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)

Apoptosis as a form of programmed cell death (PCD) in multicellular organisms is a well-established genetically controlled process that leads to elimination of unnecessary or damaged cells. Recently, PCD has also been described for unicellular organisms as a process for the socially advantageous regulation of cell survival. The human Bcl-2 family member Bak induces apoptosis in mammalian cells which is counteracted by the Bcl-x(L) protein. We show that Bak also kills the unicellular fission yeast Schizosaccharomyces pombe and that this is inhibited by coexpression of human Bcl-x(L). Moreover, the same critical BH3 domain of Bak that is required for induction of apoptosis in mammalian cells is also required for inducing death in yeast. This suggests that Bak kills mammalian and yeast cells by similar mechanisms. The phenotype of the Bak-induced death in yeast involves condensation and fragmentation of the chromatin as well as dissolution of the nuclear envelope, all of which are features of mammalian apoptosis. These data suggest that the evolutionarily conserved metazoan PCD pathway is also present in unicellular yeast.
Mol Cell Biol 1997 May
PMID:Human Bak induces cell death in Schizosaccharomyces pombe with morphological changes similar to those with apoptosis in mammalian cells. 911 15

The a beta peptide induces cell death in neurons grown in cell culture. Previous studies have shown that the mechanism of a beta-mediated cell death of central nervous system neurons appears to be via apoptosis. Apoptosis is an active process that involves both gene transcription and translation. Using semi-quantitative polymerase chain reaction, we have analyzed the levels of a variety of transcripts in primary neuronal cultures treated with a beta that are likely to play important roles in apoptosis. Following addition of 10 microM a beta 1-42 the immediate early response gene, c-fos, shows a rapid and sustained increase in transcript level while c-jun levels increase at a slower rate. Bcl-2 and its homologues, bcl-X and bax, also increase in amount with bcl-2 and bcl-X increasing more rapidly than bax. These data provide support indicating that a beta-mediated cell death in central nervous system neurons is an active process similar to that seen in apoptosis.
Mol Psychiatry 1996 Mar
PMID:Changes in gene transcription during a beta-mediated cell death. 911 17

The expression and function of the newly identified Bcl-2- and Raf-1- binding protein, Bag-1, during the cytokine-regulated growth of B and T cell lines was examined. Immunoblot analysis of lysates from the interleukin-3 (IL-3)-dependent B cell line Ba/F3, and the PRL-dependent T cell line Nb2, revealed that variations in Bag-1 levels paralleled alterations in cellular proliferation, viability, and apoptosis induced by the presence or absence of growth factor. To test whether up-regulation of Bag-1 levels altered cellular survival and proliferation, Ba/F3 cells were transfected with a Bag-1 expression construct. The overexpression of Bag-1 in transfected Ba/F3 cells induced an IL-3-independent state. Such transfectants demonstrated sustained viability and proliferation, with minimal apoptosis, in the complete absence of exogenous IL-3. Bag-1 expression was also compared in glucocorticoid-sensitive Nb2 cells and a PRL-independent, glucocorticoid-resistant subline, SFJCD1, during culture of these lines in dexamethasone (Dex). Bag-1 levels were profoundly decreased by the addition of Dex to Nb2 cells, precedent to the onset of apoptotic cell death. In contrast, Dex treatment or PRL withdrawal had no effect on levels of Bag-1 within the SFJCD1 line. These findings establish that the overexpression of Bag-1 in the appropriate cellular context promotes cellular survival and growth, events that may result from the juxtaposition of this protein with mitogenic and antiapoptotic signaling pathways.
Mol Endocrinol 1997 May
PMID:Role of Bag-1 in the survival and proliferation of the cytokine-dependent lymphocyte lines, Ba/F3 and Nb2. 913 4

Extensive programmed cell death (PCD) occurs in the developing nervous system. Neuronal death occurs, at least in part, because neurons are produced in excess during development and compete with each other for the limited amounts of the survival-promoting trophic factors secreted by target tissues. Neuronal death is apoptotic and utilizes components that are conserved in other PCD pathways. In this review, we discuss the mechanism of trophic factor-dependent neuronal cell death by focusing on the pathway of nerve growth factor (NGF) deprivation-induced sympathetic neuronal death. We describe the biochemical and genetic events that occur in NGF-deprived sympathetic neurons undergoing PCD. Participation of the Bcl-2 family of proteins and the interleukin-1beta-converting enzyme family of proteases (caspases) in this and other models of neuronal death is also examined. The order and importance of these components during NGF deprivation-induced sympathetic neuronal death are discussed.
Mol Pharmacol 1997 Jun
PMID:Programmed cell death in neurons: focus on the pathway of nerve growth factor deprivation-induced death of sympathetic neurons. 918 55

2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol-17beta and the oral contraceptive agent 17-ethylestradiol. 2-ME was recently reported to inhibit endothelial cell proliferation. The current study was undertaken to explore the mechanism of 2-ME effects on endothelial cells, especially whether 2-ME induces apoptosis, a prime mechanism in tissue remodeling and angiogenesis. Cultured bovine pulmonary artery endothelial cells (BPAEC) exposed to 2-ME showed morphological (including ultrastructural) features characteristic of apoptosis: cell shrinkage, cytoplasmic and nuclear condensation, and cell blebbing. 2-ME-induced apoptosis in BPAEC was a time- and concentration-dependent process (EC50 = 0.45 +/- 0.09 microM, n = 8). Nucleosomal DNA fragmentation in BPAEC treated with 2-ME was identified by agarose gel electrophoresis (DNA ladder) as well as in situ nick end labeling. Under the same experimental conditions, estradiol-17beta and two of its other metabolites, estriol and 2-methoxyestriol (< or =10 microM), did not have an apoptotic effect on BPAEC. 2-ME activated stress-activated protein kinase (SAPK)/c-Jun amino-terminal protein kinase in BPAEC in a concentration-dependent manner. The activity of SAPK was increased by 170 +/- 27% and 314 +/- 22% over the basal level in the presence of 0.4 and 2 microM 2-ME (n = 3-6), respectively. The activation of SAPK was detected at 10 min, peaked at 20 min, and returned to basal levels at 60 min after exposure to 2-ME. Inhibition of SAPK/c-Jun amino-terminal protein kinase activation by basic fibroblast growth factor, insulin-like growth factor, or forskolin reduced 2-ME-induced apoptosis. Immunohistochemical analysis of BPAEC indicated that 2-ME up-regulated expression of both Fas and Bcl-2. In addition, 2-ME inhibited BPAEC migration (IC50 = 0.71 +/- 0.11 microM, n = 4) and basic fibroblast growth factor-induced angiogenesis in the chick chorioallantoic membrane model. Taken together, these results suggest that promotion of endothelial cell apoptosis, thereby inhibiting endothelial cell proliferation and migration, may be a major mechanism by which 2-ME inhibits angiogenesis.
Mol Pharmacol 1997 Jun
PMID:2-Methoxyestradiol, an endogenous estrogen metabolite, induces apoptosis in endothelial cells and inhibits angiogenesis: possible role for stress-activated protein kinase signaling pathway and Fas expression. 918 61

1. Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). It is assumed that the lethal trigger is the accumulation of oxidative reactive species generated during metabolism of the natural neurotransmitter dopamine. 2. We have recently shown that dopamine is capable of inducing programmed cell death (PCD) or apoptosis in cultured postmitotic chick sympathetic neurons and rat PC12 pheochromocytoma cells. 3. The bcl-2 gene encodes a protein which blocks physiological PCD in many mammalian cells. In an attempt to elucidate further the mechanism of dopamine toxicity, we examined the potential protective effect of bcl-2 in PC12 cells which were transfected with the protooncogene. 4. In our experiments, Bcl-2 producing cells showed a marked resistance to dopamine toxicity. The percentage of nuclear condensation and DNA fragmentation visualized by the end-labeling method following dopamine treatment was significantly lower in bcl-2 expressing cells. Bcl-2 did not protect PC12 cells against toxicity induced by exposure to dopamine-melanin. Extracts of PC12 cells containing Bcl-2 inhibited dopamine autooxidation and formation of dopamine-melanin. Furthermore, the presence of Bcl-2 protected cells from thiol imbalance and prevented thiol loss following exposure to dopamine. 5. The protective effects of Bcl-2 against dopamine toxicity may be explained, in part, by its action as an antioxidant and by its interference in the production of toxic agents. The possible protection by Bcl-2 against neuronal degeneration caused by dopamine may play a role in the pathogenesis of PD and may provide a new direction for the development of neuroprotective therapies.
Cell Mol Neurobiol 1997 Jun
PMID:Dopamine-induced apoptosis is inhibited in PC12 cells expressing Bcl-2. 918 86

The effects of the expression of the human Bcl-2 family proteins Bax, Bak, Bcl-2, and Bcl-XL were examined in the fission yeast Schizosaccharomyces pombe and compared with Bax-induced cell death in mammalian cells. Expression of the proapoptotic proteins Bax and Bak conferred a lethal phenotype in this yeast, which was strongly suppressed by coexpression of the anti-apoptotic protein Bcl-XL. Bcl-2 also partially abrogated Bax-mediated cytotoxicity in S. pombe, whereas a mutant of Bcl-2 (Gly145Ala) that fails to heterodimerize with Bax or block apoptosis in mammalian cells was inactive. However, other features distinguished Bax- and Bak-induced death in S. pombe from animal cell apoptosis. Electron microscopic analysis of S. pombe cells dying in response to Bax or Bak expression demonstrated massive cytosolic vacuolization and multifocal nuclear chromatin condensation, thus distinguishing this form of cell death from the classical morphological features of apoptosis seen in animal cells. Unlike Bax-induced apoptosis in 293 cells that led to the induction of interleukin-1 beta-converting enzyme (ICE)/CED-3-like protease activity, Bax- and Bak-induced cell death in S. pombe was accompanied neither by internucleosomal DNA fragmentation nor by activation of proteases with specificities similar to the ICE/CED-3 family. In addition, the baculovirus protease inhibitor p35, which is a potent inhibitor of ICE/CED-3 family proteases and a blocker of apoptosis in animal cells, failed to prevent cell death induction by Bax or Bak in fission yeast, whereas p35 inhibited Bax-induced cell death in mammalian cells. Taken together, these findings suggest that Bcl-2 family proteins may retain an evolutionarily conserved ability to regulate cell survival and death but also indicate differences in the downstream events that are activated by overexpression of Bax or Bak in divergent cell types.
Mol Biol Cell 1997 Feb
PMID:Bax- and Bak-induced cell death in the fission yeast Schizosaccharomyces pombe. 919 Feb 11

Recent studies have documented the involvement of the atypical protein kinase C (aPKC) isoforms in important cellular functions such as cell proliferation and survival. Exposure of cells to a genotoxic stimulus that induces apoptosis, such as UV irradiation, leads to a profound inhibition of the atypical PKC activity in vivo. In this study, we addressed the relationship between this phenomenon and different proteins involved in the apoptotic response. We show that (i) the inhibition of the aPKC activity precedes UV-induced apoptosis; (ii) UV-induced aPKC inhibition and apoptosis are independent of p53; (iii) Bcl-2 proteins are potent modulators of aPKC activity; and (iv) the aPKCs are located upstream of the interleukin-converting enzyme-like protease system, which is required for the induction of apoptosis by both Par-4 (a selective aPKC inhibitor) and UV irradiation. We also demonstrate here that inhibition of aPKC activity leads to a decrease in mitogen-activated protein (MAP) kinase activity and simultaneously an increase in p38 activity. Both effects are critical for the induction of apoptosis in response to Par-4 expression and UV irradiation. Collectively, these results clarify the position of the aPKCs in the UV-induced apoptotic pathway and strongly suggest that MAP kinases play a role in this signaling cascade.
Mol Cell Biol 1997 Aug
PMID:Positioning atypical protein kinase C isoforms in the UV-induced apoptotic signaling cascade. 923 92

Cross-linking of Fas (CD95, APO-1) and Fas ligand (FasL; CD95L) induces apoptosis of Fas-bearing cells. Recent evidence suggests that FasL. expression plays an important role in maintenance of immune privilege in murine testis and eye and in tumour escape from immune rejection in colon cancer, melanoma and hepatocellular carcinoma. Bcl-2 is a membrane protein that suppresses apoptosis in response to a variety of stimuli. In this paper we describe abundant expression of FasL protein and mRNA transcripts within the immune privileged environment of the placenta by immunohistochemistry and reverse transcription in-situ polymerase chain reaction methods. The syncytiotrophoblast layer, the main site of feto-maternal interface, and extravillous trophoblasts, demonstrated consistent immunoreactivity for FasL in term placentae. Co-occurrence of Fas and Bcl-2 were detected with a similar pattern of distribution with FasL. The TUNEL method revealed evidence of apoptosis in the placental tissues. We speculate that abundant presence of FasL in the trophoblast contributes to immune privilege in this unique environment, perhaps by fostering apoptosis of activated Fas-expressing lymphocytes of maternal origin. An apoptotic process mediated by FasL may also play a role in placental invasion during implantation and underscores similarities between the trophoblast and neoplastic cells.
Mol Hum Reprod 1997 Aug
PMID:Trophoblasts express Fas ligand: a proposed mechanism for immune privilege in placenta and maternal invasion. 929 48

A newly established human lymphoma cell line (OZ) has the t(14;18)(q32;q21) translocation and expresses large amounts of Bcl-2 compared to CCRF-CEM cells. VP-16 (40 micrograms/mL), a promising agent against lymphoma, caused DNA fragmentation (26.9% of total DNA) typical for apoptosis at 6 h in CCRF-CEM cells, but no significant changes in OZ cells until 24 h after the addition of VP-16. However, coincubation with calphostin C (0.2 microgram/mL), a protein kinase C (PKC) inhibitor, induced DNA fragmentation in VP-16-treated OZ cells (13.5% of total DNA) at 6 h after the treatment. Simultaneous immunoblot analysis revealed that this induction of apoptosis coincided with the downregulation of serine-phosphorylated Bcl-2 (13% of control cells). By contrast, apoptosis induced by VP-16 in CCRF-CEM cells was attenuated by the addition of 0.5 microM phorbol 12-myristate 13-acetate, a potent PKC stimulator. These observations suggest that Bcl-2 function is partly regulated by phosphorylation/ dephosphorylation mechanisms of the PKC system, and that phosphorylated Bcl-2 in lymphoma cells may play a role in the prevention of apoptosis.
Cell Mol Life Sci 1997 Sep
PMID:Calphostin C synergistically induces apoptosis with VP-16 in lymphoma cells which express abundant phosphorylated Bcl-2 protein. 936 70


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