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 biologically active form of vitamin D3, the nuclear hormone 1 alpha,25-dihydroxyvitamin D3 (VD), is an important regulator of cellular growth, differentiation, and death. The hormone mediates its action through the activation of the transcription factor VDR, which is a member of the superfamily of nuclear receptors. In most cases the ligand-activated VDR is found in complex with the retinoid X receptor (RXR) and stimulates gene transcription mainly from VD response elements (VDREs) that are formed by two hexameric core binding motifs and are arranged either as a direct repeat spaced by three nucleotides (DR3) or as an inverted palindrome spaced by nine nucleotides (1P9). The two VD analogues CB1093 and EB1089 are both very potent inhibitors of the proliferation of MCF-7 cultured breast cancer cells displaying approximately 100-fold lower IC50 values (0.1 nM) than the natural hormone. In addition, CB1093 is even more potent in vivo than EB1089 in producing regression of experimental mammary tumors. Moreover, both VD analogues induce apoptosis in MCF-7 cells, but CB1093 is effective at concentrations approximately 10-fold lower than EB1089. In accordance, the reduction of Bcl-2 protein expression showed CB1093 to be more potent than EB1089. This suggests that the antiproliferative effect of CB1093 may be related mainly to its apoptosis inducing effect, whereas EB1089 may preferentially have effects on growth arrest. EB1089 is known to result in a selectivity for the activation of IP9-type VDREs, whereas CB1093 shows a preference for the activation of DR3-type VDREs. This promoter selectivity suggests that the effects of VD and its analogues on growth arrest and the induction of apoptosis may be mediated by different primary VD responding genes. In conclusion, CB1093 was found to be a potent inhibitor of rat mammary tumor growth in vivo. CB1093 also displayed a high potency in vitro in the induction of apoptosis, a process that may be linked to a promoter selectivity for DR3-type VDREs.
J Cell Biochem 1997 Sep 15
PMID:Sensitive induction of apoptosis in breast cancer cells by a novel 1,25-dihydroxyvitamin D3 analogue shows relation to promoter selectivity. 928 33

Programmed cell death, or apoptosis, is inhibited by the antiapoptotic oncogene, Bcl-2, and is mediated by a cascade of aspartate-specific cysteine proteases, or caspases, related to interleukin 1-beta converting enzyme. Depending on cell type, apoptosis can be induced by treatment with thapsigargin (TG); a selective inhibitor of the endoplasmic reticulum-associated calcium-ATPase. The role of caspases in mediating TG-induced apoptosis was investigated in the Bcl-2-negative human breast cancer cell line, MDA-MB-468. Apoptosis developed in MDA-MB-468 cells over a period of 24-72 h following treatment with 100 nM TG, and was prevented by Bcl-2 overexpression. TG-induced apoptosis was associated with activation of caspase-3 and was inhibited by stable expression of the baculovirus p35 protein, an inhibitor of caspase activity. Also, TG-induced apoptosis was inhibited by treating cells with Z-VAD-fmk, a cell-permeable fluoromethylketone inhibitor of caspases. These findings indicate that TG-induced apoptosis of MDA-MB-468 breast cancer cells is subject to inhibition by Bcl-2 and is mediated by caspase activity. This model system should be useful for further investigation directed toward understanding the role of calcium in signaling apoptosis, and its relationship to Bcl-2 and the caspase proteolytic cascade.
Oncogene 1997 Sep 04
PMID:Baculovirus p35 and Z-VAD-fmk inhibit thapsigargin-induced apoptosis of breast cancer cells. 929 14

1-beta-D-Arabinofuranosylcytosine (ara-C) stimulates the formation of both diglyceride and ceramide in the acute myelogenous leukemia cell line HL-60 (Strum, J. C., Small, G. W., Pauig, S. B., and Daniel, L. W. (1994) J. Biol. Chem 269, 15493-15497). ara-C also causes apoptosis in HL-60 cells which can be mimicked by exogenous ceramide. However, the signaling role for ara-C-induced diacylglycerol (DAG) is not defined. We found that Bcl-2 levels were increased by treatment of HL-60 cells with exogenous DAG or 12-O-tetradecanoylphorbol-13-acetate (TPA). In contrast, exogenous ceramide treatment caused a decrease in cellular Bcl-2 levels. Thus, ara-C stimulates the synthesis of two second messengers with opposing effects on Bcl-2. Since the effects of ara-C-induced DAG could be due to protein kinase C (PKC) activation, we determined the effects of ara-C on PKC isozymes. ara-C caused an increase in membrane-bound PKCbetaII (but not PKCalpha or PKCdelta). ara-C or TPA-induced translocation of PKCbetaII was inhibited by 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3), and ara-C-induced apoptosis was stimulated by pretreatment of the cells with ET-18-OCH3. ET-18-OCH3 also inhibited stimulation of Bcl-2 by TPA and enhanced the decrease in Bcl-2 observed in ara-C-treated cells. These data indicate that ara-C-induced apoptosis is limited by ara-C-stimulated PKCbetaII through effects on Bcl-2. To further determine the role of PKC, we used antisense oligonucleotides directed toward PKCbetaII. The antisense, but not the sense, oligonucleotide inhibited PKCbetaII activation and enhanced ara-C-induced apoptosis. These data demonstrate that the stimulation of apoptosis by ara-C is self-limiting and can be enhanced by inhibition of PKC.
J Biol Chem 1997 Sep 19
PMID:Protein kinase CbetaII activation by 1-beta-D-arabinofuranosylcytosine is antagonistic to stimulation of apoptosis and Bcl-2alpha down-regulation. 929 81

A marked feature of eukaryotic programmed cell death is an early drop in mitochondrial transmembrane potential. This results from the opening of permeability transition pores, which are composed of adenine nucleotide translocators and mitochondrial porins. The latter share striking similarities with bacterial porins, including down-regulation of their pore size by purine nucleotides), suggesting a common origin. The porins of some invasive bacteria play a crucial role during their accommodation inside the host cell and this coexistence resembles the endosymbiotic origin of mitochondria. The above observations suggest that early in eukaryotic evolution, former invaders may have used porin-type channels to enter their host and to induce its death when the levels of its cytoplasmic purine nucleotides were dropped. The appearance of adenosine nucleotide translocators in the primitive eukaryotes, which permitted usage of the oxidative metabolism of the invaders, provided the basis for the permeability transition phenomena, now linked to the apoptotic process. Bcl-2-type molecules, being able to modulate the permeability transition pores by interaction with adenosine nucleotide translocators, may have played an essential role in conferring a means of controlling apoptosis.
Bioessays 1997 Sep
PMID:Origin of eukaryotic programmed cell death: a consequence of aerobic metabolism? 929 74

The oncogene bcl-2 encodes a 26-kD protein localized to intracellular membranes, including the ER, mitochondria, and perinuclear membrane, but its mechanism of action is unknown. We have been investigating the hypothesis that Bcl-2 regulates the movement of calcium ions (Ca2+) through the ER membrane. Earlier findings in this laboratory indicated that Bcl-2 reduces Ca2+ efflux from the ER lumen in WEHI7.2 lymphoma cells treated with the Ca2+-ATPase inhibitor thapsigargin (TG) but does not prevent capacitative entry of extracellular calcium. In this report, we show that sustained elevation of cytosolic Ca2+ due to capacitative entry is not required for induction of apoptosis by TG, suggesting that ER calcium pool depletion may trigger apoptosis. Bcl-2 overexpression maintains Ca2+ uptake in the ER of TG-treated cells and prevents a TG-imposed delay in intralumenal processing of the endogenous glycoprotein cathepsin D. Also, Bcl-2 overexpression preserves the ER Ca2+ pool in untreated cells when extracellular Ca2+ is low. However, low extracellular Ca2+ reduces the antiapoptotic action of Bcl-2, suggesting that cytosolic Ca2+ elevation due to capacitative entry may be required for optimal ER pool filling and apoptosis inhibition by Bcl-2. In summary, the findings suggest that Bcl-2 maintains Ca2+ homeostasis within the ER, thereby inhibiting apoptosis induction by TG.
J Cell Biol 1997 Sep 22
PMID:Maintenance of calcium homeostasis in the endoplasmic reticulum by Bcl-2. 929 78

At the midblastula transition during Xenopus development, the cell cycle is remodeled, and zygotic transcription is initiated. Additionally, cyclin E1 is degraded at the midblastula transition independently of protein synthesis, the number of cell cycles, and the nuclear-to-cytoplasmic ratio. In the studies reported here, cell cycles were delayed by transient inhibition of protein synthesis with cycloheximide (100 microg/ml) prior to the midblastula transition. Even after reaccumulation of mitotic cyclins and resumption of cell divisions, cycloheximide-treated embryos did not resume DNA synthesis, failed to initiate transcription, and synchronously became apoptotic before the gastrula stage. These results were independent of the stage at which embryos were treated or the duration of treatment. Inhibition of zygotic transcription with alpha-amanitin also induced apoptosis. These data suggest that a developmental checkpoint at the midblastula transition is maternally regulated and can trigger apoptosis. Apoptosis induced by cycloheximide or alpha-amanitin was blocked by injection of RNA encoding Xenopus Bcl-2, suggesting that this maternal program is normally blocked by expression of an apoptotic inhibitor. Embryos pulsed with lower doses of cycloheximide (10 microg/ml) delayed development prior to the midblastula transition but resumed DNA synthesis, initiated transcription, and gastrulated normally. This indicates that the apoptotic response is initiated only when delayed embryos are unable to support initiation of zygotic transcription.
Dev Biol 1997 Sep 15
PMID:Zygotic transcription is required to block a maternal program of apoptosis in Xenopus embryos. 929 25

Previous work demonstrated that collagen fibrils were not detectable in the cartilage of transgenic mice homozygous for targeted inactivation of the collagen II gene. In the present work, we used the same mice to show that chondrocytes undergo apoptosis in the absence of collagen II, the major component of the extracellular matrix of cartilage. The chondrocytes in the homozygous mice had condensed nuclei, fragmentation of nuclear DNA, and decreased levels of the Bcl-2 protein. These results provide direct evidence that cartilage extracellular matrix lacking collagen II cannot support the survival of chondrocytes. In addition, the results suggest that apoptosis may play a role in degenerative connective tissue diseases such as osteoarthritis in which there is extensive tissue loss.
Exp Cell Res 1997 Sep 15
PMID:Apoptosis of chondrocytes in transgenic mice lacking collagen II. 929 61

To facilitate the creation of Bak knockout mice and the further analysis of this Bcl-2 family member, we have isolated and sequenced the complete mouse Bak cDNA. The cDNA is 2 kb long and shares an overall nucleotide identity to the human Bak cDNA of 62%. The mouse Bak protein is 208 amino acids long with a predicted molecular weight of 23 kDa. The mouse Bak mRNA could be detected in all mouse tissues examined. In addition we mapped the murine bak gene. It consists of six exons spanning about 10 kb on chromosome 17B. The 5' region of the murine bak gene is unmethylated on the dinucleotide CpG in the area around exon 1. Furthermore, it contains potential binding sites for transcription factors such as Sp1 and c-Myb.
Genomics 1997 Sep 01
PMID:Gene structure, cDNA sequence, and expression of murine Bak, a proapoptotic Bcl-2 family member. 929 36

Programmed cell death (PCD) characteristically involves chromatin condensation, membrane blebbing, and DNA oligonucleosomal fragmentation. These events, collectively referred to as apoptosis, represent an active cell suicide mechanism that eliminates cellular threats including potentially cancerous or virus-infected cells. Various types of programmed cell death can be blocked by the proto-oncogene Bcl-2. Levels of this protein are consistently low or undetectable in human endothelial cells (EC), which are important for immunoregulation through their interactions with circulating lymphocytes and are potential targets for infection by virus-bearing T-cells. Accumulating evidence suggests that EC may be infected in vivo to play an important role in HTLV-I-associated neuromyelopathy. In the present study, we report the establishment and characterization of human endothelial cell lines stably transfected with an HTLV-I-derived molecular clone. We observed constitutive expression of HTLV-I genes coinciding with activated Bcl-2 expression. Transient transfection of EC with the viral transactivator Tax and a reporter construct Bcl-2 promoter-CAT did not result in a significant increase in CAT activity and suggests that, in EC, expression of a second viral protein might be required for Bcl-2 activation. Further, Tax-induced apoptosis in rat fibroblasts has been shown to be blocked by Bcl-2 expression. Thus, HTLV-I-mediated induction of Bcl-2 expression in EC may provide protection against viral-induced apoptosis or extend cellular survival and create a reservoir for viral gene expression.
Virology 1997 Sep 15
PMID:Activation of Bcl-2 expression in human endothelial cells chronically expressing the human T-cell lymphotropic virus type I. 929 16

Sulfur mustard (2,2-dichlorodiethyl sulfide, HD) is a chemical warfare agent that is a threat to both troops and civilians. The focus of HD research has been on intracellular adduct formation leading to apoptosis and/or necrosis in cutaneous lesions. However, there is work which suggests that HD may have a more direct effect on the basement membrane zone. Immunohistochemical staining to desmosomal proteins, cellular fibronectin, laminin 1, laminin 5, collagen IV, collagen VII, p53, Bcl-2, and PCNA was performed on weanling pig skin exposed to vesicating doses of HD, GB3, an antibody to laminin 5, showed a progressive decrease with loss of expression during the time period of clinical vesiculation. The other basement membrane proteins showed no change or inconsistent changes. PCNA, and p53 staining increased in the overlying epidermis in areas of vesiculation without significant necrosis. Bcl-2 positive cells were decreased or absent after exposure. This study implicates laminin 5 as the main basement membrane protein affected acutely by HD exposure. The patterns of staining of PCNA, Bcl-2, and p53 within the epidermis suggest that apoptosis and cellular necrosis both may play a role in cell death secondary to HD.
J Dermatol Sci 1997 Sep
PMID:Immunohistochemical studies of basement membrane proteins and proliferation and apoptosis markers in sulfur mustard induced cutaneous lesions in weanling pigs. 930 45


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