Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 effects of interleukin 7 (IL-7) on apoptosis in interleukin 2 (IL-2)-dependent, activated, primary, human T lymphocytes (hT cells) was examined. IL-7 (like IL-2) rescued cells from apoptosis, as measured by their cellular DNA profile and fragmentation. IL-2 also acted as a mitogen in these T cells. Both cytokines abrogated the dexamethasone-induced stimulation of Caspase 3 and prevented the cleavage of poly (ADP-ribose) polymerase (PARP), a substrate for the Caspase 3. IL-7 upregulated the expression of Bc1xL and counteracted the downregulation of this anti-apoptotic protein by the synthetic glucocorticoid, dexamethasone. Bcl-2 protein expression was uupregulated by IL-7 with or without dexamethasone, but Bc1-2 was expressed at a much lower level than BclxL in these cells. Levels of Bax did not markedly change on either cytokine stimulation or dexamethasone treatment. An unidentified 23-kDa band, which was recognized by the anti-Bc1-2 antibody, was induced by dexamthasone and suppressed by IL-7 and IL-2. This protein was subject to independent regulation as compared to the p26 Bc1-2 protein, suggesting that it may be a novel factor, possibly involved in the regulation of apoptosis. A clear role for IL-7 as a survival factor for cytokine withdrawal and glucocorticoid induced apoptosis in activated primary hT cells is implicated. In addition, regulation of BclxL and downstream inhibition of Caspase 3 activity may mediate this rescue signal.
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PMID:The role of caspase 3 and BclxL in the action of interleukin 7 (IL-7): a survival factor in activated human T cells. 977 Mar 27

Fas is expressed in colonic epithelial cells and is also expressed in colon carcinomas, although its functional significance in the regulation of apoptosis in cells outside of the immune system remains unknown. In this study, we determined the role of Fas signaling on cellular growth of cultured colon carcinoma cells and demonstrated apoptosis induced by a cytotoxic anti-Fas monoclonal antibody (CH-11) in cells of the GC3/c1 lineage (GC3/c1, TS-, Thy4) but not in HCT116 or CaCo2 cells. Growth inhibition was detected at concentrations of CH-11 as low as 1 ng/ml, and clonogenic survival studies yielded IC50 values of 3-26 ng/ml. Cytotoxicity was inhibited by ZB4, a monoclonal antibody inhibitory to Fas signaling. In addition, the survival factor Bcl-2, which has demonstrated inconsistent protective effects against Fas signaling in other systems, was inhibitory to Fas-induced apoptosis in colon carcinoma cells after adenoviral transduction. Fas was expressed at the highest levels in TS- and Thy4 cells, which were the most sensitive cell lines to Fas-induced apoptosis. FAP-1, a protein tyrosine phosphatase that interacts with the cytosolic negative regulatory domain of Fas, was expressed in each cell line but did not correlate with sensitivity to Fas-mediated apoptosis. These data have therefore identified a functional Fas pathway in colon carcinoma cells when Fas is expressed at high levels. Hence, the role of Fas signaling in the regulation of apoptosis in colon carcinoma cells and its role in influencing the response to treatment with chemotherapeutic agents should be further explored.
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PMID:The fas signaling pathway is functional in colon carcinoma cells and induces apoptosis. 981 16

In a chemically defined serum-free culture system, platelet-derived growth factor (PDGF) as the only externally applied growth factor, in concert with corticosterone, 3-isobutyl-1-methylxanthine (IBMX) and low insulin (1nM), stimulates adipose conversion of 3T3-L1 preadipocytes. Omission of PDGF during the induction period results in loss of differentiation competence and apoptotic cell death. Induction of apoptosis is shown to be clearly mediated by PDGF withdrawal, since neither corticosterone nor IBMX affect the apoptotic behaviour of 3T3-L1 cells. Cell viability in the absence of the survival factor PDGF could be achieved by application of high insulin (1 microM) or ectopical expression of the anti-apoptotic proto-oncogene Bcl-2. However, PDGF-independent suppression of cell death does not trigger adipose conversion in the presence of corticosterone and IBMX. Therefore, we conclude that suppression of apoptosis per se is not permissive for differentiation of 3T3-L1 preadipocytes and PDGF might exert some additional differentiation-promoting effect(s).
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PMID:The role of PDGF-dependent suppression of apoptosis in differentiating 3T3-L1 preadipocytes. 986 Jan 38

The BCL-2 gene was identified at the chromosomal breakpoint of t(14; 18)-bearing human follicular B cell lymphomas. BCL-2 proved to block programmed cell death rather than promote proliferation. Transgenic mice that overexpress Bcl-2 in the B cell lineage demonstrate extended cell survival and progress to high-grade lymphomas. Thus, BCL-2 initiated a new category of oncogenes, regulators of cell death. Bcl-2-deficient mice demonstrate fulminant apoptosis of lymphocytes, profound renal cell death and loss of melanocytes. BCL-2 protein duels with its counteracting twin, a partner known as BAX. When BAX is in excess, cells execute a death command; but, when BCL-2 dominates, the program is inhibited and cells survive. Bax-deficient mice display cellular hyperplasia, confirming its role as a proapoptotic molecule. An expanded family of BCL-2-related proteins shares homology clustered within four conserved regions termed BCL-2 homology 1 through 4 (BH1-4). These novel domains control the ability of these proteins to dimerize and function. An amphipathic alpha helix, BH3, is of particular importance for the proapoptotic family members. BID and BAD represent an evolving set of proapoptotic molecules, which bear sequence homology only at BH3. They appear to reside more proximal in the pathway serving as death ligands. BAD connects upstream signal transduction paths with the BCL-2 family, modulating this checkpoint for apoptosis. In the presence of survival factor interleukin-3, cells phosphorylate BAD on two serine residues. This inactivated BAD is held by the 14-3-3 protein, freeing BCL-XL and BCL-2 to promote survival. Activation of BAX results in the initiation of apoptosis. Downstream events in this program include mitochondrial dysfunction, as well as Caspase activation. The pro- and antiapoptotic BCL-2 family members represent central regulators in an evolutionarily conserved pathway of cell death. Aberrations in the BCL-2 family result in disordered homeostasis, a pathogenic event in diseases, including cancer.
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PMID:BCL-2 gene family and the regulation of programmed cell death. 1019 82

The Bcl-2 protein has an anti-apoptotic effect in neuronal and other cell types. We show for the first time that the Bcl-2 promoter is activated by the neuronal survival factor nerve growth factor (NGF) and that this effect is dependent on a region of the promoter from -1472 to -1414. This activation requires the Rap-1 G protein and the MEK-1 and p42/p44 MAPK enzymes but is independent of other NGF-activated signalling pathways involving protein kinase A or protein kinase C.
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PMID:Activation of the Bcl-2 promoter by nerve growth factor is mediated by the p42/p44 MAPK cascade. 1021 80

Apoptosis is involved in the regulation of Schwann cell numbers during normal development and after axonal damage, but the molecular regulation of Schwann cell death remains unknown. We have used stably transfected rat Schwann cell lines to study the potential roles of nerve growth factor (NGF), the antiapoptotic protein Bcl-2 and the cytokine response modifier A (CrmA) in modulating Schwann cell death in vitro. Bcl-2 inhibited Schwann cell apoptosis induced by survival factor withdrawal, whereas CrmA did not. In contrast, Bcl-2-transfected Schwann cells were susceptible to apoptosis in response to exogenous NGF, whereas CrmA-expressing cell lines were resistant. Demonstration of high levels of the low-affinity neurotrophin receptor p75 but not the high-affinity TrkA receptor on the Bcl-2-transfected cell lines suggested that the NGF-induced killing was mediated by p75. This was confirmed by resistance of Schwann cells isolated from p75 knockout mice to the NGF-induced cell death. Nerve growth factor also promoted the death of wild-type mouse and rat Schwann cells in the absence of survival factor withdrawal. Endogenous Bcl-2 mRNA was expressed by wild-type Schwann cells in all conditions that promoted survival but was downregulated to undetectable levels after survival factor withdrawal. In conclusion, our results demonstrate the existence of two separate pathways that expedite apoptosis in Schwann cells: a Bcl-2-blockable pathway initiated on loss of trophic support, and a Bcl-2-independent, CrmA-blockable pathway mediated via the p75 receptor.
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PMID:Nerve growth factor signaling through p75 induces apoptosis in Schwann cells via a Bcl-2-independent pathway. 1036 17

Preeclampsia is a serious pregnancy complication diagnosed by signs of widespread maternal endothelial dysfunction. In normal pregnancy, a subpopulation of placental cytotrophoblast stem cells executes an unusual differentiation program that leads to invasion of the uterus and its vasculature. This process attaches the conceptus to the uterine wall and starts the flow of maternal blood to the placenta. Preeclampsia is associated with abnormal cytotrophoblast differentiation, shallow invasion, and decreased blood flow to the placenta. To determine whether abnormal differentiation and/or hypoxia leads to cytotrophoblast apoptosis, we used the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) method to label DNA strand breaks in tissue sections of the placenta and the uterine wall to which it attaches. Control samples (n = 9) showed almost no apoptosis, but in samples from patients with preeclampsia, 15-50% of the cytotrophoblasts that invaded the uterine wall were labeled (8/9 samples). These same cells failed to stain for Bcl-2, a survival factor normally expressed by trophoblasts in both the placenta and the uterine wall. Our results show that preeclampsia is associated with widespread apoptosis of cytotrophoblasts that invade the uterus. The magnitude of programmed cell death in this population may account for the sudden onset of symptoms in some patients, as well as the associated coagulopathies.
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PMID:Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall. 1039 61

The Bax protein is widely known as a pro-apoptotic Bcl-2 family member that when overexpressed can trigger apoptosis in multiple cell types and is important for the developmental cell death of neurons. However, Bax was found here to be a potent inhibitor of neuronal cell death in mice infected with Sindbis virus. Newborn mice, which are highly susceptible to a fatal infection with neurotropic Sindbis virus, were significantly protected from neuronal apoptosis and fatal disease when infected with a recombinant Sindbis virus encoding Bax. Deletion of the N terminus of Bax, which mimics cleaved Bax, converted Bax into a pro-apoptotic factor in vivo. As mice mature during the first week after birth, they acquire resistance to a fatal Sindbis virus infection. However, Bax-deficient mice remained very sensitive to fatal disease compared with their control littermates, indicating that endogenous Bax functions as a survival factor and contributes to age-dependent resistance to Sindbis virus-induced mortality. The protective effects of Bax were reproduced in cultured hippocampal neurons but not in cultured dorsal root ganglia neurons. These findings indicate that cell-specific factors determine the anti-apoptotic versus pro-apoptotic function of Bax.
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PMID:Inhibition of virus-induced neuronal apoptosis by Bax. 1039 31

Erythropoietin (Epo) initiates its cellular response by binding to the Epo receptor, which triggers the activation of signal transducer and activator of transcription (Stat) 5 protein. Cell culture studies of erythroid progenitors have suggested that Epo functions as a survival factor by repressing apoptosis at least in part through Bcl-x(L), an anti-apoptotic protein of the Bcl-2 family. In this report, we examine whether Stat5 can induce transactivation of the bcl-x gene in response to Epo. Two Epo-responsive progenitor cell lines, HCD-57 and Bcl-2-transfected Ba/F3-Epo receptor (Ba/F3-EpoR-Bcl-2), were used in this study. After Epo stimulation, we observed a correlation between expression of bcl-x(L) and activation of Stat5 as assessed by the expression of oncostatin M, a direct target of Stat5, and the phosphorylation and nuclear translocation of Stat5. Moreover, a Stat binding element in the bcl-x promoter was found to be active in response to Epo, a finding that was further confirmed because mutagenesis of this sequence motif abrogated its promoter activity and overexpression of a dominant negative Stat5 protein blocked transactivation. When DNA-protein binding analyses were performed, we found that Stat5, not Stat1 or Stat3, was the protein bound to the bcl-x promoter in response to Epo. These data suggest that Epo-dependent activation of Stat5 is a transcriptional pathway that can be used by Epo-responsive progenitor cells to induce the expression of bcl-x(L) and consequently to inhibit apoptosis.
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PMID:Erythropoietin can induce the expression of bcl-x(L) through Stat5 in erythropoietin-dependent progenitor cell lines. 1042 80

We have examined potential mechanisms by which the Pim-1 kinase acts as a hematopoietic cell survival factor. Enforced expression of the wild type 33 kd (FD/hpim33) and 44 kd (FD/mpim44) Pim-1 proteins in murine factor-dependent FDCP1 cells prolonged survival after withdrawal of IL-3, while expression of a dominant negative Pim-1 protein (FD/pimNT81) shortened survival. Following removal of IL-3 FDCP1 cells exhibited loss of mitochondrial transmembrane potential and production of reactive oxygen species, as determined by flow cytometry analysis. The wild type Pim-1 proteins decreased these changes while the dominant negative protein enhanced mitochondrial dysfunction. The antiapoptotic activity of the kinases could not be attributed to modulation of glutathione, catalase, or superoxide dismutase activities. Both the FD/hpim33 and FD/mpim44 cells maintained expression of bcl-2 mRNA following cytokine removal, while a substantial decrease was seen in FD/neo cells. To modulate Bcl-2 protein levels, a bcl-2 antisense RNA construct was coexpressed with the wild type pim-1 cDNAs. FD/hpim33 cells with low cellular Bcl-2 protein levels had shortened cytokine-independent survival compared with FD/hpim33 clones with high Bcl-2 expression. However survival of FD/mpim44 cells after IL-3 withdrawal was substantially independent of cellular Bcl-2 protein levels. The 33 kd protein delayed, and the 44 kd protein completely prevented enhanced cell death associated with enforced expression of human Bax protein however. Our results suggest that the 33 kd Pim-1 kinase may enhance cell survival through cooperation with and regulation of bcl-2. In addition the 44 kd kinase may regulate the expression or activity of other pro- and anti-apoptotic members of the bcl-2 family.
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PMID:The PIM-1 serine kinase prolongs survival and inhibits apoptosis-related mitochondrial dysfunction in part through a bcl-2-dependent pathway. 1043 26


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