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)

Caspases and c-Jun N-terminal kinase (JNK) are activated in tumor cells during induction of apoptosis. We investigated the signaling cascade and function of these enzymes in cisplatin-induced apoptosis. Treatment of Jurkat T-cells with cisplatin induced cell death with DNA fragmentation and activation of caspase and JNK. Bcl-2 overexpression suppressed activation of both enzymes, whereas p35 and CrmA inhibited only the DEVDase (caspase-3-like) activity, indicating that the activation of these enzymes may be differentially regulated. Cisplatin induced apoptosis with the cytochrome c release and caspase-3 activation in both wild-type and caspase-8-deficient JB-6 cells, while the Fas antibody induced these apoptotic events only in wild-type cells. This indicates that caspase-8 activation is required for Fas-mediated apoptosis, but not cisplatin-induced cell death. On the other hand, cisplatin induced the JNK activation in both the wild-type and JB-6 cells, and the caspase-3 inhibitor Z-DEVD-fmk did not inhibit this activation. The JNK overexpression resulted in a higher JNK activity, AP-1 DNA binding activity, and metallothionein expression than the empty vector-transfected cells following cisplatin treatment. It also partially protected the cells from cisplatin-induced apoptosis by decreasing DEVDase activity. These data suggest that the cisplatin-induced apoptotic signal is initiated by the caspase-8-independent cytochrome c release, and the JNK activation protects cells from cisplatin-induced apoptosis via the metallothionein expression.
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PMID:Signaling and function of caspase and c-jun N-terminal kinase in cisplatin-induced apoptosis. 1201 40

IL-7 delivers survival signals to cells at an early stage in lymphoid development. In the absence of IL-7, pro-T cells undergo programmed cell death, which has previously been associated with a decline in Bcl-2 and translocation of Bax from cytosol to mitochondria. A new, earlier feature of IL-7 withdrawal was identified using an IL-7-dependent thymocyte line. We observed that withdrawal of IL-7 induced increased expression of jun and fos family member genes including c-jun, junB, junD, c-fos and fra2. This transient response peaked 3-4 h after IL-7 was withdrawn and resulted in increased DNA-binding activity of AP-1 and in a change in the composition of the Jun/Fos family dimers shown by electrophoretic mobility shift and supershift assays. Induction of jun and fos genes and the increased DNA-binding activity of AP-1 were attributable to the phosphorylation-induced activation of the stress kinases p38 and JNK and were blocked by the chemical kinase inhibitors SB203580 and SB202190. The stress response contributed to cell death following IL-7 withdrawal as shown by blocking the activity of the stress (MAP) kinases or by blocking the production of c-Jun and c-Fos using antisense oligonucleotides.
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PMID:IL-7 withdrawal induces a stress pathway activating p38 and Jun N-terminal kinases. 1203 57

The mammalian response to stress is complex, often involving multiple signaling pathways that act in concert to influence cell fate. To examine potential interaction between the signaling cascade, we have focused on the effects of a model apoptotic system in a single cell type sensitive to TNF-alpha induced apoptosis through an examination of the relative influences of MAPKs as well as transcription factors AP-1, NF-kappaB, and various survival genes in determining apoptosis. Our results show that ERKs decreased transiently or remain unchanged, JNK decreased robustly, whereas c-Jun increased transiently, thereby indicating that members of MAPK family are differentially regulated in response to TNF-alpha induced apoptosis, whereas NF-kappaB protein expression decreased transiently and activity decreased at 24 h post-treatment. The survival genes Bcl-2, Bcl-XL, and survivin act independently and downstream of ERK and JNK to decrease the survival of TNF-alpha treated RT-101 cells. The results also suggest the involvement of the mitochondria and cytochrome c. Caspase-3 appears to be a part of a downstream event.
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PMID:Insights into the molecular mechanism of apoptosis induced by TNF-alpha in mouse epidermal JB6-derived RT-101 cells. 1208 61

The production of nitric oxide (NO) is an essential determinant in auto- and paracrine signaling. NO is generated under inflammatory conditions and may serve as a cytotoxic molecule to produce cell demise along an apoptotic or necrotic pathway. NO also gained attention as a regulator of immune function and a death inhibitor. Cytotoxicity because of substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro- and antiapoptotic Bcl-2 family members, cytochrome c relocation, activation of caspases, and DNA fragmentation. However, NO-toxicity is not a constant value and NO may protect several cell types from entering programmed cell death. Preactivation of macrophages with a nontoxic dose of S-nitrosoglutathione (200 microM) or lipopolysaccharide/interferon-gamma/N(G)-monomethyl-L-arginine for 15 hours attenuated death in response to various agonists, suppressed p53 accumulation, and abrogated caspase activation. Prestimulation of macrophages with cytokines or low-level NO activated the transcription factor NF-kappaB as well as AP-1 and promoted immediate early gene expression of cyclooxygenase-2 (COX-2). NF-kappaB activation comprised p50/p65-heterodimer formation, IkappaB degradation, and activation of a luciferase reporter construct, that contained four copies of the NF-kappaB-site derived from the murine COX-2 promoter. A NF-kappaB decoy approach (oligonucleotides directed against NF-kappaB) or transfection of a dominant-negative c-Jun mutant (TAM67) abrogated not only the COX-2 expression but also the inducible protection. Blocking NO- or cytokine-mediated inducible protection at the level of NF-kappaB and/or AP-1 restored the occurrence of apoptotic features. Our experiments underscore the role of COX-2 in attenuating natural occurring cell death (i.e., apoptosis).
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PMID:The role of nitric oxide and cyclooxygenase-2 in attenuating apoptosis. 1208 96

Previous studies have demonstrated that ovotoxicity induced in small preantral (primordial and primary) ovarian follicles by 4-vinylcyclohexene diepoxide (VCD) in rats is likely via acceleration of the normal process of atresia (apoptosis). This acceleration is associated with increased activities of caspase cascades, changes in subcellular distribution of Bcl-2 family members, and alteration of estrogen receptor-mediated signaling pathways. The present study was designed to investigate possible effects of VCD dosing on the mitogen-activated protein kinases (MAPK)/AP-1 signaling pathways in rat ovarian small follicles. Female F344 rats were given a single dose of VCD (80 mg/kg i.p., 1 day--a time when ovotoxicity has not been initiated) or dosed daily for 10 or 15 days (80 mg/kg i.p.; 10 days--a time when the earliest signs of impending follicular destruction is seen, 15 days--a time when significant ovotoxicity is underway). Four hours following the final dose, ovaries and livers were collected. Ovarian small (25-100 microm) and large (100-250 microm) preantral follicles were isolated, and cytosolic or nuclear extracts were prepared from follicles and livers for analyses. Activities of MAPKs, including extracellular signal-regulated kinase, c-Jun N-terminal protein kinase (JNK), and p38 kinase, were determined in follicular and liver cytosolic extracts, and AP-1 DNA binding activity was determined in follicular and liver nuclear extracts. Compared with control, a single dose of VCD caused a decrease in JNK activity and an increase of AP-1 binding activity in isolated small ovarian follicles. After repeated daily dosing with VCD for 10 or 15 days, JNK and p38 kinase activities in small ovarian follicles were increased (p38 kinase: 1.64 +/- 0.14 for 10 days, 1.48 +/- 0.11 for 15 days, VCD/control, P < 0.01; JNK: 1.44 +/- 0.11 for 10 days, 1.37 +/- 0.06 for 15 days, VCD/control, P < 0.01) and AP-1 binding activity in small ovarian follicles was decreased (10 days, 0.29 +/- 0.04; 15 days, 0.51 +/- 0.04, VCD/control, P < 0.01). VCD did not affect any of these measurements in large preantral follicles or liver. Phosphorylation status of c-Jun protein as measured by Western blotting was increased (1.22 +/- 0.1, VCD/control, P < 0.05) after the 15-day daily dosing with VCD, but total c-Jun protein levels were unaffected. Using antibodies against c-Jun or phospho-c-Jun for supershift DNA binding assay, c-Jun and phospho-c-Jun were identified in the AP-1-DNA binding complex, and the binding activity was reduced in tissues with increased phospho-c-Jun protein levels. Taken together, these data provide evidence that accelerated atretic signals induced by VCD is associated with MAPK/AP-1 signaling pathways and phosphorylation of c-Jun plays a significant role in transmitting the apoptotic signals.
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PMID:Activation of mitogen-activated protein kinases and AP-1 transcription factor in ovotoxicity induced by 4-vinylcyclohexene diepoxide in rats. 1219 77

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), a contaminant in our daily diet, induces apoptosis in cultured immunocytes. In this study, Trp-P-1 (1 mg/kg) was injected intraperitoneally into male Wistar rats to investigate whether Trp-P-1 induces apoptosis in immune tissues in vivo. In the thymus, Trp-P-1 induced DNA fragmentation and morphological changes. Trp-P-1 also activated the initiator and executioner caspases, caspase-8 and -3, respectively, and activated caspase-3 in turn cleaved its intracellular substrate poly(ADP-ribose) polymerase 1 hr after injection. On the other hand, Trp-P-1 upregulated anti-apoptotic factors Bcl-2 and Bcl-XL and downregulated pro-apoptotic factor Bax in mitochondria 1 hr after injection, indicating that Trp-P-1 also stimulated anti-apoptotic signals. Trp-P-1 activated the serine-threonine protein kinase Akt, which is known to be an anti-apoptotic protein, and increased the DNA binding activities of apoptosis-associated transcription factors NF-kappaB and AP-1. In addition to the thymus, increases in the activities of these transcription factors were also observed in the spleen and in mononuclear cells from the blood. Therefore, Trp-P-1 activates both pro- and anti-apoptotic signals in vivo in the immune system, particularly in the thymus, and the former signal overcomes the latter.
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PMID:Apoptosis in the thymus after intraperitoneal injection of rats with Trp-P-1. 1235 51

The cAMP-response element-binding protein (CREB) is activated by phosphorylation on serine 133 and mediates the proliferative response to a number of different signals. A mutant CREB with a serine to alanine substitution at position 133 (CREBM1) functions as a dominant-negative inhibitor. Transgenic mice that express the dominant-negative CREB protein in B lymphocytes were developed as a means to study the effects of the inhibition of CREB function on B-cell proliferation and survival. We have shown previously that CREB up-regulates Bcl-2 expression in B cells in response to activation signals. B cells from CREBM1 transgenic mice expressed lower levels of Bcl-2 with and without stimulation. Proliferation of B cells from the transgenic mice was impaired in part by lack of induction of activator protein 1 (AP1) transcription factors. B cells from the transgenic mice were more susceptible to induction of apoptosis with several different agents, consistent with the decreased expression of Bcl-2. These studies demonstrate that B-cell activation requires phosphorylation of CREB for the proliferative response and to protect against activation-induced apoptosis.
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PMID:Impaired proliferation and survival of activated B cells in transgenic mice that express a dominant-negative cAMP-response element-binding protein transcription factor in B cells. 1237 87

Human neuroblastoma cells, SH-SY5Y, contain relatively low levels of thioredoxin (Trx); thus, they serve favorably as a model for studying oxidative stress-induced apoptosis (Andoh, T., Chock, P. B., and Chiueh, C. C. (2001) J. Biol. Chem. 277, 9655-9660). When these neurotrophic cells were subjected to nonlethal 2-h serum deprivation, their neuronal nitric oxide synthase and Trx were up-regulated, and the cells became more tolerant of oxidative stress, indicating that NO may protect cells from serum deprivation-induced apoptosis. Here, the mechanism by which NO exerts its protective effects was investigated. Our results reveal that in SH-SY5Y cells, NO inhibits apoptosis through its ability to activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1 and Trx, which subsequently induces the expression of Bcl-2. Furthermore, active PKG promotes the elevation of c-Jun, phosphorylated MAPK/ERK1/2, and c-Myc, consistent with the notion that PKG enhances the expression of Trx through its c-Myc-, AP-1-, and PEA3-binding motifs. Elevation of Trx and Trx peroxidase-1 and Mn(II)-superoxide dismutase would reduce H(2)O(2) and O(2)(), respectively. Thus, the cytoprotective effect of NO in SH-SY5Y cells appears to proceed via the PKG-mediated pathway, and S-nitrosylation of caspases plays a minimal role.
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PMID:Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. 1241 92

We review the biological significance of transcription factors such as p53, Myc, E2F family and AP-1 (Jun/Fos) in anticancer drug-induced apoptosis. It is likely that the functional role of these transcription factors is complex in response to DNA damage depending on cancer cell type. Regulation of apoptosis following DNA damage is mediated by cell cycle arrest for DNA repair and subsequent signal transduction pathways leading to apoptosis, which is associated with mitochondrial dysfunction. Activation of transcription factors following anticancer drugs is located upstream of signal transduction pathways, thereby the downstream pathway is promoted, which is connected to activation or suppression of apoptosis-related proteins. Switching on apoptotic signals by anticancer drugs is amplified in mitochondria by releasing cytochrome from the ion channel to activate the caspase cascade, which is regulated by Bcl-2 families in the central gate for drug-induced apoptosis. Activation of transcription factors targeting downstream genes, some of which are apoptosis-related genes, can play a critical role in promoting apoptosis following treatment with anticancer drugs. The strategy of identification of downstream target proteins or transcription factors involved in apoptosis will be necessary for the development of an effective transcription factor-targeted chemotherapy for cancer.
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PMID:Inducing cancer cell death by targeting transcription factors. 1254 53

Survival and proliferation of cells of a human myelo-erythroid CD34+ leukemia cell line (TF-1) depend on the presence of granulocyte-macrophage colony-stimulating factor or interleukin-3. Upon hormone withdrawal these cells stop proliferating and undergo apoptotic process. In this report we demonstrate that a controlled increase in [Ca2+]i induces hormone-independent survival and proliferation of TF-1 cells. We found that moderate elevation of [Ca2+]i by the addition of cyclopiasonic-acid protected TF1 cells from apoptosis. Furthermore, a higher, but transient elevation of [Ca2+]i by ionomycin treatment induced cell proliferation. In both cases caspase-3 activity was reduced, and Bcl-2 was up-regulated. Higher elevation of [Ca2+]i by ionomycin induced MEK-dependent biphasic ERK1/2 activation, sufficient to move the cells from G0/G1 to S/M phases. Meanwhile, activation of ERK1/2, phosphorylation of the Elk-1 transcription factor, and, consequently, a substantial elevation of Egr-1 and c-Fos levels and AP-1 DNA binding were observed. Moderate elevation of [Ca2+]i, on the other hand, caused a delayed monophasic activation of ERK1/2 and Elk-1 that was accompanied with only a small increase of Egr-1 and c-Fos levels and AP-1 DNA binding. The specific MEK-1 kinase inhibitor, PD98059, inhibited all the effects of increasing [Ca2+]i, indicating that the MAPK/ERK pathway activation is essential for TF-1 cell survival and proliferation. Based on these results we suggest that the elevation of the [Ca2+]i may influence the cytokine dependence of hemopoietic progenitors and may contribute to pathological hematopoiesis.
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PMID:Calcium induces cell survival and proliferation through the activation of the MAPK pathway in a human hormone-dependent leukemia cell line, TF-1. 1264 64


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