Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Estrogen replacement therapy in menopausal women has been suggested to be beneficial in preventing the progression of cognitive impairment in Alzheimer disease. We demonstrated previously that the phosphatidylinositol 3-kinase (PI3-K)/Akt signal transduction pathway plays a pivotal role on the neuroprotection provided by 17beta-estradiol against acute glutamate toxicity. In the present study, we investigated the mechanism of neuroprotection against apoptosis because acute glutamate toxicity predominantly induced necrosis. 17beta-estradiol provided neuroprotection against apoptosis induced by staurosporine. This neuroprotection was inhibited by pretreatment with a PI3-K inhibitor, LY294002. An estrogen receptor specific antagonist, ICI182780, also suppressed the neuroprotection provided by 17beta-estradiol. Western blotting analysis demonstrated that treatment with 17beta-estradiol induced the phosphorylation of Akt within 5 min, which was suppressed by pretreatment with LY294002 and ICI182780. Furthermore, 17beta-estradiol induced phosphorylation of the cAMP response element binding protein (CREB) at Ser(133) within 15 min and then upregulated Bcl-2 in a PI3-K/Akt-dependent manner. Because CREB is known to be a transcription factor for Bcl-2, these results suggest that 17beta-estradiol exerts its antiapoptotic effects by CREB phosphorylation and Bcl-2 upregulation via nongenomic activation of the PI3-K/Akt pathway in cultured cortical neurons.
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PMID:Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons. 1139 1

The cAMP-response element-binding protein (CREB) is activated by phosphorylation on serine 133 and mediates the proliferative response to a number of different signals. A mutant CREB with a serine to alanine substitution at position 133 (CREBM1) functions as a dominant-negative inhibitor. Transgenic mice that express the dominant-negative CREB protein in B lymphocytes were developed as a means to study the effects of the inhibition of CREB function on B-cell proliferation and survival. We have shown previously that CREB up-regulates Bcl-2 expression in B cells in response to activation signals. B cells from CREBM1 transgenic mice expressed lower levels of Bcl-2 with and without stimulation. Proliferation of B cells from the transgenic mice was impaired in part by lack of induction of activator protein 1 (AP1) transcription factors. B cells from the transgenic mice were more susceptible to induction of apoptosis with several different agents, consistent with the decreased expression of Bcl-2. These studies demonstrate that B-cell activation requires phosphorylation of CREB for the proliferative response and to protect against activation-induced apoptosis.
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PMID:Impaired proliferation and survival of activated B cells in transgenic mice that express a dominant-negative cAMP-response element-binding protein transcription factor in B cells. 1237 87

Generation of oxidative stress/reactive oxygen species (ROS) is one of the causes of neuronal apoptosis. We have examined the effects of ROS at the transcriptional level in an immortalized hippocampal neuronal cell line (H19-7) and in rat primary hippocampal neurons. Treatment of H19-7 cells with hydrogen peroxide (150 micro m) resulted in a 40% decrease in Bcl-2 protein and a parallel decrease in bcl-2 mRNA levels. H19-7 cells overexpressing bcl-2 were found to be resistant to ROS-induced apoptosis. We had previously shown that bcl-2 promoter activity is positively regulated by the transcription factor cyclic AMP response element binding protein (CREB) in neurons. In the present study, we demonstrate that ROS decreases the activity of luciferase reporter gene driven by a cyclic AMP response element site containing bcl-2 promoter. Exposure of neurons to ROS for 6 h resulted in basal and fibroblast growth factor-2-stimulated phosphorylation/activation of CREB. Chronic 24 h treatment with ROS led to a significant (p < 0.01) decrease in CREB protein and CREB mRNA levels. Adenoviral overexpression of wild type CREB in H19-7 cells resulted in significant (p < 0.01) protection against ROS-induced apoptosis through up-regulation of Bcl-2 expression whereas dominant negative CREB exaggerated the injury. These findings demonstrate that loss of CREB function contributes to oxidative stress-induced neuronal dysfunction.
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PMID:Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal neurons. 1260 23

Our previous results suggested that the transcription factor CREB mediates the actions of neuroligands and growth factor signals that coupled to different signaling pathways may play different roles along oligodendrocyte (OLG) development. We showed before that CREB phosphorylation in OLG progenitors is up-regulated by neurotrophin-3 (NT-3); and moreover CREB is required for NT-3 to stimulate the proliferation of these cells. We now show that treatment of OLG progenitors with NT-3 is also accompanied by an increase in the levels of the anti-apoptotic protein Bcl-2. Interestingly, the presence of a putative CREB binding site (CRE) in the Bcl-2 gene raised the possibility that CREB could also be involved in regulating Bcl-2 expression in the OLGs. Supporting this hypothesis, the NT-3 dependent increase in Bcl-2 levels is abolished by inhibition of CREB expression. In addition, transient transfection experiments using various regions of the Bcl-2 promoter and mutation of the CRE site indicate a direct role of CREB in regulating Bcl-2 gene activity in response to NT-3. Furthermore, protein-DNA binding assays show that the CREB protein from freshly isolated OLGs indeed binds to the Bcl-2 promoter CRE. Together with our previous results, these observations suggest that CREB may play an important role in linking proliferation and survival pathways in the OLG progenitors.
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PMID:Neurotrophin-3 and a CREB-mediated signaling pathway regulate Bcl-2 expression in oligodendrocyte progenitor cells. 1514 Jan 94

There is significant controversy over the effects of hypercapnia on the human newborn brain. Previous studies have shown that 1 h of an arterial CO2 pressure (Paco2) of 80 mm Hg alters brain cell membrane Na+K+-ATPase enzyme activity in the cerebral cortex of newborn piglets. The present study tests the hypothesis that hypercapnia (either a Paco2 of 65 or 80 mm Hg) results in decreased energy metabolism and alters neuronal nuclear enzyme activity and protein expression, specifically Ca++/calmodulin-dependent kinase (CaMK) IV activity, phosphorylation of cAMP response element binding protein (CREB), and expression of apoptotic proteins in cortical neuronal nuclei of newborn piglets. Studies were performed in 20 anesthetized normoxic piglets ventilated at either a Paco2 of 65 mm Hg, 80 mm Hg, or 40 mm Hg for 6 h. Energy metabolism was documented by ATP and phosphocreatine (PCr) levels. Results show ATP and PCr levels were significantly lower in the hypercapnic groups than the normocapnic. CaMK IV activity, phosphorylated CREB density, and Bax protein expression were all significantly higher in the hypercapnic groups than the normocapnic group. Bcl-2 protein was similar in all three groups, making the ratio of Bax/Bcl-2 significantly higher in the hypercapnic groups than in the normocapnic group. We conclude that hypercapnia alters neuronal energy metabolism, increases phosphorylation of transcription factors, and increases the expression of apoptotic proteins in the cerebral cortex of newborn piglets and therefore may be deleterious to the newborn brain.
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PMID:Hypercapnia-induced modifications of neuronal function in the cerebral cortex of newborn piglets. 1558 83

At a certain point in development, axons in the mammalian CNS undergo a profound loss of intrinsic growth capacity, which leads to poor regeneration after injury. Overexpression of Bcl-2 prevents this loss, but the molecular basis of this effect remains unclear. Here, we report that Bcl-2 supports axonal growth by enhancing intracellular Ca(2+) signaling and activating cAMP response element binding protein (CREB) and extracellular-regulated kinase (Erk), which stimulate the regenerative response and neuritogenesis. Expression of Bcl-2 decreases endoplasmic reticulum (ER) Ca(2+) uptake and storage, and thereby leads to a larger intracellular Ca(2+) response induced by Ca(2+) influx or axotomy in Bcl-2-expressing neurons than in control neurons. Bcl-x(L), an antiapoptotic member of the Bcl-2 family that does not affect ER Ca(2+) uptake, supports neuronal survival but cannot activate CREB and Erk or promote axon regeneration. These results suggest a novel role for ER Ca(2+) in the regulation of neuronal response to injury and define a dedicated signaling event through which Bcl-2 supports CNS regeneration.
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PMID:Bcl-2 enhances Ca(2+) signaling to support the intrinsic regenerative capacity of CNS axons. 1571 13

We reported previously that various radiocontrast media cause apoptosis in porcine proximal tubular (LLC-PK(1)) cells, in which reduction in B-cell lymphoma (Bcl)-2 expression and caspase-3 activation are implicated. In the present study, we investigated a role for ceramide in radiocontrast media-induced apoptosis in renal tubular cells. LLC-PK(1) cells were exposed to radiocontrast media for 30 min, followed by incubation for 24 h in normal medium. Cell viability was assessed by 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, while apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling stain. Immunofluorescent stains were performed using antibodies against phosphorylated Akt (pAkt) and cAMP response element binding protein (CREB) (pCREB), and ceramide. The mRNA expression and protein content of Bcl-2 were determined by reverse transcriptase-polymerase chain reaction and enzyme immunoassay, respectively. In vivo model of contrast-induced renal injury was induced in mice with unilateral renal occlusion. The cell injury induced by the nonionic radiocontrast medium ioversol was reversed by inhibiting de novo ceramide synthesis with fumonisin B(1) (FB(1)) and L-cycloserine, but not by suppressing sphingomyelin breakdown with D609. FB(1) reversed ioversol-induced decrease in the immunoreactivities of pAkt and pCREB, reduction in Bcl-2 expression and caspase-3 activation. Like ioversol, C2 ceramide and the Akt inhibitor Src homology-6 induced apoptosis by reducing pAkt and pCREB-like immunoreactivities, lowering Bcl-2 expression and enhancing caspase-3 activity. Indeed, various radiocontrast media, excluding iodixanol which showed the least nephrotoxicity, enhanced ceramide-like immunoreactivity. The role for de novo ceramide synthesis was also shown in the in vivo model of radiocontrast nephropathy. We demonstrated here for the first time that the enhancement of de novo ceramide synthesis contributes to radiocontrast nephropathy.
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PMID:Involvement of de novo ceramide synthesis in radiocontrast-induced renal tubular cell injury. 1640 18

The present study investigates the correlation between the hypoxia-induced phosphorylation of cyclic AMP response element binding protein and the expression of apoptotic proteins (proapoptotic proteins Bax and Bad and antiapoptotic proteins Bcl-2 and Bcl-xl) during hypoxia in the cerebral cortex of newborn piglets. Piglets were divided into normoxic (Nx) and hypoxic (Hx, FiO(2)=0.06 for 1 h) groups. Cerebral tissue hypoxia was documented by ATP and phosphocreatine (PCr) levels. Ser(133) phosphorylation of cyclic AMP response element binding (CREB) protein was determined by Western blot analysis using a specific anti-phosphorylated Ser(133)-CREB protein antibody. The expression of apoptotic proteins was determined by using specific anti-Bax, anti-Bad, anti-Bcl-2 and anti-Bcl-xl antibodies. ATP and PCr values (mumoles/g brain) in Hx were significantly different from Nx (ATP: 4.40 +/- 0.39 in Nx vs. 1.19 +/- 0.44 in Hx, P<0.05 vs. Nx; PCr: 3.60 +/- 0.40 in Nx vs. 0.70 +/- 0.31 in Hx, P<0.05 vs. Nx). Ser(133) phosphorylated CREB protein (OD x mm(2)) was 74.55 +/- 4.75 in Nx and 127.13 +/- 19.36 in Hx (P<0.05 vs. Nx). The expression of proapoptotic proteins Bax and Bad increased and strongly correlated with the increase in CREB protein phosphorylation (correlation coefficient r=0.82 and r=0.85, respectively). The expression of antiapoptotic proteins Bcl-2 and Bcl-xl did not show correlation with CREB protein phosphorylation. We conclude that cerebral hypoxia results in differential regulation of CREB protein-mediated expression of proapoptotic and antiapoptotic proteins in the cerebral cortex of newborn piglets. We propose that the increased expression of proapoptotic vs antiapoptotic genes will lead to an increased potential for apoptotic programmed cell death in the Hx newborn brain.
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PMID:Differential expression of apoptotic proteins following hypoxia-induced CREB phosphorylation in the cerebral cortex of newborn piglets. 1740 58

There is growing concern over detrimental neurologic effects to human newborns caused by increased inspired oxygen concentrations. We hypothesize that hyperoxia (FiO(2)>0.95) results in increased high-affinity Ca(2+)-ATPase activity, Ca(2+)-influx, and proapoptotic protein expression in cortical neuronal nuclei of newborn piglets. Neuronal cerebral energy metabolism was documented by determining ATP and phosphocreatine levels. Neuronal nuclear conjugated dienes and fluorescent compounds were measured as indices of lipid peroxidation. High-affinity Ca(2+)-ATPase activity and ATP-dependent Ca(2+)-influx were determined to document neuronal nuclear membrane function. Hyperoxia resulted in increases in lipid peroxidation, high-affinity Ca(2+)-ATPase activity, ATP-dependent Ca(2+)-influx, and Bax/Bcl-2 ratio in the cortical neuronal nuclei of newborn piglets. We conclude that hyperoxia results in modification of neuronal nuclear membrane function leading to increased nuclear Ca(2+)-influx, and propose that hyperoxia-induced increases in intranuclear Ca(2+) activates the Ca(2+)/calmodulin-dependent protein kinase pathway, triggering increased CREB protein-mediated apoptotic protein expression in hyperoxic neurons.
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PMID:Effect of hyperoxia on cortical neuronal nuclear function and programmed cell death mechanisms. 1740 66

Bcl-2 plays a pivotal role in the control of cell death and is down-regulated in trichosanthin (TCS)-induced cell apoptosis. Because Bcl-2 expression is regulated by the transcription factor cyclic AMP response element-binding protein (CREB), we investigated the role of CREB activation in TCS-induced Hela cells apoptosis. Our results showed that TCS-caused Hela cell apoptosis was accompanied by the decrease of Bcl-2 and phosphorylated CREB protein levels. Interesting, this inhibitive effect can be abolished by the combined treatment of TCS/cAMP agonists. Furthermore, TCS-mediated Bcl-2 protein was abrogated by the suppression of CREB expression with antisense treatment, and blocking the interaction between CREB-binding protein and the Bcl-2 cyclic AMP-responsive element (CRE) by a CRE decoy oligonucleotide. Therefore, these data support the hypothesis that CREB plays a critical role in the regulation of Bcl-2 expression in TCS-induced Hela cell death.
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PMID:CREB-mediated Bcl-2 expression in trichosanthin-induced Hela cell apoptosis. 1782 90


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