Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B-cell chronic lymphocytic leukemia (B-CLL) is characterised by the proliferation and accumulation of sIgM+/CD5+ B-cells that fail to progress to the final stages of B-cell development. Despite their developmental arrest, leukemic CD5+ B-cells can undergo proliferation in vitro in the presence of different activators including phorbol esters, antibodies to cell surface antigens and human cytokines. Interleukin-10 (IL-10) has recently been found to inhibit CLL B-cell function in vitro by inducing apoptosis and down-regulating expression of bcl-2. Here, we examined the effect of IL-10 on proliferation, RNA synthesis, immunoglobulin (IgM) secretion and viability of leukemic CD5+ B-cells induced by activation with the phorbol ester PMA, alone or in combination with anti-Ig. IL-10 reduced PMA and PMA/anti-Ig induced proliferation and RNA synthesis by 50-80% and 15-40% respectively. Although proliferation and RNA synthesis induced by PMA/anti-Ig could be enhanced by the addition of IL-2, IL-4, IL-13, IFN-gamma or TNF-alpha, the presence of these cytokines failed to abrogate the IL-10-mediated inhibition of leukemic CD5+ B-cell activation. In contrast to the effects on proliferation and RNA synthesis, IL-10 did not inhibit IgM secretion, and had only a minimal effect on the viability of activated cells. Our results indicate that IL-10 inhibits proliferation of leukemic CD5+ B-cells by a mechanism distinct from induction of apoptosis and support the proposal for the utilisation of IL-10 in the therapy of B-CLL.
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PMID:Interleukin-10 inhibits the in vitro proliferation of human activated leukemic CD5+ B-cells. 972 Jul 22

IL-2, the principal mitogenic factor for activated T cells, delivers a proliferative signal through ligation of the heterotrimeric IL-2R. This proliferative signal is critically dependent upon cytoplasmic tyrosines on the beta-chain of this receptor (IL-2Rbeta) becoming phosphorylated in response to ligand. We found that at least one of these tyrosines (Y338) also mediates cell survival and induction of bcl-2, bcl-x, and c-myc in the murine T cell line CTLL-2. Since the adapter molecule Shc binds to phosphorylated Y338, the specific contribution of Shc to these events was evaluated. An IL-2Rbeta/Shc fusion protein, in which Shc was covalently tethered to a truncated version of IL-2Rbeta lacking all cytoplasmic tyrosines, revealed a robust proliferative signal mediated through Shc. This Shc-mediated signal induced expression of c-myc as well as the antiapoptotic genes bcl-2 and bcl-x with normal magnitude and kinetics. Nonetheless, signals from this fusion protein failed to sustain the long-term viability of CTLL-2 cells. Thus, induction of bcl family genes and delivery of a competent proliferative signal are not sufficient to promote cell survival and mediate the antiapoptotic effects associated with a complete IL-2 signal.
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PMID:The IL-2 receptor promotes proliferation, bcl-2 and bcl-x induction, but not cell viability through the adapter molecule Shc. 979 91

This study examines the influence of IL-7 on post-thymic CD4+ T cells using cord blood as a model system. Survival of naive cord blood T cells in the presence of IL-7 alone was significantly prolonged by up-regulating bcl-2, thereby preventing apoptosis while maintaining maximal cell viability. Cultures without IL-7 showed high rates of apoptosis resulting in 50% cell death by day 5 of culture. Upon phorbol 12-myristate 13-acetate + ionomycin stimulation, accumulation of cytoplasmic IL-2 was similar to that observed in freshly isolated cells, but no IL-4- or IFN-gamma-positive cells were detected. IL-7 maintained the naive T cells in a quiescent state expressing the CD45RA antigen. A significant finding was the loss of CD38 antigen expression on the naive cord blood T cells to levels similar to that observed on adult naive T cells. In contrast to the reduced proliferative response of fresh cord blood T cells to anti-CD2 + CD28 stimulation, the proliferative response of IL-7-treated cells was similar to that of adult naive T cells. This study shows that as well as maintaining the naive T cell pool by enhancing cell survival and up-regulating bcl-2 expression, IL-7 also functions as a maturation factor for post-thymic naive T cells.
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PMID:IL-7 promotes the survival and maturation but not differentiation of human post-thymic CD4+ T cells. 980 74

Janus kinase 3 (Jak3) plays a central role in the transduction of signals mediated by the IL-2 family of cytokine receptors. Targeted deletion of the murine Jak3 gene results in severe reduction of alphabeta and complete elimination of gammadelta lineage thymocytes and NK cells. The developmental blockade appears to be imposed on early thymocyte differentiation and/or expansion. In this study, we show that bcl-2 expression and in vivo survival of immature thymocytes are greatly compromised in Jak3-/- mice. There is no gross deficiency in rearrangements of the TCRdelta and certain gamma loci in pre-T cells, and a functional gammadelta TCR transgene cannot rescue gammadelta lineage differentiation in Jak3-/- mice. In contrast, a TCRbeta transgene is partially able to restore alphabeta thymocyte development. These data suggest that the signals mediated by Jak3 are critical for survival of all thymocyte precursors particularly during TCRbeta-chain gene rearrangement, and are continuously required in the gammadelta lineage. The results also emphasize the fundamentally different requirements for differentiation of the alphabeta and gammadelta T cell lineages.
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PMID:Distinct effects of Jak3 signaling on alphabeta and gammadelta thymocyte development. 997 1

Interleukin 10 (IL-10) has been described as a cytokine inhibitory factor downregulating IL-2 secretion and inducing T cell anergy. The data reported in this study show that preincubation of resting T cells from the human CD4+ clone SP-B21 (and clone TA-23.6) with IL-10 strongly enhances their capacity to further produce IL-2, interferon gamma (IFN-gamma), IL-4 and tumour necrosis factor alpha (TNF-alpha) after subsequent activation. In contrast, when IL-10 was added during the activation step, the previously reported specific inhibition of IL-2 synthesis was observed. Flow cytometric analysis of intracellular IL-2- and IL-4-producing cells revealed that preincubation with IL-10 increased the number of cytokine-producing cells, but did not affect their individual ability to produce these cytokines. We further show that IL-10 plays a dose-dependent role of viability maintenance factor. This effect relates to a direct anti-apoptotic effect of IL-10, which is likely independent of the expression of bcl-2, bcl-x and fas. Such paradoxal properties of IL-10 on T cells should be considered when aiming at using IL-10 as an immunosuppressive molecule in the treatment of diseases.
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PMID:Preincubation of human resting T cell clones with interleukin 10 strongly enhances their ability to produce cytokines after stimulation. 1002 77

We searched for cytokines with the potential to support the survival of human B-cell precursor acute lymphoblastic leukaemia (pre-B ALL) cells. 47 patients with pre-B ALL were classified into four stages: stage I, CD19+CD10-CD20-; stage II, CD19+CD10+CD20-; stage III, CD19+CD10+CD20+cytoplasmic mu-heavy chain (cmu)-; stage IV, CD19+CD10+CD20+cmu. Interleukin (IL)-3 receptor alpha chain (IL-3Ralpha) was expressed in all stages, whereas the expressions of IL-7Ralpha and IL-2Ralpha were pronounced in stages IV and II, respectively. Neither IL-3, IL-7 nor IL-2 supported the survival of pre-B ALL cells. When pre-B ALL cells were layered on stromal, MS-10, cells, viability of the pre-B ALL cells increased. Addition of IL-3 to culture containing MS-10 cells enhanced the survival of pre-B ALL cells in all cases, whereas addition of IL-7 augmented the survival of pre-B ALL cells of some cases of stage III and all cases of stage IV. The survival of pre-B ALL cells was also supported by the conditioned media of MS-10 cells. Stromal-cell-derived factor 1 (SDF-1) supported the survival of pre-B ALL cells. Effects of the conditioned media of MS-10 cells were abrogated by an anti-SDF-1 neutralizing antibody. The extent of survival of pre-B ALL cells supported by stromal cells and IL-3 and IL-7, correlated with the expression level of bcl-2 protein. The effects of stromal cells may be in part related to SDF-1.
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PMID:Survival of human leukaemic B-cell precursors is supported by stromal cells and cytokines: association with the expression of bcl-2 protein. 1035 35

We had previously shown that the drug undecylprodigiosin (UP) blocks human lymphocyte proliferation in vitro. We have now investigated the mechanism of action of a new analogue of UP, PNU156804, which shows a more favorable activity profile than UP in mice. We demonstrate here that the biological effect of PNU156804 in vitro is indistinguishable from UP: PNU156804 blocks human T cell proliferation in mid-late G1, as determined by cell cycle analysis, expression of cyclins, and cyclin-dependent kinases and retinoblastoma phosphorylation. In addition, we show that PNU156804 does not block significantly the induction of either IL-2 or IL-2R alpha- and gamma-chains but inhibits IL-2-dependent T cell proliferation. We have investigated several molecular pathways that are known to be activated by IL-2 in T cells. We show that PNU156804 does not inhibit c-myc and bcl-2 mRNA induction. On the other hand, PNU156804 efficiently inhibits the activation of the NF-kappa B and AP-1 transcription factors. PNU156804 inhibition of NF-kappa B activation is due to the inhibition of the degradation of I kappa B-alpha and I kappa B-beta. PNU156804 action is restricted to some signaling pathways; it does not affect NF-kappa B activation by PMA in T cells but blocks that induced by CD40 cross-linking in B lymphocytes. We conclude that the prodigiosin family of immunosuppressants is a new family of molecules that show a novel target specificity clearly distinct from that of other immunosuppressive drugs such as cyclosporin A, FK506, and rapamycin.
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PMID:New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation. 1035 54

Mercurials have been shown to cause apoptosis in human T cells. The objective of this study was to evaluate and compare the relative susceptibility of resting versus activated T cells to methyl mercury chloride (MeHgCl)-induced cell death. Apoptosis was assessed by Hoechst 33258 and 7-AAD staining and annexin V binding. Our results show that activation of T cells by PHA, PMA, and ionomycin, or IL-2, reduces mercury-induced apoptosis by approximately 50%. We have previously shown that the underlying basis for these toxic effects involves perturbation of mitochondrial function leading to oxidative stress and the release of cytochrome c to the cytosol. Therefore, the ability of MeHgCl to alter the mitochondrial transmembrane potential (delta psi m) and to induce the generation of reactive oxygen species (ROS) was evaluated in activated T-cells. Both resting and activated cells treated with MeHgCl exhibited a decrease in delta psi m when compared to respective control cells. ROS production was elevated in resting cells following treatment with mercury; in contrast, fewer activated T cells exhibit increased levels of ROS in the presence of MeHgCl. Similarly, MeHgCl treatment resulted in the release of cytochrome c to the cytoplasm in non-activated T cells but failed to do so in the activated population. These results lead us to examine intracellular levels of bcl-2, a protein that has been shown to regulate apoptosis, presumably via its ability to associate with the mitochondrial membrane. Bcl-2 levels were found, in resting cells, to be low in the presence or absence of mercury. In comparison, activated T cells expressed elevated levels of bcl-2. The relationship between mercury-induced apoptosis in human T cells, mitochondrial dysfunction, and intracellular levels of bcl-2 are discussed.
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PMID:Activated human T lymphocytes exhibit reduced susceptibility to methylmercury chloride-induced apoptosis. 1036 43

Stimulation via IL-2R ligation causes T lymphocytes to transit through the cell cycle. Previous experiments by our group have demonstrated that, in human T cells, IL-2 binding induces phosphatidic acid production through activation of the alpha isoform of diacylglycerol kinase. In this study, using the IL-2-dependent mouse T cell line CTLL-2, we demonstrate that pharmacological inhibition of IL-2-induced diacylglycerol kinase activation is found to block IL-2-induced late G1 to S transition without affecting cell viability. Herein, we demonstrate that diacylglycerol kinase inhibition has a profound effect on the induction of the protooncogenes c-myc, c-fos, and c-raf by IL-2, whereas expression of bcl-2 and bcl-xL are not affected. When the IL-2-regulated cell cycle control checkpoints are examined in detail, we demonstrate that inhibition of diacylglycerol kinase activation prevents IL-2 induction of cyclin D3 without affecting p27 down-regulation. The strict control of cell proliferation exerted by phosphatidic acid through activation of diacylglycerol kinase is independent of other well-characterized IL-2R-derived signals, such as the phosphatidylinositol-3 kinase/Akt pathway, indicating the existence of a different and important mechanism to control cell division.
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PMID:Diacylglycerol kinase inhibition prevents IL-2-induced G1 to S transition through a phosphatidylinositol-3 kinase-independent mechanism. 1039 61

Several alterations in the mechanism of cell cycle control have been observed in human T-lymphotropic virus type I (HTLV-I)-infected cells. Here, it is reported that HTLV-I-infected cells both in their immortalized and transformed phase do not undergo apoptosis following ionizing radiation (IR) treatment. However, when IL-2 withdrawal is combined with genotoxic stress, HTLV-I-infected T-cells in their immortalized phase (IL-2-dependent) undergo apoptosis where as their transformed counterparts (IL-2-independent) do not. These results suggest that, during the transformation process, the HTLV-I-infected T-cells become less sensitive to cell death signals through the acquisition of constitutive activation of the IL-2 receptor pathway. The expression of bcl-2 and bcl-XL proteins, which are known to increase cell survival mediated by IL-2, as well as of p21waf1 and p53, was not substantially different in immortalized and transformed cells following IR. All together, these findings suggest that activation of alternative anti-apoptotic pathways, regulated by IL-2, might be responsible for the differential cell death response observed in immortalized versus transformed HTLV-I-infected T-cells.
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PMID:Differential response to genotoxic stress in immortalized or transformed human T-lymphotropic virus type I-infected T-cells. 1042 24


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