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 recent demonstration of the anti-oxidant properties of the Bcl-2 gene product suggested that expression of Bcl-2 may interfere with the nuclear migration of the NF-kappa B transcription factor, which is thought to depend on the presence of reactive oxygen intermediates. In mouse L cells, overexpression of Bcl-2 interfered with the activation of NF-kappa B by H2O2. However, Bcl-2 had no effect on the activation of NF-kappa B by TNF, even though it protected cells from TNF-induced apoptosis. The effects of exogenous pyrrolidine dithiocarbamate were very similar to those of Bcl-2 overexpression. We conclude that the protective effects of anti-oxidants against induced apoptotic cell death are unrelated to their ability to interfere with NF-kappa B activation.
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PMID:Bcl-2 protects from oxidative damage and apoptotic cell death without interfering with activation of NF-kappa B by TNF. 807 91

The uniformly fatal plasma cell malignancy, multiple myeloma (MM), currently represents 10-15% of hematologic neoplasms in the USA and has been steadily increasing in incidence for several decades. Therapeutic alternatives have lagged significantly behind insights into the biology and pathogenesis of this entity. Traditionally felt to be a neoplasm of fully differentiated plasma cells, evidence has been mounting that the self renewing population consist of cells derived from a much earlier compartment; perhaps prior to B-cell lineage commitment or even at the level of an earlier 'stem cell'. Bcl-2 protein overexpression has been almost uniformly seen in both clinical myeloma specimens as well as in myeloma cell lines. The failure to consistently identify the t(14;18) translocation, normally found in follicular lymphomas and characteristically associated with overexpression of bcl-2, implies a unique mechanism in MM. A number of cytokines, including TNF alpha, IL-1 and IL-6 have been found to play a central role not only in the biology of the malignant clone but also in the bony and other systemic manifestations of this disease. Since both IL-6 and bcl-2 protein have been shown to prevent programmed cell death, this may be the unifying event in MM. Standard therapy for MM has been an alkylating agent and corticosteroid. Combination chemotherapy provides more prompt palliation but no clear survival advantage. In advanced stages, adriamycin may offer some survival advantage. High dose chemotherapy with or without stem cell support offers a potentially curative therapeutic approach. New interventions directed at the complex cytokine networks pertinent to the pathogenesis of MM are an exciting new area of investigation. Identification of new prognostic parameters as well as new active agents remains the central theme in clinical myeloma research.
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PMID:Biology and treatment of multiple myeloma. 846 29

Apoptosis, or programmed cell death, is characterized by an active autodestruction of cells. Several proteins inducing (CED-3) or preventing (CED-9) neuronal death have been described in the nematode C. elegans. There is an homology between these proteins and Bcl-2 and ICE (Interleukin-1 beta-Converting Enzyme) in vertebrates. The cascade of biochemical events leading to this active neuronal "suicide" is triggered by initiating factors such as genotoxicity, growth factors deprivation, cytokines (TNF alpha). As the molecular mechanisms of nerve cell death start to be understood, clinicians and neurobiologists are confronted with the difficult problem of pathological aging and neuronal death in patients with neurodegenerative disorders compared to normal aging. In order to distinguish the biochemical abnormalities underlying dysfunction of neurons during aging, neuronal loss during neurodegeneration (Parkinson's disease) and nerve cell death, we searched for morphological and biochemical signs of apoptosis in dopaminergic neurons of the substantia nigra of parkinsonian patients and controls. We found characteristic histopathological features of apoptosis in about 5% of dopaminergic neurons in the brain of patients. In addition, the presence of TNF alpha receptors and the expression of the gene bcl-2 were observed in dopaminergic neurons. Thus, apoptosis could represent the ultimate step of dopaminergic neuronal degeneration in Parkinson's disease. Whether this is also the case in other neurodegenerative diseases still remains to be proven. In brief, neurons in the human brain could be classified into three categories: those which loose slowly part of their functions but are still spared by the process of neuronal death (senescence); those which are lost more rapidly than similar effects due to aging (neurodegeneration); a small number of neurons which die rapidly through apoptosis. The consequences of such observation may be important both for neurobiologists and pharmacologists as the basic mechanisms which result in senescence, disease and death of neurons could be different.
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PMID:[Aging, disease and nerve cell death]. 854 48

We examined c-Myc and Bcl-2 protein expressions during the induction of apoptosis and differentiation in TNF alpha-treated HL-60 cells using a two-color flow cytometric method. We found that c-Myc protein was rapidly down-regulated in the apoptotic cells while Bcl-2 protein was expressed at relatively high levels. Concomitantly with terminal differentiation Bcl-2 protein was down-regulated in differentiating cells as well as c-Myc protein. We also showed that c-myc antisense oligonucleotides could induce apoptosis in HL-60 cells whereas bcl-2 antisense did not induce apoptosis during the early time of treatment. These results suggest that the down-regulation of c-Myc protein expression is a primary event to induce apoptosis and neither consistent expression of c-Myc protein nor rapid down-regulation of Bcl-2 protein is necessary for the initial processing of apoptosis in HL-60 cells. Furthermore, concomitant down-regulation of c-Myc and Bcl-2 is closely associated with terminal differentiation and apoptotic cell death of HL-60 cells treated with TNF alpha.
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PMID:C-Myc and Bcl-2 protein expression during the induction of apoptosis and differentiation in TNF alpha-treated HL-60 cells. 903 Nov 21

Actinomycin D (ActD) enhances the potency of tumor necrosis factor-alpha (TNF-alpha) in killing cancer cells. However, it is determined in this study that murine L929 fibrosarcoma cells, when pretreated with bovine testicular hyaluronidase for 12-24 h, became resistant to the cytotoxic effect of TNF-alpha in the presence of DNA intercalators, such as ActD, doxorubicin, and daunorubicin. Monoclonal anti-Fas antibody-mediated apoptosis in the presence of ActD was also blocked in hyaluronidase-pretreated L929 cells. Hyaluronidase failed to up- or downregulate the expression of apoptosis regulatory proteins, including Bcl-2, Bcl-xL, ICH-1, and TIAR, suggesting that these proteins were not involved in the hyaluronidase-induced resistance to TNF/ActD. A semisynthetic polysulfated hyaluronic acid (HA) inhibited the increased TNF/ActD resistance, whereas unmodified HA, dextran sulfate, and naturally polysulfated glycosaminoglycans had no effect. Evidence is provided here that the induced resistance is related to serum fetuin and a novel intracellular 35-kDa TNF-binding protein (intra TBP). Under serum-free conditions, L929 became refractory to TNF/ActD cytotoxicity and hyaluronidase reversed the resistance. Exogenous fetuin increased L929 cell spreading and proliferation, and restored hyaluronidase-induction of TNF/ActD resistance in these serum-starved cells. Hyaluronidase failed to reduce the expression of TNF-receptors and their binding of TNF-alpha. However, binding and Western-blotting analyses revealed that hyaluronidase downregulated the intra-TBP. Overall, these observations suggest that serum fetuin and intraTBP are involved in the hyaluronidase induction of TNF/ ActD resistance.
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PMID:Hyaluronidase induces murine L929 fibrosarcoma cells resistant to tumor necrosis factor and Fas cytotoxicity in the presence of actinomycin D. 910 95

Based on previously published observations regarding the protective effects of interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) against gamma radiation, alkylating agents and ultraviolet radiation, we hypothesized that the protection against such DNA damaging treatments can be the result of a 'stress'-like response induced by these cytokines and mediated by early response cellular gene(s). By applying the mRNA differential display to RNA obtained from A549 lung carcinoma cell line that was incubated with 50 ng/ml IL-1 for 0, 1, 2, and 6 h, we identified several cDNA fragments that correspond to genes regulated by IL-1. The full length cDNA for one fragment was obtained using 5'RACE, cloned, sequenced, and found to be homologous to human A1, a Bcl-2-related gene. In this study, we report that the expression of human A1 is either absent or present at low levels in leukemic cells, while it is expressed in human bone marrow cells and abundant in peripheral blood progenitors. It is induced by IL-1 and TNF alpha in A549 lung carcinoma, bone marrow, and certain leukemic cells. A1 is also induced in leukemic cells during granulocytic or macrophage but not erythroid differentiation. In conclusion, this is the first demonstration that A1 is inducible by cytokines in human bone marrow and certain tumor cells as well as myeloid differentiation in leukemic cells.
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PMID:Human A1, a Bcl-2-related gene, is induced in leukemic cells by cytokines as well as differentiating factors. 920 81

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

During inflammation, polymorphonuclear neutrophils (PMN) are exposed to and influenced by various cytokines, including the chemoattractant interleukin-8 (IL-8). We tested the hypothesis that IL-8 affects apoptosis in PMN. We investigated which IL-8 receptor (RI or RII) might be involved, as well as the role of Bcl-2. Human PMN were isolated and cultured up to 30 hours. Apoptosis was detected by UV and light microscopy, as well as by DNA-fragmentation assay, and quantitated by flow cytometry. Interleukin-8 significantly delayed spontaneous apoptosis at 10, 20, and 30 hours in a dose-dependent fashion. Polymorphonuclear neutrophil treatment with the highest concentration of IL-8 (100 nM) decreased the percentage of apoptotic cells from 2.1 +/- 1.5 to 0.8 +/- 0.2 after 10 hours, from 31 +/- 14 to 8 +/- 5 after 20 hours, and from 47 +/- 15 to 18 +/- 8 after 30 hours of incubation (P < 0.05 for all time points, N = 6). Interleukin-8 also inhibited TNF alpha-mediated PMN apoptosis. Incubation with 20 ng/ml TNF alpha resulted in 23 +/- 6% apoptotic cells at four hours, whereas pretreatment with IL-8 (50 nM) decreased this percentage to 11 +/- 3 (N = 5, P < 0.05). We next studied the role of both types of IL-8 receptors, RI and RII, by comparing the effect of IL-8 and the product of growth-related oncogene alpha (Gro alpha) on PMN cultured for 20 hours. Both IL-8 and Gro alpha attenuated apoptosis, although IL-8 was more effective than Gro alpha. Bcl-2 was detected by intracellular fluorescent antibody cell sorter analysis, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR). Neither resting PMN nor IL-8-treated neutrophils expressed BCL-2 protein, which was readily detected in control cells. Furthermore, we could not detect BCL-2 gene expression by RT-PCR. We conclude that IL-8 prolongs the lifespan of human neutrophils in vitro by delaying apoptosis. This effect may be important for a controlled and effective inflammatory response. The delay in apoptosis can be mediated by the IL-8 RII, while RI may provide an added effect. The actions of IL-8 on apoptosis are Bcl-2 independent.
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PMID:Interleukin-8 delays spontaneous and tumor necrosis factor-alpha-mediated apoptosis of human neutrophils. 945 3

The aim of this review is to summarize the interactions between the oocyte and its surrounding granulosa cells which are involved in the control of oocyte growth or apoptosis as well as those playing a key role in the ability of the oocyte to undergo nuclear (resumption as meiosis to reach the MII stage) or cytoplasmic maturation (ability to fertilize and develop to the blastocyst stage). The respective roles of the oocyte and of the granulosa cells in controlling the initiation of growth are poorly understood. During the preantral follicular stage when most oocyte growth is achieved, a local regulation appears to be in operation involving growth factors such as fibroblast growth factor (FGF) or epidermal growth factor/transforming growth factor alpha (EGF/TGF alpha), together with two proteins (c-kit present on the oocyte's membrane and its ligand KL produced by granulosa cells). In-situ techniques used to detect apoptosis demonstrate apoptotic oocytes in the reserves of primordial follicles but seldom within preantral follicles (because it is too fast?). Proteins involved in cell death (bax) or cell survival (bcl2) are present in oocytes as well as compounds (TNF alpha, Fas) involved in the initiation of apoptosis. However, the molecular and cellular mechanisms triggering oocyte apoptosis are not fully clarified. Three approaches have been used to identify compounds which are relevant to the oocyte's nuclear or cytoplasmic maturation. a) Correlation between amounts of specific compounds in follicular fluid or within follicle cells and the oocyte's ability to mature. b) Analysis of the consequences of pharmacological disruption of mechanisms such as steroidogenesis on oocyte maturation. c) Analysis of the consequences of addition of graded amounts of specific compounds on oocyte maturation in defined media. Factors playing a key role in stimulating nuclear maturation appear to be epidermal growth factor (EGF) and the inhibin (cattle)/activin (rodents) family, while testosterone has an inhibitory effect. Cytoplasmic maturation of the oocyte appears to be stimulated by oestradiol, EGF and inhibin.
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PMID:Control of oocyte growth and maturation by follicular cells and molecules present in follicular fluid. A review. 979 80

We have investigated the molecular mechanisms underlying the ability of peripheral blood monocytes to block apoptosis induction in endothelial cells. Monocytes stimulated the expression of the bcl-2 homologue A1 in serum-starved endothelial cells after 6 h of coincubation, with elevated A1 levels persisting for up to 21 h. IL-1 and TNF also stimulated A1 expression at 6 h, but A1 transcript levels fell by 21 h. Direct cellular contact with monocytes was required for stimulation of A1 mRNA in endothelial cells. Stimulation of endothelial cell A1 mRNA by monocytes was not inhibited by anti-beta2 integrin Abs, but anti-platelet endothelial cell adhesion molecule-1 (PECAM-1) mAb reduced A1 transcript levels at 21 h. Studies employing either TNF on its own, or anti-TNF in endothelium/monocyte cocultures showed that TNF plays a role in the early (6-h) stimulation of A1, but is less important for the sustained elevation of A1 levels at 21 h. Serum-starved endothelial cells demonstrated increased survival and decreased apoptosis after coculture with monocytes. IL-10 reduced A1 mRNA expression in, as well as survival of, endothelial cells that were cocultured with monocytes. In comparison with A1, Bcl-2 was expressed at low levels and was up-regulated by monocytes only at 21 h, while neither Bax nor Bcl-xL levels were altered by monocytes. The interaction of monocytes with endothelium during the course of an inflammatory reaction may provide survival signals to endothelial cells.
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PMID:Monocytes stimulate expression of the Bcl-2 family member, A1, in endothelial cells and confer protection against apoptosis. 997 92


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