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)

Bcl-2 protein is able to repress a number of apoptotic death programs. To investigate the mechanism of Bcl-2's effect, we examined whether Bcl-2 interacted with other proteins. We identified an associated 21 kd protein partner, Bax, that has extensive amino acid homology with Bcl-2, focused within highly conserved domains I and II. Bax is encoded by six exons and demonstrates a complex pattern of alternative RNA splicing that predicts a 21 kd membrane (alpha) and two forms of cytosolic protein (beta and gamma). Bax homodimerizes and forms heterodimers with Bcl-2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of Bcl-2. These data suggest a model in which the ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus.
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PMID:Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. 835 90

Bcl-2 is a novel protooncogene which prolongs cell survival and suppresses apoptosis. We examined whether constitutive expression of transfected human bcl-2 conferred resistance to two different DNA damaging drugs, nitrogen mustard (HN2) and camptothecin (CPT) in a murine, IL-3 dependent cell line (FL5.12). HN2 treatment produced 2-fold less cell death and DNA degradation in cells overexpressing bcl-2 relative to control cells transfected with a construct bearing only the neoR gene. DNA degradation was characterized by oligonucleosomal length fragments indicating that programmed cell death or apoptosis had occurred. Equimolar HN2 produced similar extents of interstrand cross-link formation and repair in each cell line. Cell cycle characteristics were similar for both cell lines following equimolar HN2 treatment, exhibiting a brief S phase delay followed by a longer G2 arrest. Time course studies indicated that DNA fragmentation occurred following peak G2 arrest in control cells and 12 h later in bcl-2 transfected cells. Equimolar CPT exposure also induced 2-fold less death and apoptotic DNA fragmentation in bcl-2 transfected compared to control cells. DNA single strand break formation and resealing kinetics were comparable in both cell lines following equimolar CPT treatment. CPT caused similar cell cycle perturbations in both cell lines, with a brief S phase block detectable 12 h after an equimolar drug dose. Kinetic studies showed apoptosis occurred following maximal S phase arrest in control and 12 h later in bcl-2 transfected cells. By contrast, IL-3 withdrawal produced rapid and extensive DNA degradation and apoptosis in controls 24 h postwithdrawal, and this process was inhibited 3-4-fold in bcl-2 transfectants. Cell cycle analysis showed both cell lines arrested in G0/G1 following IL-3 removal. In summary, bcl-2 transfection affords a 2-fold protection from HN2 and CPT cytotoxicity and decreases drug induced apoptosis in FL5.12 cells, despite the different mechanisms of action and cell cycle effects of each agent. Bcl-2 overexpression appears to represent a novel drug resistance mechanism of potential clinical significance.
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PMID:Constitutive expression of human Bcl-2 modulates nitrogen mustard and camptothecin induced apoptosis. 846 5

Methional is a potent inducer of apoptosis in an interleukin 3-dependent murine lymphoid cell line BAF3 b0 when it is added to the culture medium. In these cells transfected with the bcl2 gene, BAF3 bcl2, the apoptotic-inducing activity of methional is dramatically reduced. The addition of disulfiram (an inhibitor of aldehyde dehydrogenase) in order to reduce methional oxidation brought about an increase in apoptosis in BAF3 b0 but not in BAF3 bcl2 cells. In contrast, the addition of quercetin (an inhibitor of aldehyde reductase) in an attempt to diminish methional reduction increased apoptosis in both BAF3 b0 and BAF3 bcl2 cells. The extent of DNA fragmentation in BAF3 bcl2 cells approached that in BAF3 b0 cells in the presence of quercetin and exogenous methional, suggesting a defect in methional biosynthesis in BAF3 bcl2 cells. Direct evidence for this was obtained by measuring labelled methional in cells incubated with the sodium, salt of [U-14C]4-methylthio-2-oxobutanoic acid (MTOB), the precursor of methional. The 80% decrease in labelled methional in BAF3 bcl2 compared with BAF3 b0 cells was accompanied by a concomitant rise in the transamination of [14C]MTOB to [14C]methionine in BAF3 bcl2 cells. Inhibition of the transaminase, however, by a synthetic transition-state-type compound, pyridoxal-L-methionine ethyl ester, induced apoptosis in BAF3 b0 but not in BAF3 bcl2 cells, confirming that the defect in BAF3 bcl2 cells was not in the transaminase itself but rather in the oxidative decarboxylation step MTOB --> methional. In addition, no evidence was obtained for the synthesis of [14C]malondialdehyde from [14C]methional in BAF3 bcl2 cells. As these cells show no deficiency in their content of reactive oxygen species compared with that of BAF3 b0 cells, they may possess some other defect in the beta-hydroxylase enzyme system itself.
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PMID:Altered methional homoeostasis is associated with decreased apoptosis in BAF3 bcl2 murine lymphoid cells. 861 Nov 83

In our previous studies aiming at the design of appropriate strategies to accelerate the recovery of the immune system after irradiation, we found that recombinant murine (rmu) IL-3 treatment induces differentiation and growth of thymocytes and splenic T and B lymphocytes in mice exposed to X-rays (200-500 cGy). These studies were extended to investigate the effects of recombinant human (rhu) IL-11. Results indicate that rhuIL-11 is able to restore thymus and spleen cell numbers as well as T and B cell mitotic responsiveness in mice exposed to 200 cGy but not to 300 cGy. However, recovery of thymus and spleen cell numbers and functions could be accelerated also in mice exposed to higher dose if rhuIL-11 was given with rmuIL-3. Recovery was complete as soon as 7 days after irradiation. A large dose of both cytokines was explored and the synergistic effect of the two cytokines was evident when a relatively small dose of rhuIL-11 was injected with graded doses of rmuIL-3. The recovery of the immune system in irradiated mice injected with these cytokines was independent from Bcl-2 expression, suggesting that elimination of damaged cells by apoptosis is unaffected by hematopoietic cytokines.
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PMID:IL-11 synergizes with IL-3 in promoting the recovery of the immune system after irradiation. 988 88

Mutations in the retinoblastoma (pRb) tumor suppressor pathway including its cyclin-cdk regulatory kinases, or cdk inhibitors, are a hallmark of most cancers and allow unrestrained E2F-1 transcription factor activity, which leads to unregulated G1-to-S-phase cell cycle progression. Moderate levels of E2F-1 overexpression are tolerated in interleukin 3 (IL-3)-dependent 32D.3 myeloid progenitor cells, yet this induces apoptosis when these cells are deprived of IL-3. However, when E2F activity is augmented by coexpression of its heterodimeric partner, DP-1, the effects of survival factors are abrogated. To determine whether enforced E2F-1 expression selectively sensitizes cells to cytotoxic agents, we examined the effects of chemotherapeutic agents and radiation used in cancer therapy. E2F-1 overexpression in the myeloid cells preferentially sensitized cells to apoptosis when they were treated with the topoisomerase II inhibitor etoposide. Although E2F-1 alone induces moderate levels of p53 and treatment with drugs markedly increased p53, the deleterious effects of etoposide in E2F-1-overexpressing cells were independent of p53 accumulation. Coexpression of Bcl-2 and E2F-1 in 32D.3 cells protected them from etoposide-mediated apoptosis. However, Bcl-2 also prevented apoptosis of these cells upon exposure to 5-fluorouracil and doxorubicin, which were also cytotoxic for control cells. Pretreating E2F-1-expressing cells with ICRF-193, a second topoisomerase II inhibitor that does not damage DNA, protected the cells from etoposide-induced apoptosis. However, ICRF-193 cooperated with DNA-damaging agents to induce apoptosis. Therefore, topoisomerase II inhibition and DNA damage can cooperate to selectively induce p53-independent apoptosis in cells that have unregulated E2F-1 activity resulting from mutations in the pRb pathway.
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PMID:E2F-1 cooperates with topoisomerase II inhibition and DNA damage to selectively augment p53-independent apoptosis. 903 31

The inhibition of cell death by growth factors plays a key role in the maintenance of the haematopoietic system homeostasis. However the mechanisms involved in this inhibition are still poorly understood. In order to determine if inhibition of apoptosis by growth factors is dependent only on the expression of survival genes, we have studied that process in the bone marrow derived IL-3 dependent cell line Baf-3. We show that, following IL-3 starvation, mRNA and protein levels of Bcl-X but not Bcl-2 decrease rapidly preceeding the onset of death. The death of IL-3 starved cells is asynchronous, starting between 6 to 8 h with 50% death being reached after 10 to 12 h. At any time point, apoptosis can be rapidly inhibited by growth factor re-addition. This has allowed us to determine that the inhibition of apoptosis by growth factor takes place at two levels. The first one, which we have called short term inhibition, is independent of mRNA and protein synthesis i.e. it takes place in the absence of survival gene neosynthesis and can be demonstrated during the first 6 h following growth factor re-addition. The second one corresponds to long-term survival-more than 24 h survival-and is strongly correlated with the induction of Bcl-X but not Bcl-2 gene expression. This induction of Bcl-X by IL-3 is shown to be dependent on MAP-kinase activation.
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PMID:In bone marrow derived Baf-3 cells, inhibition of apoptosis by IL-3 is mediated by two independent pathways. 905 39

ICE-like protease activation and DNA fragmentation are preceded by a decrease in intracellular pH (pHi) during apoptosis in the IL-3 dependent cell line BAF3. Acidification occurs after 7 hours in cells deprived of IL-3 and after 4 hours when cells are treated with etoposide, close to the time of detection of ICE-like protease activity. Increasing extracellular pH reduces ICE-like protease activation and DNA fragmentation. Bcl-2 over-expression both delays acidification and inhibits ICE-like protease activation. Generation of a rapid intracellular pH decrease, using the ionophore nigericin, induces ICE-like protease activation and apoptosis. ZVAD, a cell permeable inhibitor of ICE-like proteases, does not affect acidification but inhibits apoptosis induced by IL-3 removal or nigericin treatment. These data suggest that intracellular acidification triggers apoptosis by directly or indirectly activating ICE-like proteases.
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PMID:Intracellular acidification induces apoptosis by stimulating ICE-like protease activity. 909 47

The interleukin-2 (IL-2) receptor (IL-2R) is composed of three subunits. Of these, IL-2Ra is required for high-affinity IL-2 binding, while IL-2R beta and IL-2R gamma(c) are required for the transduction of IL-2-generated signals. Signals transduced via the S region of the IL-2R beta (amino acids 267-322) in BAF/3 cells activate the phosphatidylinositol 3-kinase (PI3-kinase) and induce the expression of Bcl-2 and c-myc. Through the induction of Bcl-2, IL-2 inhibits apoptosis and through the combination of Bcl-2 and c-myc it stimulates progression through the cell cycle. Here we show that the protein kinase encoded by the Akt proto-oncogene is activated by IL-2. Akt activation by IL-2 depends on PI3-kinase signals transduced via the S region of the IL-2R beta and is linked to the translocation of Akt to the cell membrane. Expression of catalytically active Akt mutants in BAF/3 cells expressing IL-2R beta[A0]delta S promotes the expression of Bcl-2 and c-myc, inhibits apoptosis induced by IL-3 deprivation or staurosporine, and stimulates cell cycle progression. The same mutants also stimulate cell cycle progression in 2780a, an IL-2-dependent T cell line that undergoes G1 arrest rather than apoptosis after IL-2 deprivation. The activation of Akt by IL-2 via the PI3-kinase and the rescue of the PI3-kinase-mediated antiapoptotic and proliferative IL-2 signals by catalytically active Akt indicate that these signals are transduced by Akt.
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PMID:Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. 910 28

The protooncogene Bcl-2 functions as a suppressor of apoptosis in growth factor-dependent cells, but a post-receptor signaling mechanism is not known. We recently reported that interleukin 3 (IL-3) and erythropoietin, or the protein kinase C activator bryostatin-1 (Bryo), not only suppresses apoptosis but also stimulates the phosphorylation of Bcl-2 (May, W. S., Tyler, P. G., Ito, T., Armstrong, D. K., Qatsha, K. A., and Davidson, N. E. (1994) J. Biol. Chem. 269, 26865-26870). To test whether phosphorylation is required for Bcl-2 function, conservative serine --> alanine mutations were produced at the seven putative protein kinase C phosphorylation sites in Bcl-2. Results indicate that the S70A Bcl-2 mutant fails to be phosphorylated after IL-3 or Bryo stimulation and is unable to support prolonged cell survival either upon IL-3 deprivation or etoposide treatment when compared with wild-type Bcl-2. In contrast, a Ser --> Glu mutant, S70E, which may mimic a potential phosphate charge, more potently suppressed the etoposide-induced apoptosis than wild type in the absence of IL-3. Since the loss of function S70A mutant can heterodimerize with its partner protein and death effector Bax, these findings demonstrate that Bcl-2:Bax heterodimerization is not sufficient and Bcl-2 phosphorylation is required for full Bcl-2 death suppressor signaling activity.
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PMID:Bcl-2 phosphorylation required for anti-apoptosis function. 911 13

The proto-oncogene product Bcl-2 regulates cell survival in both the immune and central nervous systems. We withdrew growth factors from IL-3-dependent murine myeloid progenitor cells (factor dependent cell progenitors (FDCP)) and measured a time-dependent 80% reduction in endogenous expression of Bcl-2. This decline in Bcl-2 is directly associated with a fourfold increase in the apoptotic population after 12 h and an eightfold increase after 24 h. Since IL-4 and insulin-like growth factor-I (IGF-I) regulate myeloid cell growth, we used IL-3-deprived FDCP cells to determine whether IL-4 and IGF-I maintain Bcl-2 expression and prevent apoptosis. We demonstrate that IL-4, like IGF-I and IL-3, promotes survival of FDCP cells by reducing the apoptotic population. Flow cytometric measurement of intracellular Bcl-2 established that IL-4 and IGF-I maintain 10-fold higher levels of Bcl-2 than in IL-3-deprived cells. Similarly, Western analysis of Bcl-2 in lysates of IL-3-deprived myeloid progenitors confirmed that both IL-4 and IGF-I share with IL-3 the ability to maintain intact Bcl-2 protein. However, IL-4 and IGF-I do not change expression of the apoptotic inducer, Bax, although they maintain high levels of Bcl-2 that coimmunoprecipitate with Bax. Collectively, these data demonstrate that IL-4 and IGF-I, like IL-3, inhibit apoptosis in myeloid progenitors and maintain high levels of Bcl-2/Bax heterodimers, suggesting that Bcl-2 is a critical convergence point in the signaling pathways used by IL-4 and IGF-I.
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PMID:IL-4 and insulin-like growth factor-I inhibit the decline in Bcl-2 and promote the survival of IL-3-deprived myeloid progenitors. 923 17


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