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)

In Down syndrome, enhanced apoptosis (programmed cell death) may play a role in the pathogenesis of characteristic early mental retardation and precocious neurodegeneration of Alzheimer type. Various apoptosis-associated proteins (Bax, Bcl-2, Fas, p53, Hsp70, neuronal apoptosis inhibitory protein-like immunoreactivity) were investigated in four different cortical regions and the cerebellum of one fetal Down syndrome (35 weeks' gestation) postmortem brain sample compared with a control brain sample. The most impressive finding was an at least fivefold elevation of Bax protein together with decreased Bcl-2 values in all Down syndrome cerebral regions investigated. In addition, antiapoptotic, presumably caspase-inhibitory, principles like heat shock protein 70 and neuronal apoptosis inhibitory protein were also reduced. Whereas Fas protein, an important member of receptor-mediated apoptosis, was inconsistently altered, a rather surprising finding was reduced proapoptotic, regulatory protein p53 in four of five regions. The findings are in good agreement with the proposed role of the Bcl-2 protein family in regulating developmental (naturally occurring) apoptotic neuronal death and further suggest that developmental apoptosis may be inappropriately commandeered by so far undefined pathologic processes in Down syndrome.
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PMID:Evidence for apoptosis in the fetal Down syndrome brain. 1141 11

Mild metabolic stress may increase resistance of neurons in the brain to subsequent, more severe insults, as demonstrated by the ability of ischemic pre-conditioning and dietary restriction to protect neurons in experimental models of stroke- and age-related neurodegenerative disorders. In the present study we employed iodoacetic acid (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, to test the hypothesis that inhibition of glycolysis can protect neurons. Pre-treatment of cultured hippocampal neurons with IAA can protect them against cell death induced by glutamate, iron and trophic factor withdrawal. Surprisingly, protection occurred with concentrations of IAA (2-200 nM) much lower than those required to inhibit glycolysis. Pre-treatment with IAA results in suppression of oxyradical production and stabilization of mitochondrial function in neurons after exposure to oxidative insults. Levels of the stress heat-shock proteins HSP70 and HSP90, and of the anti-apoptotic protein Bcl-2, were increased in neurons exposed to IAA. Our data demonstrate that IAA can stimulate cytoprotective mechanisms within neurons, and suggest the possible use of IAA and related compounds in the prevention and/or treatment of neurodegenerative conditions.
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PMID:Iodoacetate protects hippocampal neurons against excitotoxic and oxidative injury: involvement of heat-shock proteins and Bcl-2. 1167 64

Hypertrophy is one mechanism of pancreatic beta-cell growth and is seen as an important compensatory response to insulin resistance. We hypothesized that the induction of protective genes contributes to the survival of enlarged (hypertrophied) beta-cells. Here, we evaluated changes in stress gene expression that accompany beta-cell hypertrophy in islets from hyperglycemic rats 4 weeks after partial pancreatectomy (Px). A variety of protective genes were upregulated, with markedly increased expression of the antioxidant genes heme oxygenase-1 and glutathione peroxidase and the antiapoptotic gene A20. Cu/Zn-superoxide dismutase (SOD) and Mn-SOD were modestly induced, and Bcl-2 was modestly reduced; however, several other stress genes (catalase, heat shock protein 70, and p53) were unaltered. The increases in mRNA levels corresponded to the degree of hyperglycemia and were reversed in Px rats by 2-week treatment with phlorizin (treatment that normalized hyperglycemia), strongly suggesting the specificity of hyperglycemia in eliciting the response. Hyperglycemia in Px rats also led to activation of nuclear factor-kappaB in islets. The profound change in beta-cell phenotype of hyperglycemic Px rats resulted in a reduced sensitivity to the beta-cell toxin streptozotocin. Sensitivity to the toxin was restored, along with the beta-cell phenotype, in islets from phlorizin-treated Px rats. Furthermore, beta-cells of Px rats were not vulnerable to apoptosis when further challenged in vivo with dexamethasone, which increases insulin resistance. In conclusion, beta-cell adaptation to chronic hyperglycemia and, hence, increased insulin demand is accompanied by the induction of protective stress genes that may contribute to the survival of hypertrophied beta-cells.
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PMID:Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survival during chronic hyperglycemia. 1181 49

The consequences of heat-induced phospholipase C-gamma1 (PLC-gamma1) phosphorylation are not known. We investigated the role of PLC-gamma1 activation and its downstream targets during the cellular response to heat stress using mouse embryonic fibroblasts genetically deficient in PLC-gamma1 (Plcg1 null MEF) and its wild type (wt MEF) as models. Treatment of wt MEF with heat resulted in temperature- and heating duration-dependent tyrosine phosphorylation of PLC-gamma1. HSP70 synthesis and the activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun N-terminal protein kinase (JNK) increased equally following heat treatment in both cell lines. However, heat-induced protein kinase C (PKC) activation was dramatically reduced in Plcg1 null MEF compared with wt MEF. Importantly, the mitochondrial localization of PKCalpha, PKC-dependent phosphorylation of Bcl-2, and cell viability in Plcg1 null MEF following heat treatment, were significantly decreased compared with the wild type. Furthermore, pretreatment with bryostatin-1, a PKC activator, enhanced Bcl-2 phosphorylation and cellular resistance to heat-induced apoptosis in Plcg1 null MEF. Taken together, these results suggest that PLC-gamma1 activation enhances cell survival through the PKC-dependent phosphorylation of Bcl-2 during the cellular response to heat stress.
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PMID:Phospholipase C-gamma1 is required for survival in heat stress: involvement of protein kinase C-dependent Bcl-2 phosphorylation. 1182 Sep 33

The present study further revealed the teratogenic mechanism of methylmercury chloride (MMC) during rat neurulation by means of nonradioactive in situ hybridization (ISH), semiquantitative analysis of immunohistochemical staining and in vivo teratogenic test. The main aim was to teat the hypothesis that iNOS, HSP70, NT, TGF-beta and Bcl-2 genes contribute to MMC-induced day 9.5 embryonic damages. Results showed there were no obvious poisoning signs and death of pregnant female rats injected intraperitoncally with 0, 0.2, 0.4, 0.8, 1.6 and 3.2 mg/kg MMC. While the doses increased, the total morphological scores decreased gradually, and the rates of embryo deformity and development delay increased step by step to 34% and 76% respectively. The levels of iNOS mRNA and protein and HSP70 mRNA increased, and NT mRNA with its protein became down, all these changes were concentration dependent. In addition, MMC could inhibit the level of TGF-beta mRNA, but no obvious influence on the levels of Bcl-2 mRNA and Bcl-2 protein. On the basis of parallel findings from embryos, genes and proteins, abnormal expression of genes in transcriptional level might be related to MMC-induced teratogenic insult.
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PMID:[Studies on molecular teratogenic mechanism of methylmercury in early developing rat embryos]. 1193 43

Photodynamic therapy (PDT) of cancer is a very promising technique based on the formation of singlet oxygen induced by a sensitizer after irradiation with visible light. The stimulation of tumor growth by nitric oxide (NO) was reported recently, and NO was shown to have a protective effect against PDT-induced tumor death. We investigated a putative direct effect of NO on tumor cell death induced by PDT, using the human lymphoblastoid CCRF-CEM cells and bisulfonated aluminum phthalocyanine (AlPcS2) as a sensitizer. Cells were incubated with AlPcS2 in the presence or absence of NO donors ((Z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, hydroxylamine and S-nitroso-N-acetylpenicillamine) or L-arginine. Under these conditions, in the absence of NO donors or L-arginine the cells died rapidly by apoptosis upon photosensitization. In the presence of NO donors or L-arginine, apoptotic cell death after photosensitization was significantly decreased. Modulation of cell death by NO was not due to S-nitrosylation of caspases and occurred at the level or upstream of caspase-9 processing. The protective effect of NO was reversed by incubating the cells with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of guanylyl cyclase, or with KT5823, an inhibitor of protein kinase G (PKG). Incubation with 8-bromo-cyclic guanosine monophosphate, a membrane permeable cyclic guanosine monophosphate analog, also decreased cell death induced by PDT. Although the protective effect of NO against apoptotic cell death in several models has been attributed to an increase in the expression of heme oxygenase-1, heat shock protein 70 or Bcl-2, this was not the case under our experimental conditions. These results show that NO decreases the extent of apoptotic cell death after PDT treatment through a PKG-dependent mechanism, upstream or at the level of caspase activation.
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PMID:Nitric oxide modulates tumor cell death induced by photodynamic therapy through a cGMP-dependent mechanism. 1240 51

Calcitriol [1alpha,25-dihydroxyvitamin D3] is the natural ligand of the vitamin D receptor (VDR). Using cultured prostate cancer (PC) cell lines, LN-CaP and ALVA-31, we studied the effects of 1alpha,25(OH)2-Vitamin D3 (VD3) on expression of several apoptosis-regulating proteins including: (a) Bcl-2 family proteins (Bcl-2, Bcl-X(L), Mcl-1, Bax, and Bak); (b) the heat shock protein 70-binding protein BAG1L; and (c) IAP family proteins (XIAP, cIAP1, and cIAP2). VD3 induced decreases in levels of antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1, BAG1L, XIAP, cIAP1, and cIAP2 (without altering proapoptotic Bax and Bak) in association with increases in apoptosis. In contrast to VDR-expressing LN-CaP and ALVA-31 cells, VDR-deficient prostate cancer line Du-145 demonstrated no changes in apoptosis protein expression after treatment with VD3. In sensitive PC cell lines, VD3 activates downstream effector protease, caspase-3, and upstream initiator protease caspase-9, the apical protease in the mitochondrial ("intrinsic") pathway for apoptosis, but not caspase-8, an initiator caspase linked to an alternative ("extrinsic") apoptosis pathway triggered by cytokine receptors. VD3 induced declines in antiapoptotic proteins and also stimulated cytochrome c release from mitochondria by a caspase-independent mechanism. Moreover, apoptosis induction by VD3 was suppressed by overexpressing Bcl-2, a known blocker of cytochrome c release, whereas the caspase-8 suppressor CrmA afforded little protection. Thus, VD3 is capable of inhibiting expression of multiple antiapoptotic proteins in VDR-expressing prostate cancer cells, leading to activation of the mitochondrial pathway for apoptosis.
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PMID:Apoptosis induction by 1alpha,25-dihydroxyvitamin D3 in prostate cancer. 1247 63

Tetrocarcin-A (TC-A), an antibiotic agent isolated from actinomycetes, has recently been described to antagonize Bcl-2 functions, thereby sensitizing tumor cells to cell death signals under control of Bcl-2. In this study, we analyzed the direct proapoptotic effect of TC-A in the B-chronic lymphocytic leukemia (B-CLL) model. We focused on the signal cascade triggered by TC-A in B-CLL cells and identified activated mitochondrial as well as endoplasmatic reticulum (ER) stress signals. The expression levels of known effector molecules mediating mitochondrial signaling, such as Bax and Bid, and the antagonistic molecule Bcl-2 did not influence sensitivity of B-CLL cells to TC-A. Furthermore, the molecular chaperone and sensor of ER stress, HSP70, though significantly up-regulated in B-CLL cells undergoing TC-A-triggered apoptosis, was ineffective to exert its anti-apoptotic function described in multiple cell death pathways. Autologous T cells of B-CLL patients were significantly less sensitive to TC-A as were also T cells from healthy donors when compared with their normal B-cell fraction. Furthermore, sensitivity of B-CLL cells to TC-A treatment in vitro was dependent neither on the expression levels of CD38-a prognostic factor for survival of B-CLL patients as well as for their response to therapy-nor on the clinical stage or pretreatment status of patients. From our data showing that TC-A induced a cell death pathway via ER stress preferentially in B cells and that it acted independently of important markers of drug sensitivity and of clinical markers, we conclude that TC-A might represent an attractive candidate drug for further evaluation in preclinical trials.
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PMID:Tetrocarcin-A--induced ER stress mediates apoptosis in B-CLL cells via a Bcl-2--independent pathway. 1256 Feb 33

We focused on heat shock protein 70 (HSP70) as a marker of viability in hepatic warm ischemia-reperfusion. Segmental hepatic warm ischemia was produced in rats for 15, 30, 60, 90, 120, or 180 min. Liver sections were evaluated at 30, 60, and 120 min of reperfusion. Expression of HSP70 and messenger RNA (mRNA), apoptosis, and apoptosis-associated genes such as Bcl-2 and Bax were studied. Expression of HSP70 and mRNA was augmented as warm ischemia was prolonged, but was markedly suppressed in livers with more than 120 min of ischemia. The highest accumulation of HSP70 was observed in the nucleus. In livers subjected to longer duration of warm ischemia, necrosis and apoptosis were evident and Bcl-2 mRNA expression and Bcl-2/Bax protein ratio were markedly diminished. Apoptosis may be related to the process of cellular injury induced by warm ischemia-reperfusion. Expression of HSP70 and the Bcl-2 family can be effective markers of viability in hepatic warm ischemia-reperfusion.
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PMID:Evaluation of warm ischemia-reperfusion injury using heat shock protein in the rat liver. 1259 70

Chronic hypoxia during pregnancy is one of the most common insults to fetal development. We tested the hypothesis that maternal hypoxia induced apoptosis in the hearts of near-term fetal rats. Pregnant rats were divided into two groups, normoxic control and continuous hypoxic exposure (10.5% O2) from day 15 to 21 of gestation. Hearts were isolated from fetal rats of 21-day gestational age. Maternal hypoxia increased hypoxia-inducible factor-1alpha protein in fetal hearts. Chronic hypoxia significantly increased the percentage and size of binucleated myocytes and increased apoptotic cells from 1.4 +/- 0.14% to 2.7 +/- 0.3% in the fetal heart. In addition, the active cleaved form of caspase 3 was significantly increased in the hypoxic heart, which was associated with an increase in caspase 3 activity. There was a significant increase in Fas protein levels in the hypoxic heart. Chronic hypoxia did not change Bax protein levels but significantly decreased Bcl-2 proteins. In addition, chronic hypoxia significantly suppressed expression of heat shock protein 70. However, chronic hypoxia significantly increased expression of the anti-apoptotic protein 14-3-3, among other 14-3-3 isoforms. Chronic hypoxia differentially regulated beta-adrenoreceptor (beta-AR) subtypes with an increase in beta1-AR levels but no changes in beta2-AR. The results demonstrate that maternal hypoxia increases apoptosis in fetal rat heart, which may be mediated by an increase in Fas and a decrease in Bcl-2 proteins. Chronic hypoxia-mediated increase in beta1-AR and decrease in heat shock proteins may also play an important role in apoptosis in the fetal heart.
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PMID:Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart. 1275 58


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