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)

Recent evidence suggests that apoptotic deletion of activated mature lymphocytes is an essential physiological process implicated in both the regulation of the immune response and the control of the overall number of immunocompetent cells. Tightly interrelated signaling mechanisms convey either activation or death messages, achieving the necessary equilibrium between cell proliferation and cell deletion. During the course of aging, numerous alterations of these signaling pathways may shift the balance toward cell death. In the present investigation, the reduced DNA synthesis of anti-CD3 activated T lymphocytes isolated from elderly individuals is associated with an important and early cell deletion from the cultures. Visualization of DNA fragmentation in the remaining activated cells argues in favour of the apoptotic nature of the cell deletion. Quantification of histone-associated DNA fragments shows that the apoptotic process is greatly amplified in activated lymphocytes derived from senescent organisms. Further analysis reveals that IL-2 deprivation does not play a significant role in the age-related increase in apoptosis. Partial correction of this excessive apoptosis by products that bypass the early steps of the signaling cascade suggests that transmembrane signaling defects are involved in this process. Exploration of the antioxidant pathway reveals that the increased susceptibility of lymphocytes from senescent organisms to apoptosis is not explained by a decreased Bcl-2 expression and is not influenced by a modification of the intracellular concentration of glutathione (GSH).
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PMID:Excessive apoptosis of mature T lymphocytes is a characteristic feature of human immune senescence. 880 91

Endotoxic shock results in multiple organ failure. At present, two different mechanisms of cellular destruction are of interest: necrosis and apoptosis. Therefore, we started to investigate in pigs whether cell death due to apoptosis is involved in this pathophysiological process. DNA fragments were detected by ELISA specific for histone-associated DNA fragments in three different experimental settings, Pigs were laparotomized followed by endotoxin infusion (ETOX group, n = 6), or laparotomized without endotoxin infusion (LAP group; n = 3) and compared with control animals (n = 3). 6 h of continuous endotoxin-infusion (5 micrograms/kg/h) resulted in a significantly enhanced apoptosis in liver as compared with controls animals (295 +/- 11%; p < .01), whereas in the LAP group, only a minor increase of 166 +/- 14% was detectable. In spleen of endotoxin-treated animals, an enhanced apoptosis of 150 +/- 12% compared with controls was shown in the ETOX group (p = .02), whereas kidney remained unaffected. These results were confirmed by agarose DNA gel electrophoresis. A typical DNA ladder was detected in liver and spleen, but not in kidney of endotoxin-treated animals. Furthermore, immunohistochemical detection of DNA strand breaks with terminal deoxynucleotidyl transferase in liver sections revealed a drastic increase of stained cells. The induction of apoptosis correlated with a reduced Bcl-2 content in endotoxin-treated animals. Our study demonstrates that 6 h of endotoxin treatment leads to apoptosis in liver and spleen in vivo, whereas kidney of endotoxin-treated animals remains unaffected. This process may be mediated by reduction of Bcl-2 by endotoxin treatment.
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PMID:Endotoxic shock leads to apoptosis in vivo and reduces Bcl-2. 896 90

Programmed cell death, an essential function in all cells, plays a central role in maintaining immune system homeostasis and controlling autoimmune reactions. Cell death may be an essential element in disseminated lupus erythematosus: defective cell death could lead to the development of autoreactive lymphocyte clones and degradation products of cell death could be implicated in autoimmunity induction and onset of renal lesions. Anomalies in programmed cell death have been demonstrated in murine models of lupus: mutations of the fas and fas-ligand genes, which play a known role in programmed cell death, produce the lpr and gld phenotypes associating lymphoproliferation and lupus. Transgenic mice which express Bcl-2 (the product of Bcl-2 inhibits programmed cell death) on B lymphocytes develop a lupus-type autoimmune disease. The role of these types of anomalies in human disease is not yet elucidated. However, cell death, via the degradation fragments of chromatin, could play a role in inducing antibody production and development of renal lesions. The anti-DNA antibodies, with characteristic antigen-induced immune response (clone expansion, class computation and somatic mutations) could be induced by nucleosomes released during cell death. Several arguments favor this mechanism including cation residues of histone nucleosomes which would bind to anionic residues of sulfate heparan and lead to deposit of autoantibodies in the glomerulus. The dual role of cell death is not really contradictory in autoimmune disease controlled by several independent genes, but would be compatible with several different genetic backgrounds.
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PMID:[Cell death and lupus]. 909 57

The histone deacetylase inhibitor and potential anti-cancer drug sodium butyrate is a general inducer of growth arrest, differentiation, and in certain cell types, apoptosis. In human CCRF-CEM, acute T lymphoblastic leukemia cells, butyrate, and other histone deacetylase inhibitors caused G2/M cell cycle arrest as well as apoptotic cell death. Forced G0/G1 arrest by tetracycline-regulated expression of transgenic p16/INK4A protected the cells from butyrate-induced cell death without affecting the extent of histone hyperacetylation, suggesting that the latter may be necessary, but not sufficient, for cell death induction. Nuclear apoptosis, but not G2/M arrest, was delayed but not prevented by the tripeptide broad-range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp.fluoromethylketone (zVAD) and, to a lesser extent, by the tetrapeptide 'effector caspase' inhibitors benzyloxycarbonyl-Asp-Glu-Val-Asp.fluoromethylketone (DEVD) and benzyloxycarbonyl-Val-Glu-Ile-Asp.fluoromethyl-ketone (VEID); however, the viral protein inhibitor of 'inducer caspases', crmA, had no effect. Bcl-2 overexpression partially protected stably transfected CCRF-CEM sublines from butyrate-induced apoptosis, but showed no effect on butyrate-induced growth inhibition, further distinguishing these two butyrate effects. c-myc, constitutively expressed in CCRF-CEM cells, was down-regulated by butyrate, but this was not causative for cell death. On the contrary, tetracycline-induced transgenic c-myc sensitized stably transfected CCRF-CEM derivatives to butyrate-induced cell death.
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PMID:Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts. 1054 82

Human oral cancer cells may have any of several genetic changes, but the role of the bcl-2 oncogene is relatively unexplored. To find out if this gene plays a significant role and whether it could act as a target for gene therapy of oral cancer, we have examined the effects of an anti-bcl-2 ribozyme on the phenotype of oral cancer cells. A hammer-head ribozyme was designed to cleave the bcl-2 transcript after nucleotide 279 and was confirmed to be effective against a synthetic bcl-2 transcript. A gene encoding the ribozyme was cloned into an adenovirus vector and transferred to the human oral cancer cell lines 686LN, 1483, and Tu183. Over a 6-day period, the growth of each cancer cell line was reduced, whereas growth of the fibroblast cell line FS7 was less inhibited. Inhibition of the oral cancer cells could be attributed to apoptosis, as indicated by the detection of histone-associated DNA fragments in an immunoassay. Northern blots showed no detectable reduction in the level of bcl-2 mRNA of Tu183 cells, but Western blots showed a reduction of Bcl-2 protein at 24 h after infection with the ribozyme-expressing adenovirus vector. The results imply that (a) expression of the bcl-2 oncogene is necessary for the survival of oral cancer cells, (b) the bcl-2 gene transcript presents a target for gene therapy by ribozymes, and (c) an adenovirus vector is a suitable method for transfection of the ribozyme-expressing gene.
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PMID:Induction of apoptosis in oral cancer cells by an anti-bcl-2 ribozyme delivered by an adenovirus vector. 1065 52

Hair follicle (HF) growth and regression is an exquisitely regulated process of cell proliferation followed by massive cell death and is accompanied by cyclical expression of the apoptosis regulatory gene pair, Bcl-2 and Bax. To further investigate the role of Bcl-2 expression in the control of hair growth and keratinocyte apoptosis, we have used transgenic mice that overexpress human Bcl-2 in basal epidermis and in the outer root sheath under the control of the human keratin-14 promoter (K14/Bcl-2). When irradiated with ultraviolet B (UVB) light, K14/Bcl-2 mice developed about 5-10-fold fewer sunburn cells (ie, apoptotic keratinocytes) in the basal layer of the epidermis, compared to wild-type mice, whereas cultures of primary keratinocytes from transgenic mice were completely resistant to UVB-induced histone formation, at doses that readily induced histone release from wild-type cells. K14/Bcl-2 mice show no alteration of neonatal hair follicle morphogenesis or of the onset of the first wave of HF regression (catagen). However, compared to wild-type controls, K14/Bcl-2 mice subsequently displayed a significant acceleration of spontaneous catagen progression. During chemotherapy-induced alopecia, follicular dystrophy was promoted in K14/Bcl-2 mice. Thus, although K14-driven overexpression of Bcl-2 protected murine epidermal keratinocytes from UVB-induced apoptosis, it surprisingly promoted catagen- and chemotherapy-associated keratinocyte apoptosis.
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PMID:Overexpression of Bcl-2 protects from ultraviolet B-induced apoptosis but promotes hair follicle regression and chemotherapy-induced alopecia. 1075 63

A CpG-specific commitment common to both caspase-dependent and -independent cell deaths implies critical gene activity from epigenetic modulation. Using a focused microarray (genechip) of 22 housekeeping genes, which have canonical CpG islands at 5'-promoter regions, here we show critical regulation of vital intermediary metabolism and cell structure that are common to both caspase-dependent fasL-mediated and caspase-independent etoposide-mediated cell deaths. Gene activity of at least twofold under or over control levels and common to both cell death pathways was considered to be significantly regulated in common. Seven genes controlling energy production in glycolysis, tricarboxylic acid cycle, and the respiratory electron transport chain were significantly downregulated in common. Energy depletion is lethal. Downregulated pyruvate dehydrogenase E1 gene, in addition, suggested primary metabolic acidification. Cell acidification is also lethal. Critical derangement of the cell structure was suggested by common downregulation of the basal histone gene H2A.X which is required for nucleosome assembly. Common upregulation of the alpha-tubulin gene suggested perturbation of vital microtubular dynamics. Gene-commanded cell suicide was suggested. We further show that a Bcl-2 overexpression of three- to fourfold above normal levels could not prevent the CpG-specific megabase DNA cleavages in the two cell death pathways, but abolished their low-molecular-weight 200-bp ladder cleavages. Together with incomplete suppression of the other apoptotic expressions, the Bcl-2 inhibition point appeared downstream from the CpG-cleavage commitment point.
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PMID:Housekeeping genes commanded to commit suicide in CpG-cleavage commitment upstream of Bcl-2 inhibition in caspase-dependent and -independent pathways. 1096 57

Efforts in prevention and control of tuberculosis suffer from the lack of detailed knowledge of the mechanisms used by pathogenic mycobacteria for survival within host cell macrophages. The exploitation of host cell signaling pathways to the benefit of the pathogen is a phenomenon that deserves to be looked into in detail. We have tested the hypothesis that lipoarabinomannan (LAM) from the virulent species of Mycobacterium tuberculosis possesses the ability to modulate signaling pathways linked to cell survival. The Bcl-2 family member Bad is a proapoptotic protein. Phosphorylation of Bad promotes cell survival in many cell types. We demonstrate that man-LAM stimulates Bad phosphorylation in a phosphatidylinositol 3-kinase (PI-3K)-dependent pathway in THP-1 cells. Man-LAM activated PI-3K. LAM-stimulated phosphorylation of Bad was abrogated in cells transfected with a dominant-negative mutant of PI-3K (Delta p85), indicating that activation of PI-3K is sufficient to trigger phosphorylation of Bad by LAM. Since phosphorylation of Bad occurred at serine 136, the target of the serine/threonine kinase Akt, the effect of LAM on Akt kinase activity was tested. Man-LAM could activate Akt as evidenced from phosphorylation of Akt at Thr(308) and by the phosphorylation of the exogenous substrate histone 2B. Akt activation was abrogated in cells transfected with Deltap85. The phosphorylation of Bad by man-LAM was abrogated in cells transfected with a kinase-dead mutant of Akt. These results establish that LAM-mediated Bad phosphorylation occurs in a PI-3K/Akt-dependent manner. It is therefore the first demonstration of the ability of a mycobacterial virulence factor to up-regulate a signaling pathway involved in cell survival. This is likely to be one of a number of virulence-associated mechanisms by which bacilli control host cell apoptosis.
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PMID:Lipoarabinomannan from Mycobacterium tuberculosis promotes macrophage survival by phosphorylating Bad through a phosphatidylinositol 3-kinase/Akt pathway. 1102 Mar 82

Our results demonstrate that sodium phenylbutyrate, a compound with a low degree of toxicity, exerted a cytotoxic effect on human retinoblastoma Y79 cells in a time- and dose-dependent manner. Treatment of Y79 cells for 72 h with phenylbutyrate reduced cell viability by 63% at 2 mM and 90% at 4 mM. Cell death caused by phenylbutyrate exhibited the typical features of apoptosis, as shown by light and fluorescent microscopy. Western blot analysis demonstrated that exposure of Y79 cells to phenylbutyrate decreased the level of the antiapoptotic factor Bcl-2 and induced the activation of caspase-3, a key enzyme in the execution phase of apoptosis. Moreover, treatment with phenylbutyrate markedly increased the level of acetylated histone-H3. Combined treatment with phenylbutyrate and topotecan, a topoisomerase I-inhibitor, resulted in a clear synergistic effect. We suggest that the effects exerted by phenylbutyrate on Y79 cells essentially depend on modifications of gene expression consequent to histone hyperacetylation.
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PMID:Sodium phenylbutyrate induces apoptosis in human retinoblastoma Y79 cells: the effect of combined treatment with the topoisomerase I-inhibitor topotecan. 1135 Dec 56

The impact of dysregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1/MDA6 has been examined in U937 human monocytic leukemia cells in relation to cell cycle arrest and differentiation following treatment with the histone deacetylase inhibitor sodium butyrate (SB). Cells stably transfected with a p21WAF1/CIP1/MDA6 antisense construct, in marked contrast to their wild-type counterparts, failed to up-regulate p21WAF1/CIP1/MDA6, undergo G1 arrest, or express the maturation marker CD11b when exposed to 1 or 3 mM SB. However, antisense-expressing cells were significantly more susceptible to SB-mediated mitochondrial injury and apoptosis, manifested by increased cytosolic translocation of cytochrome c, activation of pro-caspase 3, and degradation of PARP. Dysregulation of p21WAF1/CIP1/MDA6 did not modify the extent of SB-induced histone acetylation, but did result in cleavage of p27KIP1, Bcl-2 and pRb, as well as diminished levels of full-length underphosphorylated pRb. Finally, dysregulation of p21WAF1/CIP1/MDA6 did not modify SB-mediated down-regulation of E2F-1 or c-Myc, but was associated with enhanced down-regulation of cyclins D1 and E. Together, these findings indicate that in U937 leukemia cells, p21WAF1/CIP1/MDA6 plays a critical functional role in SB-mediated G1 arrest and maturation, and suggest that cells displaying dysregulation of this CDKI respond to SB by engaging a default apoptotic program.
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PMID:Evidence of a functional role for the cyclin-dependent kinase-inhibitor p21WAF1/CIP1/MDA6 in promoting differentiation and preventing mitochondrial dysfunction and apoptosis induced by sodium butyrate in human myelomonocytic leukemia cells (U937). 1140 41


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