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)

Mcl-1 is an anti-apoptotic member of the Bcl-2 family which is tightly regulated during myeloid and B cell differentiation. We have recently reported that Mcl-1 is expressed in human myeloma cells and that Mcl-1 and Bcl-x(L) expression are correlated. In the current study, we demonstrate that IL-6, a survival factor for the human myeloma cell line MDN, rapidly up-regulates Mcl-1 whereas it has no effect on Bcl-2 protein level. In MDN cells, IL-6 induces both extracellular signal-regulated protein kinase (ERK)1,2 and STAT3 activation whereas STAT1 and STAT5 activation remains undetectable. Furthermore, while investigating the IL-6 signaling pathway leading to Mcl-1 up-regulation, we show that a janus kinase (JAK)-2 inhibitor is able to inhibit both STAT3 activation and Mcl-1 up-regulation whereas an MAP/ERK kinase (MEK) inhibitor has no effect. In conclusion, our data suggest the involvement of the JAK / STAT pathway but not of the Ras / mitogen-activated protein (MAP) kinase pathway in IL-6-induced Mcl-1 up-regulation.
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PMID:IL-6 up-regulates mcl-1 in human myeloma cells through JAK / STAT rather than ras / MAP kinase pathway. 1060 2

Damage to DNA produces cell cycle arrest, apoptosis, or both. The response in cells with p53 tumor suppressor function involves transcriptional changes, but whether that holds for cells lacking active p53, as in most tumors, is not known. Better characterization of the DNA damage response in tumors lacking p53 function is relevant to cytotoxic therapy. We have explored whether gamma-irradiated p53-null mouse T lymphoma cells undergo marked changes in transcription. Their arrest in G2/M prior to apoptosis required transcription. Transcripts whose abundance altered on irradiation were sought by subtractive hybridization, and 1010 candidate clones from two oppositely enriched cDNA populations were sequenced. Hybridization revealed small (<3-fold) increases or decreases in the transcripts of more than 15 genes, including some implicated in cell cycle control (e.g., BTG, Bap1) or apoptosis (e.g., STAT1, calpain), but no marked changes like those associated with other forms of T-cell death. Moreover, the expression of some critical apoptosis regulators, such as Bcl-2 family members, did not change. Hence, the G2/M arrest and apoptosis in the irradiated p53-null lymphoma appears to involve modest expression changes for many genes, but post-transcriptional alterations may be more critical.
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PMID:Gamma-radiation-induced growth arrest and apoptosis in p53-null lymphoma cells is accompanied by modest transcriptional changes in many genes. 1066 89

The ubiquitin-proteasome pathway is responsible for selective degradation of short-lived cellular proteins and is critical for the regulation of many cellular processes. We previously showed that ubiquitin (Ub) secreted from hairy cell leukemia cells had inhibitory effects on clonogenic growth of normal hematopoietic progenitor cells. In this study, we examined the effects of exogenous Ub on the growth and survival of a series of human hematopoietic cells, including myeloid cell lines (HL-60 and U937), a B-cell line (Daudi), and T-cell lines (KT-3, MT-4, YTC-3, and MOLT-4). Exogenous Ub inhibited the growth of various hematopoietic cell lines tested, especially of KT-3 and HL-60 cells. The growth-suppressive effects of Ub on KT-3 and HL-60 cells were almost completely abrogated by the proteasome inhibitor PSI or MG132, suggesting the involvement of the proteasome pathway in this process. Furthermore, exogenous Ub evoked severe apoptosis of KT-3 and HL-60 cells through the activation of caspase-3. In interleukin-6 (IL-6)-dependent KT-3 cells, STAT3 was found to be conjugated by exogenous biotinylated Ub and to be degraded in a proteasome-dependent manner, whereas expression levels of STAT1, STAT5, or mitogen-activated protein kinase were not affected. Moreover, IL-6-induced the up-regulation of Bcl-2 and c-myc, and JunB was impaired in Ub-treated KT-3 cells, suggesting that the anti-apoptotic and mitogenic effects of IL-6 were disrupted by Ub. These results suggest that extracellular Ub was incorporated into hematopoietic cells and mediated their growth suppression and apoptosis through proteasome-dependent degradation of selective cellular proteins such as STAT3. (Blood. 2000;95:2577-2585)
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PMID:Induction of apoptosis by extracellular ubiquitin in human hematopoietic cells: possible involvement of STAT3 degradation by proteasome pathway in interleukin 6-dependent hematopoietic cells. 1075 37

Polymorphonuclear neutrophils (PMN) are phagocytic cells constitutively programmed for apoptotic cell death. Exposure to GM-CSF delays apoptosis as measured by annexin-V staining and cell morphological change. We found that STAT5B, STAT1, and STAT3 DNA-binding activity was induced by GM-CSF. We also detected activation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway after GM-CSF treatment which was inhibited by treatment with the PI 3-kinase inhibitors, wortmannin and LY294002. We investigated whether STAT or PI 3-kinase activity was necessary for the pro-survival response of GM-CSF in PMN. Exposure of PMN to GM-CSF in the presence of either AG-490, antisense STAT3 oligonucleotides, or wortmannin resulted in a partial inhibition of GM-CSF-mediated pro-survival activity. GM-CSF induced a time-dependent increase in the mRNA and protein expression of the anti-apoptotic Bcl-2-family protein, Mcl-1. We examined the hypothesis that Janus kinase/STAT and PI 3-kinase regulation of Mcl-1 contributed to GM-CSF-delayed apoptosis. Using either AG-490 or wortmannin alone, we observed a dose-dependent inhibition of GM-CSF-induced Mcl-1 expression. Using suboptimal doses of AG-490 and wortmannin, we found that both drugs together had an additive effect on delayed apoptosis and Mcl-1 expression. These data suggest that cooperative regulation of Mcl-1 by the Janus kinase/STAT and PI 3-kinase pathways contribute to GM-CSF-delayed apoptosis.
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PMID:Cooperative regulation of Mcl-1 by Janus kinase/stat and phosphatidylinositol 3-kinase contribute to granulocyte-macrophage colony-stimulating factor-delayed apoptosis in human neutrophils. 1139 May 2

Interferon-alpha and -beta inhibit the interleukin-7-mediated growth and survival of T and B lymphoid progenitors via an unknown, STAT1-independent pathway. Gene expression profile analysis of interferon-beta-treated progenitor B cells revealed enhanced Daxx expression, with concomitant Daxx protein increase and nuclear body translocation. The interferon effects included downregulation of cell cycle regulating genes and cell cycle arrest, followed by Bcl-2 downregulation and apoptosis. Daxx antisense oligonucleotides rescued the interferon-treated pro-B cells from growth arrest and apoptosis in parallel with the reduction of nuclear Daxx. These findings implicate the gene repressor function of Daxx in interferon-induced apoptosis of lymphoid progenitors.
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PMID:An essential role for Daxx in the inhibition of B lymphopoiesis by type I interferons. 1142 43

PANcreatic DERived factor (PANDER, FAM3B) is a recently discovered islet-specific cytokine. We have previously shown that, in vitro, truncated recombinant PANDER isoforms (20 and 21 kDa) are cytotoxic to beta-cell lines but the effects of full-length PANDER on islet biology remain unclear. In this study, we used adenovirus (Ad-PANDER) to overexpress full-length cDNA of PANDER in islets and betaTC3 cells. BetaTC3 cells were infected with Ad-PANDER or control vector. After 48 h, cell viability was significantly decreased as evaluated by MTT assay. The number of dead cells was significantly increased as indicated by the fluorescent intensity of the propidium iodide-stained cells (160 +/- 13 vs. control 100 +/- 7%, P = 0.001). Flow cytometric Tunel assay showed that overexpressing PANDER induced a significant fourfold increase in beta-cell apoptosis (19.4 +/- 6.3 vs. control 4.1 +/- 0.8%, P < 0.05). There was a significant increase in the number of annexin V-positive (apoptotic) cells and propidium iodide-positive (dead) cells in mouse islets infected with Ad-PANDER compared with control cells infected with Ad-LacZ. Addition of 4 nM recombinant PANDER protein to betaTC3 cells or infection of Ad-PANDER did not affect Akt and STAT1 phosphorylation, Bcl-2, Fas, and NF-kappaB protein levels. However, activation of caspase-3 was observed in betaTC3 and islets infected with Ad-PANDER. Overexpression of PANDER in mouse islets or addition of recombinant PANDER decreased insulin secretion induced by carbachol plus glucose or high potassium but not that by glucose alone. Culture with recombinant PANDER did not affect glucose-induced NAD(P)H elevation in mouse islets. In conclusion, Ad-PANDER infection is as effective as truncated recombinant PANDER to induce betaTC3 cell and mouse islet apoptosis.
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PMID:Effects of overexpression of pancreatic derived factor (FAM3B) in isolated mouse islets and insulin-secreting betaTC3 cells. 1592 25

The membrane receptor Fas (Apo-1/CD95) is an important initiator of programmed cell death induced by anti-Fas antibody or Fas ligand. MCF-7 human breast cancer cells have low levels of Fas receptor (FasR) and are resistant to anti-FasR antibody mediated apoptosis, however two naturally occurring substances, interferon and all-trans retinoic acid (AT), act synergistically to enhance antiproliferative processes in these cells, suggesting this combination may also be an effective means for enhancing FasR expression. When this was studied, it was found that IFN-gamma and AT in combination acted synergistically to induce expression of FasR mRNA and FasR protein in a time-dependent and dose-dependent manner. This induction required continuous protein synthesis, and STAT1 protein, but not PKR or TR1 protein, was induced in a manner quantitatively and temporally related to FasR protein induction, and consistent with STAT1 mediation of the synergistic effect of IFN-gamma and AT on FasR expression. FasR-induced cells were resistant to stimulation of apoptosis by anti-FasR antibody, however treatment with cycloheximide rendered these cells sensitive to antibody-induced apoptosis, suggesting endogenous blockade to signaling. These cells did not express caspase 3, or FLIP(L), but strongly expressed the endogenous inhibitor of apoptosis Bcl-2, indicating a type II Fas signaling pathway. Expression of these proteins was not modulated by IFN/AT, however treatment of Fas-induced cells with Bcl-2 specific small interfering RNA (SiRNA) downregulated Bcl-2 protein expression and rendered these cells sensitive to the cytotoxic effects of anti-Fas antibody. These findings indicate that IFN-gamma+AT in combination modulate Fas signaling and provide a novel mechanism for the promotion of cell death in breast cancer cells.
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PMID:Conversion of Fas-resistant to Fas-sensitive MCF-7 breast cancer cells by the synergistic interaction of interferon-gamma and all-trans retinoic acid. 1613 69

The transcription factor STAT3 is activated by interleukin-6-related cytokines and has been implicated as an oncogene; it promotes cell proliferation and is anti-apoptotic. However, in some cases, STAT3 has been shown to be pro-apoptotic, especially in mammary epithelial cells. In this report, we generated SOCS3-deficient murine embryonic fibroblasts (MEFs), in which STAT3 activation is extremely enhanced and prolonged. We found that LIF induces caspase-3 activation and apoptosis of SOCS3(-/-) MEFs. Exogenous expression of the dominant negative form of STAT3 but not STAT1 suppressed LIF-induced apoptosis of SOCS3(-/-) MEFs, indicating that STAT3 plays a critical role in apoptosis induction. As shown in mammary gland epithelial cells, expression of the phosphatidylinositol 3-kinase regulatory subunits p50alpha and p55alpha was induced in response to LIF in SOCS3(-/-) MEFs but not in wild-type MEFs, and Akt/protein kinase B activity was substantially reduced in SOCS3(-/-) MEFs. Furthermore, we found that some of the STAT3 target genes related to apoptosis and proliferation, such as Bcl-2 and cyclin D1, were repressed upon LIF treatment in SOCS3(-/-) cells. Not only the up-regulation of p50alpha and p55alpha but also the repression of cyclin D1 and Bcl-2 in SOCS3(-/-) MEFs was inhibited by dominant negative STAT3. These data suggest that prolonged activation of STAT3 could induce apoptosis/growth arrest rather than anti-apoptosis and proliferation in certain cases, and SOCS3 is a critical regulator of this balance.
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PMID:Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic. 1702 85

Norcantharidin (NCTD) is known to have anti-cancer potentials. The aim of this study was to assess the apoptosis-inducing effect of NCTD on human leukemic Jurkat cells. We found that NCTD preferentially inhibited the growth of Jurkat cells in a dose- and time-dependent manner, but not the growth of normal blood mononuclear cells (MNC). Pretreatment with agonistic (CH-11) and antagonistic (ZB4) Fas antibodies on Jurkat cells showed that NCTD-induced apoptosis might not involve Fas-FasL signaling. Flow cytometric assay of Jurkat cells treated with NCTD showed a markedly increased sub-G1 DNA phase and cell cycle arrest at S phase. Western blot analysis of NCTD-treated cells showed increased expressions of cytochrome c, active caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase (PARP), but the expressions of Bcl-2, Bax and apoptosis-inducing factor were not increased. The transcription factor STAT1 was translocated from cytosol to nucleus. Pancaspase inhibitor z-VAD-FMK not only limited the level of sub-G1 phase, but also prevented the degradation of PARP in NCTD-treated cells. The NCTD-induced cell cycle arrest and apoptosis were mediated through the regulation of ataxia-telangiectasia mutated (ATM), rather than P63 protein. The conditioned medium produced from human MNC (NCTD-MNC-CM) increased the percentage of apoptotic cells and the expression of PARP cleavage in Jurkat cells. Protein array assay of NCTD-MNC-CM showed 32.4- and 6.2-folds increases in TNF-alpha and GM-CSF, respectively, and the expression of MCP-1, GRO, RANTES and IL-10 was decreased. We conclude that NCTD can induce apoptosis in human leukemic Jurkat cells via a caspase-dependent pathway without affecting the viability of normal MNC, and that the apoptosis-inducing effect of NCTD can also be achieved by soluble cytokines produced from peripheral MNC.
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PMID:Norcantharidin preferentially induces apoptosis in human leukemic Jurkat cells without affecting viability of normal blood mononuclear cells. 1744 74

In multiple myeloma, which commonly depends on interleukin 6, IL-6, survival signaling induced by this cytokine is largely mediated by activation of STAT3. Interferon alpha (IFNalpha) treatment of cell lines derived from multiple myeloma or of myeloma tumor cells ex vivo leads to apoptosis. In this study we demonstrate that IFNalpha treatment of the two myeloma cell lines, U266-1984 and U-1958, results in the decrease of STAT3 activity as demonstrated by a diminished STAT3/3 DNA-binding activity and the shift from STAT3/3 towards STAT1/1 and STAT3/1 complexes in EMSA, leading to the down-regulation of known STAT3 target genes such as Bcl-X(L), Mcl-1 and survivin. Ectopic expression of a form of STAT3, STAT3C, rescued U266-1984 cells from IFNalpha-induced apoptosis. IFNalpha promoted sustained accumulation of tyrosine phosphorylated STAT3C in the nucleus and a prolonged DNA binding of the STAT3/3 homodimers in EMSA. The shift towards a sustained STAT3 response in IFNalpha-treated STAT3C-transfected cells led to a hyper-induction of Bcl-2 and Mcl-1 proteins. Thus our data demonstrated that IFNalpha is able to interfere with IL-6 signaling by inhibiting STAT3 activity and that the abrogation of STAT3 activity accounts for the ability of IFNalpha to induce apoptosis in myeloma cells.
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PMID:Interferon alpha induces cell death through interference with interleukin 6 signaling and inhibition of STAT3 activity. 1788 Sep 40


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