase, catalase, superoxide dismutase, and glutathione reductase activities as control cells. PC12 cells overexpressing bcl-2 had a twofold increase in superoxide dismutase and catalase activity when compared with matched control transfected cells. The levels of glutathione peroxidase and glutathione reductase in PC12 cells overexpressing bcl-2 were similar to those of control cells. These results indicate that the overexpression of bcl-2 shifts the cellular redox potential to a more reduced state, without consistently affecting the major cellular antioxidant enzymes.
 ...
PMID:Shift of the cellular oxidation-reduction potential in neural cells expressing Bcl-2. 875 34

It has become increasingly clear that deregulation of programmed cell death is a critical component in multistep tumorigenesis. Previous studies have demonstrated a high frequency of Bcl-2 expression in tumors arising from cells derived from the neural crest and in tumor cell lines of neural origin. The present investigation was undertaken to determine whether similar molecular events occur in human pheochromocytoma. With the aim of determining the potential role of apoptosis in the pathogenesis of this tumor, we assessed proto-oncogene Bcl-2 and c-myc protein products as well as Bcl-2 messenger RNA levels in a collection of such tumors. Western blot analysis revealed that such tumors expressed the 26 kDa Bcl-2 (5 of 8 cases) and the 64 kDa c-Myc (7 of 8 cases) proteins. Northern blot analysis detected the Bcl-2 transcripts in 6 of 8 tumors. Immunoperoxidase staining, using a monoclonal anti-Bcl-2 antibody, was positive in 18 (82%), including 5 malignant tumors, of the 22 specimens examined. This Bcl-2 immunoreactivity was seen in 14 of 18 (78%) sporadic tumors, including 2 that were extra-adrenal, and all familial tumors. Of the 22 tumor samples examined for c-Myc protein, 20 (91%) tumors were positive. Our results suggest that deregulation of programmed cell death may be a critical component in the multistep tumorigenesis of human pheochromocytoma. The genetic complementation of simultaneously deregulated Bcl-2 and c-myc may be implicated in this process.
 ...
PMID:Expression of the apoptosis-suppressing gene BCL-2 in pheochromocytoma is associated with the expression of C-MYC. 917 12

1. Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). It is assumed that the lethal trigger is the accumulation of oxidative reactive species generated during metabolism of the natural neurotransmitter dopamine. 2. We have recently shown that dopamine is capable of inducing programmed cell death (PCD) or apoptosis in cultured postmitotic chick sympathetic neurons and rat PC12 pheochromocytoma cells. 3. The bcl-2 gene encodes a protein which blocks physiological PCD in many mammalian cells. In an attempt to elucidate further the mechanism of dopamine toxicity, we examined the potential protective effect of bcl-2 in PC12 cells which were transfected with the protooncogene. 4. In our experiments, Bcl-2 producing cells showed a marked resistance to dopamine toxicity. The percentage of nuclear condensation and DNA fragmentation visualized by the end-labeling method following dopamine treatment was significantly lower in bcl-2 expressing cells. Bcl-2 did not protect PC12 cells against toxicity induced by exposure to dopamine-melanin. Extracts of PC12 cells containing Bcl-2 inhibited dopamine autooxidation and formation of dopamine-melanin. Furthermore, the presence of Bcl-2 protected cells from thiol imbalance and prevented thiol loss following exposure to dopamine. 5. The protective effects of Bcl-2 against dopamine toxicity may be explained, in part, by its action as an antioxidant and by its interference in the production of toxic agents. The possible protection by Bcl-2 against neuronal degeneration caused by dopamine may play a role in the pathogenesis of PD and may provide a new direction for the development of neuroprotective therapies.
 ...
PMID:Dopamine-induced apoptosis is inhibited in PC12 cells expressing Bcl-2. 918 86

We examined the cellular and signaling mechanism of angiotensin II (Ang II) type 2 (AT2) receptor-induced apoptosis in PC12W (rat pheochromocytoma cell line) cells that express abundant AT2 receptor but not Ang II type 1 receptor. In these cells, nerve growth factor (NGF) inhibited the internucleosomal DNA fragmentation induced by serum depletion, whereas Ang II antagonized this NGF cell survival action and induced apoptosis. We studied the mechanism of NGF and AT2 receptor interaction on apoptosis by examining their effects on the survival factor Bcl-2. AT2 receptor activation did affect intracellular Bcl-2 protein levels. Bcl-2 phosphorylation was stimulated by NGF, whereas AT2 receptor activation blocked this NGF effect. Pretreatment with antisense oligonucleotide of mitogen-activated protein (MAP) kinase phosphatase-1 enhanced the effects of NGF on MAP kinase activation and Bcl-2 phosphorylation but attenuated the inhibitory effects of AT2 receptor on MAP kinase, Bcl-2 phosphorylation, and apoptosis. Taken together, these results suggest that MAP kinase plays a critical role in inhibiting apoptosis by phosphorylating Bcl-2. The AT2 receptor inhibits MAP kinase activation, resulting in the inactivation of Bcl-2 and the induction of apoptosis.
 ...
PMID:Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis. 922 85

Comparisons of the developing human sympathetic nervous system (SNS) to tumors presumed to derive from these cells may suggest tumor progenitors and predict tumor biologic behavior. Classic neuroblastoma (NB) and its more highly differentiated stroma-rich subtypes, extra-adrenal sympathetic paraganglioma, and pheochromocytoma were examined for the presence of the developmentally characterized gene products NSE, S-100, CD44, Bcl-2, HNK-1, PNMT, TrkA, IGF2, and tyrosine hydroxylase. The marker gene expression profiles of these tumors were compared with those similarly determined for a number of normal prenatal and postnatal human SNS cell types. Sympathetic paraganglioma, pheochromocytoma, and stroma-rich NB display marker expression profiles mimicking those of childhood sympathetic paraganglia, adrenal chromaffin cells, and sympathetic neurons, respectively. A selection of differentiating, extra-adrenal NB tumors with prognostically favorable features possess marker gene expression profiles paralleling that observed for fetal extra-adrenal sympathetic paraganglia/small intensely fluorescent cells. In contrast, undifferentiated, clinically aggressive NB tumors manifest characteristics mirroring that of embryonic/early fetal sympathetic neuroblasts of sympathetic ganglia and of the adrenal gland. These findings suggest that clinical features, such as primary tumor location and age at diagnosis, provide prognostic information for NB patients by virtue of the existence and biology of the presumed tumor progenitor cell type.
 ...
PMID:Developmental gene expression of sympathetic nervous system tumors reflects their histogenesis. 946 Nov 20

Clinical and histopathological features do not reliably distinguish between benign and malignant pheochromocytomas. Additional markers that might be useful prognostic indicators in the pathological assessment of these tumors are sought. Immunohistochemical expression of MIB-1, Bcl-2, cathepsin B, cathepsin D, basic fibroblast growth factor (bFGF), c-met, and type IV collagenase were studied on formalin-fixed tissue from 33 nonconsecutive cases of pheochromocytoma, selected on the basis of reliable long-term follow-up, to determine associations with malignancy. The study group included 33 patients, 19 men and 14 women, with a mean age of 45 years, including five cases of neurofibromatosis (NF), three familial, and one MEN IIb. Mean follow-up was 63.2 months. Ten patients were determined to have malignant pheochromocytomas by the presence of metastatic disease. Features found to be associated with malignancy included MIB-1 labeling index (5% vs 1%) (P = .0009), male gender (90% vs 43%) (P = .008), extra-adrenal location (40% vs 9%) (P = .03), tumor weight (481 g vs 124 g) (P = .05), and young age (38 years vs 49 years) (P = .05). None of the five cases with NF were malignant (P = .04). S-100 positivity showed a significant (P = .02) but nonlinear association with benign tumors. Absent S-100 correlated with greater tumor weight. Malignancy was not associated with right versus left side or bilaterality, although bilateral tumors were smaller. C-met, bFGF, cathepsin B, cathepsin D, and collagenase were strongly expressed in most tumors and were not predictive of outcome, nor was bcl-2, which was variably expressed. Using multiple logistic regression with malignancy as the dependent variable, MIB-1 continued to show a significant association with malignancy (P = .005) independent of any association with sex, age, or extra-adrenal location. Using a cutoff value of MIB-1 labeling of greater than 3% yielded a specificity of 100% and a sensitivity of 50% in predicting malignancy.
 ...
PMID:Prognostic markers in pheochromocytoma. 1020 74

The proto-oncogene product Bcl-2 is unique in that it inhibits apoptosis rather than promoting cell proliferation. In the present study, we encountered a new possible role of Bcl-2 in the neuronal differentiation. Rat pheochromocytoma PC12 cells have been known as the model of neuronal differentiation by the stimulation of NGF. Bcl-2 transfected PC12 (MB2) cells showed the accelerated neuronal differentiation, as compared with control PC12 (V4) cells. In addition, chemotherapeutic agents Taxol which has been known as neurotoxic compound, induced the acute neuronal cell atrophy and suppressed neuronal differentiation. This neuronal cell atrophy and suppression of neuronal differentiation were not due to apoptotic cell death. Interestingly, Bcl-2 rescued PC12 cells from both neuronal cell atrophy and suppression of neuronal differentiation. Taxol suppressed polymerization between neurofilament light and heavy (NF-L and NF-H), and MB2 cell extract rescued it. We, therefore, suggest the acceleration of polymerization between NF-L and NF-H as the new possible role of Bcl-2.
 ...
PMID:Bcl-2 accelerates the neuronal differentiation: new evidence approaching to the biofunction of bcl-2 in the neuronal system. 972 79

We previously reported that rat pheochromocytoma PC12 cells express the neuronal differentiated phenotype under hyperoxia through the production of reactive oxygen species (ROS). In the present study, we found that in this phenotype, Bcl-2, an apoptosis inhibitor, affects mitogen-activated protein (MAP)-kinase activity, which is known as a key enzyme of the signal-transduction cascade for differentiation. When PC12 cells were cultured under hyperoxia, a rapid increase in MAP-kinase activity, including that of both p42 and p44, was observed. Although the activity level then decreased quickly, activity higher than the control level was observed for 48 h. PD98059, an inhibitor of MAP kinase, suppressed the hyperoxia-induced neurite extensions, suggesting the involvement of MAP-kinase activity in the mechanism of differentiation induced by ROS. An elevation of Bcl-2 expression was observed after culturing PC12 cells for 24 h under hyperoxia. This Bcl-2 elevation was not affected by treatment with PD98059, suggesting that it did not directly induce neurite extension under hyperoxia. However, the blockade of the Bcl-2 elevation by an antisense oligonucleotide inhibited the sustained MAP-kinase activity and neurite extensions under hyperoxia. Further, in PC12 cells highly expressing Bcl-2, the sustained MAP-kinase activity and neurite extensions under hyperoxia were enhanced. These results suggested that MAP kinase is activated through the production of ROS, and the subsequent elevation of Bcl-2 expression sustains the MAP-kinase activity, resulting in the induction of the neuronal-differentiation phenotype of PC12 cells under hyperoxia.
 ...
PMID:Hyperoxia induces the neuronal differentiated phenotype of PC12 cells via a sustained activity of mitogen-activated protein kinase induced by Bcl-2. 1002 24


1 2 3 4 5 6 7 8 9 10 Next >>