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 common cytokine receptor gamma chain (gamma(c)) is an indispensable subunit for the formation of lymphoid-related cytokine receptors, including IL-7 and IL-15 receptors, that mediate nonredundant or critical signals for the differentiation of T and B cells and natural killer (NK) cells, respectively. We introduced the bcl-2 transgene driven by E mu or H-2K promoters into gamma(c)-deficient mice that lack all three lymphoid subclasses. The forced expression of Bcl-2 restored all stages of T lymphopoiesis, but not B or NK cell development, indicating that a primary function of gamma(c)-mediated signals in the T lineage might be to maintain cell survival. Therefore, the development of T, B, and NK cells may be influenced by distinct intracytoplasmic signaling cascades that are activated by coupling of gamma(c)-related receptors.
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PMID:Bcl-2 rescues T lymphopoiesis, but not B or NK cell development, in common gamma chain-deficient mice. 925 28

During proliferative glomerulonephritis, the early phase of mesangiolysis is linked to increased nitric oxide (NO) production. NO. as well as superoxide (O2-) are inflammatory mediators that are generated by mesangial cells (MC) after cytokine stimulation. Added individually, both radicals induce MC apoptosis. However, the co-existence of a defined NO./O2- ratio is cross-protective. Apoptosis is characterized by specific features such as chromatin condensation, DNA strand breaks, and the occurrence of apoptotic regulating proteins. The tumor suppressor p53 and Bax (Bcl-2 associated protein x) are considered to be classical death promotors, which accumulate after toxic insults. To study p53 and Bax protein accumulation in NO. and/or O2(-)-induced apoptosis, we used the NO-donor S-nitrosoglutathione (GSNO) and the redox cycler 2,3-dimethoxy-1,4-naphtoquione (DMNQ). Both agonists initiated DNA fragmentation in a concentration dependent manner associated with transient p53 and Bax up-regulation. Co-generation of NO./O2- resulted not only in reduced DNA fragmentation, but also in decreased Bax accumulation. Comparable to the NO./O2- co-generation, cytokines failed to induce apoptosis. In contrast, cytokines in combination with pyrrolidine dithiocarbamate, which blocks endogenous superoxide dismutase, allowed p53 and Bax accumulation as well as DNA fragmentation. Our results demonstrate p53 and Bax as early components in NO. and O2(-)-induced rat MC apoptosis and point to the NO./O2- interaction as a naturally occurring cell defense mechanism.
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PMID:Nitric oxide and superoxide induced p53 and Bax accumulation during mesangial cell apoptosis. 926 93

Recent studies have shown that the treatment of nonmetastatic K-1735 murine melanoma cells with cytokines induces the production of nitric oxide (NO) and hence cell death. The purpose of this study was to determine the mechanism of this cytokine-induced NO-mediated apoptosis. Incubation of nonmetastatic K-1735 cells with interleukin-1 alpha (IL-1alpha) and interferon-gamma (IFN-gamma) induced high NO production, Bcl-2 downregulation, and apoptotic cell death. In contrast, incubation of metastatic K-1735 cells with IL-1alpha and IFN-gamma did not induce significant production of NO, downregulation of Bcl-2, or cell death. The exposure to exogenous NO derived from the NO donors, sodium nitroprusside (SNP), or GEA5024 produced a dose-dependent apoptotic cell death in both the metastatic and nonmetastatic K-1735 cells, which was associated with downregulation of Bcl-2 at the mRNA level and, to a lesser extent, at the protein level. Nonmetastatic and metastatic K-1735 cells transfected with the Bcl-2 gene were more resistant to apoptosis mediated by both endogenous and exogenous NO. Subsequent to intravenous injection, the tumor cells transfected with the Bcl-2 gene had an increased survival rate in the lungs of nude mice and produced a higher number of experimental lung metastases. These data suggest that NO-induced apoptosis in K-1735 melanoma cells is associated with downregulation of Bcl-2.
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PMID:Nitric oxide-mediated apoptosis of K-1735 melanoma cells is associated with downregulation of Bcl-2. 926 63

The Bcl-2 family of proteins regulate apoptosis, some antagonizing cell death and others facilitating it. It has recently been demonstrated that Bcl-2 not only inhibits apoptosis but also restrains cell cycle entry. We show here that these two functions can be genetically dissociated. Mutation of a tyrosine residue within the conserved N-terminal BH4 region had no effect on the ability of Bcl-2 or its closest homologs to enhance cell survival and did not prevent heterodimerization with death-enhancing family members Bax, Bak, Bad and Bik. Neither did this mutation override the growth-inhibitory effect of p53. However, on stimulation with cytokine or serum, starved quiescent cells expressing the mutant proteins re-entered the cell cycle much faster than those expressing comparable levels of wild-type proteins. When wild-type and Y28 mutant Bcl-2 were co-expressed, the mutant was dominant. Although R-Ras p23 has been reported to bind to Bcl-2, no interaction was detectable in transfected cells and R-Ras p23 did not interfere with the ability of Bcl-2 to inhibit apoptosis or cell cycle entry. These observations provide evidence that the anti-apoptotic function of Bcl-2 is mechanistically distinct from its inhibitory influence on cell cycle entry.
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PMID:The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. 930 7

Resolution of glomerular inflammation requires the removal of proliferating resident glomerular mesangial cells, but excessive loss of glomerular cells is a feature of postinflammatory scarring. Because apoptosis regulates mesangial cell number in glomerular inflammation, we have studied the exogenous control of apoptosis triggered in cultured mesangial cells by stimuli likely to be important in vivo. Apoptosis could be induced by serum deprivation to model decreased availability of survival factors, by etoposide as an example of DNA-damaging agents, by ligation of mesangial cell Fas, and by protein synthesis inhibition by cycloheximide. Insulin-like growth factor I (IGF-I), IGF-II, and basic fibroblast growth factor were each able to suppress apoptosis induced by serum deprivation, whereas TGF-beta 1, epidermal growth factor, and platelet-derived growth factor had no effect. IGF-I and IGF-II (but not basic fibroblast growth factor) were also able to protect cells from apoptosis induced by etoposide or cycloheximide. However, Fas-mediated apoptosis was resistant to suppression by all three cytokines. None of the cytokines tested caused a change in the levels of expression of Bcl-2, Bax, Bcl-x, or Bak proteins. The survival-promoting properties of serum-free medium conditioned by mesangial cells was abrogated by neutralizing IGF-I Ab. These experiments are the first to define cytokines that inhibit apoptosis and thereby promote survival of mesangial cells, and the data indicate a paracrine survival signaling role for IGF-I. Finally, the data show that Fas ligation can override cytokine survival signaling, emphasizing a candidate role for this molecule in the undesirable apoptotic loss of mesangial cells during the progression of glomerular scarring.
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PMID:Cytokines promote glomerular mesangial cell survival in vitro by stimulus-dependent inhibition of apoptosis. 937 83

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces apoptosis in various cell systems by binding to the TNF receptor (TNFR). To study TNF-alpha-induced apoptosis, we isolated and characterized a novel TNF-alpha-resistant variant, U937/TNF clone UA, from human monocytic leukemia U937 cells. The UA cells resist apoptosis induced by TNF-alpha and anti-Fas antibody but not by anticancer drugs, such as VP-16 and Ara-C. Somatic cell hybridization between U937 and UA showed that apoptosis resistance to TNF-alpha in UA was genetically recessive. The hybridization analysis also showed that UA and another recessive mutant clone, UC, belong to different complementation groups in TNF-alpha-induced apoptosis signaling. In UA cells, TNF-alpha-induced disruption of mitochondrial membrane potential and CPP32 activation were abrogated. Expression of TNFR, Fas, and Bcl-2 family proteins was not changed in UA cells. These results suggest that the apoptosis resistant UA cells could have a functional defect in apoptosis signaling from the TNFR to mitochondria and interleukin-1beta converting enzyme (ICE) family protease activation. UA cells could be used to study signaling linkage between cell death-inducing receptor and mitochondria.
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PMID:Genetically recessive mutant of human monocytic leukemia U937 resistant to tumor necrosis factor-alpha-induced apoptosis. 942 4

Interleukin 3 (IL-3)-dependent 32D.3 myeloid cells are an attractive model system for the analysis of hematopoietic cell growth, differentiation, and apoptosis. In these cells, E2F-3, E2F-4, and DP-1 are regulated by both IL-3 and granulocyte colony-stimulating factor (G-CSF), whereas E2F-1 was expressed at low levels and was not regulated by either cytokine. E2F-2 and E2F-5 were not detectable. To examine phenotypes associated with the loss of normal cell cycle regulation by pRb, we established E2F-1- and E2F-3-overexpressing cell lines. In contrast to E2F-1, E2F-3 overexpression did not accelerate apoptosis or promote S-phase entry in the absence of IL-3, demonstrating that they are not functionally redundant. In addition, when cells were cultured in G-CSF to stimulate granulocytic differentiation, E2F-1 overexpression overrode survival functions provided by G-CSF and serum and induced apoptosis. In contrast, cells overexpressing E2F-3 exhibited normal granulocytic differentiation. Bcl-2 coexpression blocked E2F-1-induced apoptosis in the presence of G-CSF. However, these cells were blocked in the granulocytic differentiation program at the metamyelocyte stage and remained dependent on G-CSF for continuous culture. Cells overexpressing both E2F-1 and Bcl-2 exhibited slowed but continuous cell cycling in the absence of IL-3 until they eventually succumbed to apoptosis. Therefore, E2F-1, but not E2F-3, can temporally replace the requirement for growth factors to promote cell cycle progression, and in terminally differentiating cells, this leads to a block in differentiation and induction of apoptosis.
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PMID:E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation. 943 89

The hallmark of chronic myeloid leukemia (CML) is the chimeric tyrosine kinase oncogene bcr-abl. Since expression of bcr-abl mRNA frequently increases with disease progression and a duplication of the Philadelphia chromosome (harbouring the bcr-abl hybrid locus) represents the most frequent karyotypic abnormality in acute phase CML, we hypothesized that the level of BCR-ABL protein may affect the disease phenotype. Therefore, the biological effects of high and low levels of BCR-ABL expression were compared in growth factor-dependent and -independent myeloid and lymphoid cell lines. Our results demonstrated that low levels of BCR - ABL were sufficient to render these cell lines growth factor independent and tumorigenic, but higher levels were mandatory for additional protection against apoptotic stimuli. The provision of growth factor or an activated ras oncogene did not afford the same degree of protection as high levels of BCR-ABL and there were qualitative differences between the survival signals mediated by BCR-ABL and Bcl-2. These results have enabled us to establish a dose-dependent hierarchy of BCR-ABL induced biological effects, thus distinguishing the activation of pathways mediating protection from cytokine withdrawal from those protecting against other apoptotic stimuli.
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PMID:BCR-ABL activates pathways mediating cytokine independence and protection against apoptosis in murine hematopoietic cells in a dose-dependent manner. 946 59

The anti-tumour alkaloid taxol shows strong cytotoxic and antiproliferative activity in two human malignant glioma cell lines, T98G and LN-229. CD95 (Fas/APO-1) ligand is a novel cytotoxic cytokine of the tumour necrosis factor (TNF) family that exerts prominent antiglioma activity. At clinically relevant taxol concentrations of 5-100 nM, taxol and CD95 ligand showed significant synergistic cytotoxicity and growth inhibition. High concentrations of taxol induced G/M cell cycle arrest in both cell lines. The synergy of taxol and CD95 ligand was independent of cell cycle effects of taxol as synergy was achieved at much lower taxol concentrations than G2/M arrest and as cell cycle effects of taxol were unaffected by co-exposure to CD95 ligand. Similarly, high concentrations of taxol were required to induce p53 activity in the p53 wild-type cell line LN-229. This effect was not modulated by CD95 ligand, suggesting that synergy is also independent of p53 activation. However, taxol induced a mobility shift of the bcl-2 protein on immunoblot analysis, indicative of bcl-2 phosphorylation. Bcl-2 phosphorylation on serine was confirmed by immunoprecipitation and phosphoserine immunoblot analysis. Considering (1) that phosphorylation of bcl-2 interferes with its heterodimerization with bax and (2) the inhibition of CD95-mediated apoptosis by bcl-2, we propose that taxol sensitizes malignant glioma cells to CD95 ligand by increasing the functional bax/bcl-2 rheostat in favour of bax and thus cell death.
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PMID:Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest. 947 35

Fas antigen is constitutively expressed in the normal colon epithelium, but considerably diminished in most colorectal carcinomas. In the present study, we examine the relationship between Fas antigen expression and apoptosis using the colorectal carcinoma cell line COLO 201, on which a low grade of Fas antigen is expressed. Anti-Fas antibody had no effect on the induction of apoptosis of COLO 201. However, TNF-alpha and/or IFN-gamma, independently and additively, up-regulated Fas antigen expression on COLO 201 and induced apoptosis in a dose-dependent manner. Both cytokines also increased the COLO 201 sensitivity to anti-Fas antibody, resulting from the down-modulation of Bcl-2 and the up-regulation of Bax. These findings indicate that cytokine(s) plus anti-Fas antibody (which mimics natural Fas ligand) are more effective in inducing apoptosis of COLO 201 than cytokine(s) alone. These findings suggest that immunotherapy in combination with cytokine(s) and lymphokine-activated killer (LAK) cells will become a more effective therapy for cancer than cytokine(s) or LAK cells alone, since the Fas ligand is expressed on activated T cells, natural killer cells and macrophages.
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PMID:Apoptosis of colorectal adenocarcinoma (COLO 201) by tumour necrosis factor-alpha (TNF-alpha) and/or interferon-gamma (IFN-gamma), resulting from down-modulation of Bcl-2 expression. 3192 65


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