UNIPROT:P10415 - FACTA Search

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)

Giant proerythroblasts are hallmarks of human parvovirus B19 infection. We attempted to characterize these cells in 5 patients with parvovirus B19-induced pure red cell aplasia using immunostaining of paraffin-embedded bone marrow sections with antibodies against erythroid-lineage-specific proteins, viral capsid antigen VP-1, and apoptosis- and cell-cycle-related proteins. Giant proerythroblasts are immunohistochemically consistent with early erythroid precursors of cells in the differentiation stage of CD34-, cytoplasmic spectrin+, glycophorin A-, and band-3-. VP-1 was expressed in the nucleus and cytoplasm of small- to medium-sized spectrin+ erythroid cells but not in giant proerythroblasts. The giant proerythroblasts displayed nuclear staining for p53 (41%+/-16%) and Ki-67 antigen (100%+/-0%) and cytoplasmic staining for Bax (65%+/-11%) and procaspase-3 (78%+/-10%), whereas they were not stained for p21Wafl/Cip1, active form of caspase-3, or terminal deoxynucleotidyltransferase-mediated deoxyuridine nick-end labeling (TUNEL). Antiapoptotic proteins, Bcl-2 and Mcl-1, were not expressed in the giant cells, and Bcl-x was infrequently expressed in these cells (11%+/-4%). These immunohistochemical findings suggest that giant proerythroblasts are proliferating erythroid precursors with accumulation of nonfunctional p53.
...
PMID:Expression of p53 and Ki-67 antigen in bone marrow giant proerythroblasts associated with human parvovirus B19 infection. 1159 14

It has been shown that the novel synthetic triterpenoid CDDO inhibits proliferation and induces differentiation and apoptosis in myeloid leukemia cells. In the current study the effects of the C-28 methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and apoptosis of leukemic cell lines and primary acute myelogenous leukemia (AML). CDDO-Me decreased the viability of leukemic cell lines, including multidrug resistant (MDR)-1-overexpressing, p53(null) HL-60-Dox and of primary AML cells, and it was 3- to 5-fold more active than CDDO. CDDO-Me induced a loss of mitochondrial membrane potential, induction of caspase-3 cleavage, increase in annexin V binding and DNA fragmentation, suggesting the induction of apoptosis. CDDO-Me induced pro-apoptotic Bax protein that preceded caspase activation. Furthermore, CDDO-Me inhibited the activation of ERK1/2, as determined by the inhibition of mitochondrial ERK1/2 phosphorylation, and it blocked Bcl-2 phosphorylation, rendering Bcl-2 less anti-apoptotic. CDDO-Me induced granulo-monocytic differentiation in HL-60 cells and monocytic differentiation in primary cells. Of significance, colony formation of AML progenitors was significantly inhibited in a dose-dependent fashion, whereas normal CD34(+) progenitor cells were less affected. Combinations with ATRA or the RXR-specific ligand LG100268 enhanced the effects of CDDO-Me on cell viability and terminal differentiation of myeloid leukemic cell lines. In conclusion, CDDO-Me is an MDR-1- and a p53-independent compound that exerts strong antiproliferative, apoptotic, and differentiating effects in myeloid leukemic cell lines and in primary AML samples when given in submicromolar concentrations. Differential effects of CDDO-Me on leukemic and normal progenitor cells suggest that CDDO-Me has potential as a novel compound in the treatment of hematologic malignancies.
...
PMID:Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. 1175 88

Excessive apoptosis is implicated in the pathogenesis of myelodysplastic syndromes (MDS). We assessed by flow cytometry the expression of several members of the Bcl-2 family in bone marrow mononuclear cells (BMMNC) of 168 MDS samples at diagnosis. The proteins studied were Bcl-2, Bcl-xL (anti-apoptotic), Bax, Bad, Bak, and Bcl-xS (pro-apoptotic). The percentage of BMMNC expressing Bcl-2 and Bcl-xL was higher in refractory anemia with excess of blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML) than in refractory anemia (RA) and RA with ringed sideroblasts (RAS). Conversely pro-apoptotic proteins Bad, Bak, and Bcl-xS were detected in a higher percentage of cells in RA and RAS. RA and RAS were associated with an increased Bcl-xS/Bcl-xL ratio. The expression of anti-apoptotic proteins was also correlated with that of CD34 and P170 and with the percentage of blast cells. Two-color analyses demonstrated that CD34 and Bcl-2 were usually expressed in the same cells. No significant correlation was found with cytogenetic abnormalities. Higher expression of pro-apoptotic Bcl-2-family proteins (Bak, Bad, Bcl-xS) and higher Bcl-xS/Bcl-xL ratio were associated with longer survival and decreased risk of leukemic transformation in univariate analysis, whereas expression of anti-apoptotic proteins was associated with decreased survival. Consequently Bcl-2 proteins expression was well correlated with the International Prognostic Scoring System (IPSS). Our data confirm that the control of apoptosis is deregulated in MDS cells. Moreover, the study of markers such as CD34 (or Bcl-2), Bcl-xL, and Bcl-xS provides additional prognostic information.
...
PMID:Expression and prognostic significance of Bcl-2 family proteins in myelodysplastic syndromes. 1211 84

Platelets are formed from mature megakaryocytes (MKs) and arise from the development of long and thin cytoplasmic extensions called proplatelets. After platelet release, the senescent MKs (nucleus surrounded by some cytoplasm) undergo cell death by apoptosis. To explore the precise role of apoptosis in proplatelet formation, we grew human MKs from CD34(+) cells and assessed the possible role of caspases. Proteolytic maturation of procaspase-3 and procaspase-9 was detected by immunoblots in maturing MKs as well as in proplatelet-bearing MKs and senescent MKs. Cleavage of caspase substrates such as gelsolin or poly adenosine diphosphate (ADP)-ribose polymerase (PARP) was also detected. Interestingly, activated forms of caspase-3 were detected in maturing MKs, before proplatelet formation, with a punctuate cytoplasmic distribution, whereas a diffuse staining pattern was seen in senescent and apoptotic MKs. This localized activation of caspase-3 was associated with a mitochondrial membrane permeabilization as assessed by the release of cytochrome c, suggesting an activation of the intrinsic pathway. Moreover, these MKs with localized activated caspase-3 had no detectable DNA fragmentation. In contrast, when apoptosis was induced by staurosporine, diffuse caspase activation was seen; these MKs had signs of DNA fragmentation, and no proplatelet formation occurred. The pan-caspase inhibitor z-VAD.fmk as well as more specific inhibitors of caspase-3 and caspase-9 blocked proplatelet formation, whereas an inhibitor of calpeptin had no effect. Overexpression of Bcl-2 also inhibited proplatelet formation in maturing MKs. Thus, localized caspase activation is causal to proplatelet formation. We conclude that proplatelet formation is regulated by a caspase activation limited to only some cellular compartments.
...
PMID:Platelet formation is the consequence of caspase activation within megakaryocytes. 1214 86

The aim of this study was to study interactions between stromal bone marrow microenvironment and leukemic cells. We tested the hypothesis that stromal cells prevent apoptosis of AML cells by up-regulating anti-apoptotic proteins in leukemic blasts. In HL-60 and NB-4 cells, serum deprivation- and ara-C-induced apoptosis was diminished when cells were cocultured with murine MS-5 stromal cells (P < 0.02). This effect was reproduced with conditioned medium from MS-5 cells. Cocultivation with stromal cells induced Bcl-2 expression levels, both by PCR analysis and flow cytometry. In primary AML (n = 14), ara-C-induced apoptosis was significantly lower in cells cocultured with MS-5 cells than in controls (P < 0.001). This effect was partially preserved when leukemic cells were separated from stromal cells by a microporous insert (in 5/9 samples, P = 0.04). In addition, Bcl-2 levels were significantly higher in stroma-supported than in control CD34(+) AML cells (P < 0.01). Bcl-X(L) levels were higher in 5/7 samples grown on stromal layers. Of note, in AML patients resistant to induction chemotherapy (n = 6), Bcl-2 increased significantly after cultivation with stromal cells, but no such increase was noted in cells from chemotherapy-sensitive patients. In conclusion, MS-5 stromal cells prevented apoptosis in HL-60 cells and in primary AML blasts via modulation of Bcl-2 family proteins. The observed association of high Bcl-2 expression in stroma-supported AML blasts in vitro with resistance to chemotherapy in vivo suggests that the same mechanisms may be operational in vivo.
...
PMID:Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. 1220 Jun 86

The aim of this study was to examine the effect of two of the most commonly used viral vectors, that is, retrovirus and adenovirus, on the antigen presentation of dendritic cells (DCs). DCs were generated from CD34(+) hematopoietic precursors and CD14(+) monocytes of the same prostate cancer patients. Adenoviral transduction of monocyte-derived DCs (MO-DCs) resulted in upregulation of CD80, CD86, and CD83 expression. Adenovirus-transduced MO-DCs were also more potent stimulators of allogeneic lymphocytes, produced increased amounts of the cytokines tumor necrosis factor alpha and interleukin 12 p70, and exhibited increased expression of NF-kappaB and antiapoptotic molecules Bcl-X(L) and Bcl-2. Enhanced expression of the antiapoptotic molecules correlated with increased resistance of adenovirus-transduced MO-DCs to spontaneous as well as Fas-mediated cell death. In contrast to the adenoviral construct, no significant transduction of MO-DCs with the retrovirus could be obtained. Transduction of CD34(+) cell-derived DCs with the retrovirus or the adenovirus did not significantly alter expression of the costimulatory molecules or cytokines studied. At lower stimulation ratios, CD34(+) cell-derived DCs transduced with retrovirus were less potent in their ability to stimulate allogeneic lymphocytes in comparison with nontransduced DCs. Our results indicate that adenoviral vectors may be more suitable for gene delivery to DCs for immunotherapy.
...
PMID:Recombinant adenovirus vector activates and protects human monocyte-derived dendritic cells from apoptosis. 1222 9

Immature dendritic cells (DCs) reside in interstitial tissues (int-DC) or in the epidermis, where they capture antigen and, thereafter, mature and migrate to draining lymph nodes (LNs), where they present processed antigen to T cells. We have identified int-DCs that express both TRANCE (tumor necrosis factor-related activation-induced cytokine) and RANK (receptor activator of NF-kappaB) and have generated these cells from CD34(+) human progenitor cells using macrophage colony-stimulating factor (M-CSF). These CD34(+)-derived int-DCs, which are related to macrophages, are long-lived, but addition of soluble RANK leads to significant reduction of cell viability and Bcl-2 expression. This suggests that constitutive TRANCE-RANK interaction is responsible for CD34(+)-derived int-DC longevity. Conversely, CD1a(+) DCs express only RANK and are short-lived. However, they can be rescued from cell death either by recombinant soluble TRANCE or by CD34(+)-derived int-DCs. CD34(+)-derived int-DCs mature in response to lipopolysaccharide (LPS) plus CD40 ligand (L) and become capable of CCL21/CCL19-mediated chemotaxis and naive T-cell activation. Upon maturation, they lose TRANCE, making them, like CD1a(+) DCs, dependent on exogenous TRANCE for survival. These findings provide evidence that TRANCE and RANK play important roles in the homeostasis of DCs.
...
PMID:Long-lived immature dendritic cells mediated by TRANCE-RANK interaction. 1239 86

Signal transducers and activators of transcription (STATs) have been reported to play a critical role in the differentiation of several myeloid cell lines, although the importance of STATs in the differentiation of primary human hematopoietic cells remains to be established. Terminal eosinophil differentiation is induced by interleukin-5 (IL-5), which has also been demonstrated to activate STAT5. We have investigated whether STAT5 plays a critical role during eosinophil differentiation using umbilical cord blood-derived CD34(+) cells. In this ex vivo system, STAT5 expression and activation are high early during differentiation, and STAT5 protein expression is down-regulated during the final stages of eosinophil differentiation. Retroviral transductions were performed to ectopically express wild-type and dominant-negative STAT5a (STAT5aDelta750) in CD34(+) cells. Transduction of cells with STAT5a resulted in enhanced proliferation compared with cells transduced with empty vector alone. Interestingly, ectopic expression of STAT5a also resulted in accelerated differentiation. In contrast, ectopic expression of STAT5aDelta750 resulted in a block in differentiation, whereas proliferation was also severely inhibited. Similar results were obtained with dominant-negative STAT5b. Forced expression of STAT5a enhanced expression of the STAT5 target genes Bcl-2 and p21(WAF/Cip1), suggesting they may be important in STAT5a-mediated eosinophil differentiation. These results demonstrate that STAT5 plays a critical role in eosinophil differentiation of primary human hematopoietic cells.
...
PMID:Signal transducer and activator of transcription 5a (STAT5a) is required for eosinophil differentiation of human cord blood-derived CD34+ cells. 1239 7

In the present paper we show that transendothelial migration of a subset of CD14(+) circulating leukocytes, coexpressing the CD34 precursor marker, leads to protection from the apoptosis that follows growth factor(s) withdrawal. The resistance of this cell subset to starvation-induced programmed cell death, lasting from 48 to 96 hours, is accompanied by a rise of mitochondrial adenosine triphosphate (ATP), a high nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, and by the up-regulation of expression of the antiapoptotic proteins Bcl-2 and Bcl-X, together with an increase in the cytoplasmic, inactive, form of Bax. This suggests that protection from apoptosis is due to the preservation of mitochondrial function(s). Interestingly, ligation of the platelet endothelial cell adhesion molecule-1 (PECAM-1), which drives CD14(+)CD34(+) transendothelial migration, leads to an increase in Bcl-2 A1 and Bcl-X intracellular content, and to protection from starvation-induced apoptosis. This event is dependent on the engagement of phosphatidylinositol-3 kinase and activation of Akt/PKB that is known to contribute to Bcl-2 and Bcl-X induction. These data point to a critical role of endothelium in preventing the apoptotic program triggered by starvation, possibly inducing a prolonged survival of antigen presenting cell precursors, in order to allow recirculation of these cells and localization to the site of priming of T lymphocytes.
...
PMID:Transendothelial migration leads to protection from starvation-induced apoptosis in CD34+CD14+ circulating precursors: evidence for PECAM-1 involvement through Akt/PKB activation. 1239 47

Diagnosing monophasic fibrous and poorly differentiated synovial sarcoma (SS) on morphology alone is often a source of problems for pathologists. SS bear the t(X;18)(p11.2,q11.2) translocation, which proved to be specific for this tumor type and is currently considered one of the most reliable diagnostic criteria. To evaluate the sensitivity of immunohistochemical techniques in diagnosing monophasic fibrous SS (MFSS) and poorly differentiated SS (PDSS), we examined 60 t(X;18)(SYT-SSX)-positive cases (47 MFSS and 13 PDSS) for cytokeratin AE1/AE3, cytokeratin KL1, epithelial membrane antigen, E-cadherin, CD34, S-100 protein, alpha-smooth muscle actin, desmin, h-caldesmon, CD99, bcl2, and C-kit (CD117) antibodies. Of the four epithelial markers tested, epithelial membrane antigen proved to be the most sensitive, reacting with 100% of MFSS and 92% of PDSS, followed by cytokeratin AE1/AE3 (70% of MFSS, 46% of PDSS), cytokeratin KL1 (49% of MFSS, 38% of PDSS), and E-cadherin (47% of MFSS, 54% of PDSS). A staining for cytokeratin AE1/AE3 and/or E-cadherin was observed in 79% of MFSS and 69% of PDSS, and a staining for cytokeratin KL1 and/or E-cadherin was observed in 74% of MFSS and 62% of PDSS. S-100 protein was positive in 38% of MFSS and 23% of PDSS, and alpha-smooth muscle actin in 21% of MFSS and 8% of PDSS. Tumor cells were rarely positive for CD34 (6% of MFSS, 0% of PDSS) and desmin (2% of MFSS, 0% of PDSS). Most SS were strongly positive for bcl-2 (91% of MFSS, 92% of PDSS) and CD99 (91% of MFSS, 100% of PDSS). A weak and focal cytoplasmic reactivity for CD117 was observed in 11% of MFSS (only one case had a strong immunoreactivity) and 8% of PDSS. Staining with h-caldesmon was consistently negative. In conclusion, in keeping with literature data, our results show that reactivity for epithelial membrane antigen, cytokeratin AE1/AE3, and E-cadherin, in combination with CD34 negativity, are the most useful and sensitive markers for diagnosing monophasic fibrous and poorly differentiated t(X;18)-positive SS. They also support the fact that about one third of MFSS and one fourth of PDSS are positive for S-100 protein, a finding of diagnostic relevance when considering their distinction from other spindle to round cell sarcomas, especially malignant peripheral nerve sheath tumors.
...
PMID:Monophasic fibrous and poorly differentiated synovial sarcoma: immunohistochemical reassessment of 60 t(X;18)(SYT-SSX)-positive cases. 1240 19

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