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)

We have shown that the ability of the human follicular lymphoma-derived cell line SU-DHL-6 to proliferate and survive in vitro depends on both Bcl-2 expression and multiple autocrine growth factors. Treatment with Bcl-2 antisense (AS Bcl-2) decreased Bcl-2 protein levels. However, a cytotoxic effect was seen only at very restricted cell densities. Below such densities cells underwent spontaneous death without any treatment, while above these cell densities no cytotoxic effect of AS Bcl-2 could be seen. The conditioned medium of SU-DHL cells supported the survival and growth of these cells cultivated at low cell densities and partially reversed the cytotoxicity associated with Bcl-2 depletion. RT/PCR analysis revealed autocrine expression of IL-1 beta, IL-2, IL-5 and TNF-beta in SU-DHL cells. Neutralizing antibodies against these cytokines inhibited SU-DHL proliferation. Thus, development of autocrine GF secretion may be the second step in the pathogenesis of follicular lymphomas.
Eur Cytokine Netw
PMID:The role of Bcl-2 protein and autocrine growth factors in a human follicular lymphoma-derived B cell line. 779 71

Cytokine-mediated cell death in tumor cells can be achieved through endogenous nitric oxide (NO) from within tumor cells or exogenous NO from either activated macrophages or endothelial cells. The purpose of this study was to determine the role of Bcl-2 in NO-mediated apoptosis. The incubation of murine L929 and NIH3T3 cells with interleukin-1 alpha (IL-1 alpha) and interferon gamma (IFN gamma) induced high endogenous NO production only in the L929 cells that also underwent apoptosis. NIH3T3 cells were not resistant to NO-mediated apoptosis. In fact, the incubation of L929 and NIH3T3 cells with exogenous NO derived from NO donors, sodium nitroprusside, or S-nitroso-N-acetyl-DL-penicillamine (SNAP) induced death, characterized by typical apoptotic morphology and DNA fragmentation, in both cell types, but to a higher degree in NIH3T3 cells than in the L929 cells. We then measured the effect of Bcl-2 expression on exogenous NO-induced apoptosis. At both the mRNA and protein levels, L929 fibroblasts expressed higher levels of endogenous mouse Bcl-2 than did NIH3T3 cells. At the same time, L929 cells were much more resistant to exogenous NO-induced cell death than were NIH3T3 cells. The inverse correlation between mouse Bcl-2 expression and sensitivity to exogenous NO-mediated cell death was also found in the murine K-1735 melanoma C-23 and X-21 clonal populations. Transfection of both NIH3T3 cells and L929 cells with the human bcl-2 gene led to resistance to both exogenous and endogenous NO-mediated apoptosis. These data demonstrate that NO-mediated apoptosis can be suppressed by expression of Bcl-2, suggesting that abnormal expression of Bcl-2 may influence the efficacy of tumor immunotherapy.
 ...
PMID:Bcl-2 protects cells from cytokine-induced nitric-oxide-dependent apoptosis. 895 45

Proteases are now firmly established as major regulators of the "execution" phase of apoptosis. Here, we examine the role of proteases and their relationship to ceramide, a proposed mediator of apoptosis, in the tumor necrosis factor-alpha (TNF-alpha)-induced pathway of cell death. Ceramide induced activation of prICE, the protease that cleaves the death substrate poly(ADP-ribose) polymerase. Bcl-2 inhibited ceramide-induced death, but not ceramide generation. In contrast, Cytokine response modifier A (CrmA), a potent inhibitor of Interleukin-1 beta converting enzyme and related proteases, inhibited ceramide generation and prevented TNF-alpha-induced death. Exogenous ceramide could overcome the CrmA block to cell death, but not the Bcl-2 block. CrmA, however, did not inhibit the activation of nuclear factor (NF)-kappa B by TNF-alpha, demonstrating that other signaling functions of TNF-alpha remain intact and that ceramide does not play a role in the activation of NF-kappa B. These studies support a distinct role for proteases in the signaling/activation phase of apoptosis acting upstream of ceramide formation.
 ...
PMID:Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-alpha: CrmA and Bcl-2 target distinct components in the apoptotic pathway. 905 48

Cytokines such as IL-2 or IL-3 prevent cell death through apoptosis, either by preventing apoptosis directly or by sensitizing cells to survival factors present in serum. We demonstrate herein that BAF-B03 cells transfected with the wild-type IL-2R beta-chain undergo apoptosis when stimulated with IL-2 or IL-3 in the absence of serum. IL-2 also induced apoptosis in normal IL-2-responsive human T cell blasts in the absence of serum, and furthermore, epidermal growth factor and fibroblast growth factor induced increased rates of apoptosis in fibroblasts in the absence of serum, suggesting that cytokine-induced apoptosis in the absence of serum survival factors might represent an important biologic phenomenon. In the presence or the absence of serum, IL-2 and IL-3 induced expression of both c-Myc and Bax. In contrast, optimal cytokine-induced expression of Bcl-2 requires serum. Constitutive expression of Bcl-2 prevented cytokine-induced apoptosis. Transferrin mimicked serum by inducing an increase in Bcl-2 expression levels and concurrently prevented apoptosis. These results suggest that the balance between cytokine- and serum-induced Bcl-2 expression and cytokine-induced Bax expression may determine whether a cell undergoes cytokine-induced apoptosis. In BAF/BO3 cells expressing a mutant IL-2Rbeta with a deletion of the acidic domain, IL-2 did not induce either Bax expression or apoptosis. This suggests that the acidic domain of the IL-2R beta-chain plays an essential role in regulating IL-2-mediated Bax expression and apoptosis. Cytokine-induced apoptosis and its counterbalance by survival factors present in serum may play an important role in the regulation of cellular homeostasis during pathophysiologic processes.
 ...
PMID:Dissociation of cytokine signals for proliferation and apoptosis. 954 71

Interleukin 2 (IL-2)- and IL-4-mediated stimulation of survival and growth, reflected by the induction of bcl2 and c-myc, respectively, depends on the integrity of the membrane-proximal region (S-region) in the IL-2 receptor beta-chain (IL-2R beta) and the haematopoietin homology box1-containing region of the IL-4 receptor alpha-chain (IL-4R alpha). In contrast to IL-4, IL-2 induces the expression of c-fos and c-jun family genes, mediated by the acidic region (A-region) within the cytoplasmic domain of IL-2R beta. A highly acidic motif is also present in IL-4R alpha, and evidence in favour and against its importance has been published. The authors have constructed chimeric receptors between IL-2R beta and IL-4R alpha by substitution of either the S-region or the A-region of IL-2R beta with sequences derived from IL-4R alpha. These chimeras were stably transfected into BA/F3 cells and assayed for the capacity to restore functions of IL-2 beta, such as growth mediation by IL-2 and the induction of proto-oncogenes (c-myc, c-junB and c-fos). Replacement of both the S- and A-region of IL-2R beta with IL-4R alpha derived regions of similar size and cytoplasmic location supported growth-stimulation by IL-2 as well as proto-oncogene induction. In contrast, all IL-2R functions were lost by exchange of the S-region with the corresponding part of IL-4R alpha. Induction of c-junB and c-fos RNA as an indicator of A-region function, however, was maintained in an IL-2R beta chimera containing the acidic box-bearing region of IL-4R alpha. These data indicate a functional role of the acidic region in the IL-4R alpha-chain.
Cytokine 1998 May
PMID:Function of the human interleukin 4 receptor (IL-4R)-derived acidic motif revealed by cytoplasmic domain chimeras of the IL-4R alpha chain and the IL-2R beta chain. 961 70

Aging is associated with a decline in T cell proliferative responses and aberrations in cytokine production. In the present study, we examined if aging might alter the expression of the tumor-suppressor protein p53 and the retinoblastoma susceptibility gene product (Rb) as well as the levels of Bcl-2 in resting and activated human T cells. No significant differences were observed in the basal levels of p53 protein among resting T cells from young and elderly humans. After stimulation with anti-CD3 monoclonal antibody (mAb) OKT3 and phorbol myristate acetate (PMA), T cells from young humans exhibited severalfold increases in p53 protein expression compared with resting T cells. By contrast, T cells from a substantial portion of elderly humans failed to demonstrate significant increases in p53 in response to anti-CD3 plus PMA. No age-related alterations in the levels of Rb or Bcl-2 proteins were observed in resting or anti-CD3/PMA-stimulated T cells. To delineate whether the age-related reductions in p53 expression might be linked to decreased interleukin-2 (IL-2) production, we compared the expression of p53 and IL-2 in anti-CD3/PMA-stimulated T cells from elderly people. The results showed that impaired induction of p53 expression in activated T cells from certain elderly people could be observed without considerable impairments in IL-2 production. These observations suggest that age-related reductions in T cell expression of p53 may contribute to the decline of T cell competence independent of the impairments in IL-2 production.
J Interferon Cytokine Res 1998 May
PMID:Differential expression of p53 tumor suppressor protein and IL-2 in activated T cells from elderly humans. 962 Mar 58

Cytokine-mediated enhancement of spontaneous cytotoxicity depends, at least in part, on modulation of the expression of surface molecules responsible for recognition of target cell structures and triggering or inhibition of the cytotoxic machinery. We previously demonstrated that expression of transcription factors (e.g., Egr-1, JunB, and c-Fos) is differentially regulated by IL-2 and IL-12. Here we show that expression of CD161/NKR-P1A, a molecule involved in triggering cytotoxicity, is specifically upregulated by IL-12. CD161 transcription, mRNA accumulation, and surface expression are increased by IL-12. Other cytokines sharing the IL-2R beta- and/or common gamma-chains (i.e., IL-15, IL-4, and IL-7) do not mediate these effects. In an effort to analyze the mechanisms by which IL-2, IL-12, and IL-15 differentially regulate gene transcription, we have isolated a novel gene, 197/15a, the expression of which in NK and T cells is down-regulated by IL-2 and IL-15, up-regulated by IL-12, and not affected by IL-4 and IL-7. IL-2 and IL-15 act, at least in part, repressing 197/15a transcription; their effect on 197/15a mRNA accumulation is partially independent of novel protein synthesis, likely not mediated by JunB, Bcl-2, or Bax, and requires the activity of rapamycin-sensitive molecule(s). The observation that IL-2 and IL-12 differentially modulate CD161 expression suggests the existence of cytokine-specific mechanisms of modulation of spontaneous cytotoxicity based on the regulation of expression of surface molecules involved in target cell recognition and/or triggering of the cytolytic machinery.
 ...
PMID:Differential transcriptional regulation of CD161 and a novel gene, 197/15a, by IL-2, IL-15, and IL-12 in NK and T cells. 975 69

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.
Cytokine 1998 Sep
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

-Cytokine-induced NO production depresses myocardial contractility and has been shown to be cytotoxic to cardiac myocytes. However, the mechanisms of cytokine-induced cardiac myocyte cell death are unclear. To analyze these mechanisms in detail, we treated neonatal cardiac myocytes in serum-free culture with a combination of the macrophage-derived cytokines interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma. These cytokines caused a time-dependent induction of cardiac myocyte apoptosis, but not necrosis, beginning 72 hours after treatment, as determined by nuclear morphology, DNA internucleosomal cleavage, and cleavage of poly(ADP-ribose) polymerase, reflecting caspase activation. Apoptosis was preceded by a >50-fold induction of inducible NO synthase mRNA and the release of large amounts (5 to 8 nmol/ microgram protein) of NO metabolites (NOx) into the medium. Cell death was completely blocked by an NO synthase inhibitor and attenuated by antioxidants (N-acetylcysteine and DTT) and the caspase inhibitor ZVAD-fmk. Cytokines also mediated an NO-dependent, sustained increase in myocyte expression of the Bcl-2 homologs Bak and Bcl-x(L). The NO donor S-nitrosoglutathione also induced apoptosis and cell levels of Bak, but not of Bcl-x(L). All effects of cytokines, including poly(ADP-ribose) polymerase cleavage, could be attributed to interleukin-1beta; interferon-gamma and tumor necrosis factor-alpha had no independent effects on apoptosis or on NOx production. We conclude that cytokine toxicity to neonatal cardiac myocytes results from the induction of NO and subsequent activation of apoptosis, at least in part through the generation of oxygen free radicals. The rate and extent of this apoptosis is modulated by alterations in the cellular balance of Bak and Bcl-x(L), which respond differentially to cytokine-induced and exogenous NO and by the availability of oxidant species.
 ...
PMID:Modulation of cytokine-induced cardiac myocyte apoptosis by nitric oxide, Bak, and Bcl-x. 991 71

To investigate the protection mechanism of Bcl-2 against tumour necrosis factor (TNF)-mediated cell death, the bcl2 gene was transfected into the L929 cells and stably expressed. Two clones having different sensitivity among bcl2-transfected L929 clones had been isolated, and termed clone R1 and R2. It was observed that activation of manganese superoxide dismutase (MnSOD) and suppression of Jun kinase of clone R1 and R2 were correlated with protection from TNF cytotoxicity. Upon treatment with TNF, clone R1 and R2 were more resistant than control L929 cells against TNF cytotoxicity and the protective effect of clone R1 was stronger than clone R2. However, in case of TNF plus actinomycin D treatment, clone R1 was still resistant against TNF cytotoxicity, whereas clone R2 became more sensitive than control L929 cells. The JNK activities of clone R1 and R2 were suppressed upon TNF treatment and in case of TNF plus actinomycin D treatment, clone R2 showed a marked increase in JNK activities and had higher activity than control L929 cells. The specific activities of MnSOD of clone R1 and R2 upon TNF treatment were 70 U/ml and 33 U/ml, respectively, while the MnSOD activity was not detectable in control L929 cells. When TNF and actinomycin D were treated simultaneously, MnSOD activity was not detectable in control L929 cells and bcl2 -transfected L929 cells (clone R1, R2). Consistent with these results, both clone R1 and R2 showed higher levels of MnSOD mRNA expression than control L929 cells after TNF treatment. These data suggest that suppression of Jun kinase and increase of MnSOD may be involved in inhibitory action of Bcl-2 against TNF, and the balance between MnSOD and JNK signalling pathway may be an important factor for the protection of bcl2-transfected L929 cells from TNF cytotoxicity.
Cytokine 1999 Apr
PMID:Increase of MnSOD expression and decrease of JNK activity determine the TNF sensitivity in bcl2-transfected L929 cells. 1032 66


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