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 of intestinal epithelial cells (EC) plays a role in total parenteral nutrition (TPN)-induced villus atrophy. Among the mediators of apoptosis in EC are some members of the Bcl-2 family of proteins. Bcl-2 members can either be anti- (Bcl-2, Bcl-x(L), Bcl-w) or pro-apoptotic (Bax, Bak, Bid, Bad, Bcl-x(S)). To determine whether the observed increase in apoptosis induced by TPN is associated with an alteration in these Bcl-2 members' mRNA expression, mice were randomized to either TPN or oral feeding (controls). Animals were killed after 7 days and the intestine was harvested. EC were purified with magnetic beads. Apoptosis was detected by cell-surface expression of phosphatidylserine using flow cytometry. EC mRNA expression was determined by reverse-transcriptase polymerase chain reaction. Results were expressed relative to beta-actin. TPN resulted in a significant ( P < 0.05, unpaired t-test) increase in apoptosis: TPN 29.4 +/- 11.3% versus control 14.4 +/- 5.1%. The expression of the pro-apoptotic members Bax, Bak, Bid, and Bcl-x(S) was significantly ( P < 0.05) decreased after TPN. In contrast, a significant increase was observed in the anti-apoptotic member Bcl-2. mRNA expression of Bcl-w, Bad, and Bcl-x(L) was not significantly different between the control and TPN groups. Thus TPN-induced apoptosis was associated with an increased expression of anti-apoptotic factors and a decrease in pro-apoptotic factors. This contrasts with other reports where these factors showed converse effects under apoptotic conditions. Our results may demonstrate a unique regulatory pathway that may counter the observed increase in TPN-induced EC apoptosis.
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PMID:Total parenteral nutrition-induced apoptosis in mouse intestinal epithelium: regulation by the Bcl-2 protein family. 1247 68

To determine a cellular factor supporting the survival of gastric cancer cells, a comparative study was performed using two human adenocarcinoma cell lines, SNU-16 and SNU-620. The latter cells were significantly less susceptible to various lethal stimuli including anti-Fas, H(2)O(2), etoposide, and serum withdrawal than the former. These stimuli were found to kill the SNU-16 cells by activating stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK), whereas SAPK/JNK activation was not efficiently induced in the SNU-620 cells. Western blot analysis revealed that Bcl-w, but not the other tested members of the Bcl-2 family, was expressed in the SNU-620 cells to levels higher than that observed in SNU-16 cells. An elevation of the Bcl-w levels in the SNU-16 cells by its stable transfection attenuated both the SAPK/JNK activation and the cell death induced by all of the tested stimuli. These results suggest that the susceptibility of gastric cancer cells to death stimuli is determined, at least in part, by the levels of Bcl-w that suppress the cell death by blocking SAPK/JNK activation. To examine whether Bcl-w was expressed in patients, tumor specimens were obtained from 50 consecutive advanced gastric adenocarcinoma cases. An immunohistochemical analysis showed that Bcl-w was expressed in cancer cells but not in the neighboring normal mucosa of the 23 cases (46%). Interestingly, Bcl-w expression was associated significantly with certain histopathological characteristics of the cancer, notably with the infiltrative morphotypes (P < 0.001). Therefore, Bcl-w appears to be important for gastric cancer cell survival, particularly in infiltrative tumors.
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PMID:Bcl-w is expressed in a majority of infiltrative gastric adenocarcinomas and suppresses the cancer cell death by blocking stress-activated protein kinase/c-Jun NH2-terminal kinase activation. 1261 27

Previous research has suggested that repletion of cellular glutathione peroxidase (GPX1) activity by a single injection of Se was dissociated from the Se protection against the pro-oxidant-induced liver necrosis in Se-deficient rodents. Using the GPX1 knockout (GPX1-/-) mice, TUNEL assay, and apoptosis gene expression microarray, we have demonstrated strikingly different impacts of GPX1 knockout on hepatotoxicity and the related signaling induced by an intraperitoneal injection of 12.5 mg paraquat/kg body weight (b.wt.). In both Se-deficient GPX1-/- and wild-type (WT) mice, the paraquat did not induce typical liver necrosis, rather aponecrosis or necrapoptosis, a syncretic process of cell death sharing characteristics of both apoptosis and necrosis. The severity of liver aponecrosis and the associated mortality were reduced to a much greater extent by an injection of Se (ip, 50 microg/kg b.wt. as Na2SeO3) prior to paraquat stress in the WT mice, compared with the GPX1-/- mice. The induced liver aponecrosis seemed to be more apoptotic in the GPX1-/- mice but more necrotic in the WT mice. The paraquat-mediated gene or protein expression of proapoptotic Bax, Bcl-w, and Bcl-X(S), cell survival/death factors GADD45, MDM2, c-Myc, and caspase-3 was upregulated, but that of antiapoptotic Bcl-2 was downregulated in the GPX1-/- mice vs. the WT mice. Overall, these differences between the two groups of mice were related to a low level of liver GPX1 activity in the WT mice that represented < 4% of the normal physiological level. Therefore, the low level of GPX1 activity in the Se-deficient mice can exert a potent role in defending against liver aponecrosis induced by moderate oxidative stress.
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PMID:Impacts of glutathione peroxidase-1 knockout on the protection by injected selenium against the pro-oxidant-induced liver aponecrosis and signaling in selenium-deficient mice. 1265 81

Pro-survival Bcl-2-related proteins, critical regulators of apoptosis, contain a hydrophobic groove targeted for binding by the BH3 domain of the pro-apoptotic BH3-only proteins. The solution structure of the pro-survival protein Bcl-w, presented here, reveals that the binding groove is not freely accessible as predicted by previous structures of pro-survival Bcl-2-like molecules. Unexpectedly, the groove appears to be occluded by the C-terminal residues. Binding and kinetic data suggest that the C-terminal residues of Bcl-w and Bcl-x(L) modulate pro-survival activity by regulating ligand access to the groove. Binding of the BH3-only proteins, critical for cell death initiation, is likely to displace the hydrophobic C-terminal region of Bcl-w and Bcl-x(L). Moreover, Bcl-w does not act only by sequestering the BH3-only proteins. There fore, pro-survival Bcl-2-like molecules probably control the activation of downstream effectors by a mechanism that remains to be elucidated.
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PMID:The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity. 1266 Jan 57

Oligodendroglial lineage cells (OLC) vary in susceptibility to both necrosis and apoptosis depending on their developmental stages, which might be regulated by differential expression of Bcl-2-related genes. As an initial step to test this hypothesis, we examined the expression of 19 Bcl-2-related genes in purified cultures of rat oligodendroglial progenitors, immature and mature oligodendrocytes. All 'multidomain' anti-apoptotic members (Bcl-x, Bcl-2, Mcl-1, Bcl-w and Bcl2l10/Diva/Boo) except Bcl2a1/A1 are expressed in OLC. Semiquantitative and real-time RT-PCR revealed that Bcl-xL and Mcl-1 mRNAs are the dominant anti-apoptotic members and increase four- and twofold, respectively, with maturation. Bcl-2 mRNA is less abundant than Bcl-xL mRNA in progenitors and falls an additional 10-fold during differentiation. Bcl-w mRNA also increases, with significant changes in its splicing pattern, as OLC mature. Transfection studies demonstrated that Bcl-xL overexpression protects against kainate-induced excitotoxicity, whereas Bcl-2 overexpression does not. As for 'multidomain' pro-apoptotic members (Bax, Bad and Bok/Mtd), Bax and Bak are highly expressed throughout differentiation. Among 'BH3 domain-only' members examined (Bim, Biklk, DP5/Hrk, Bad, Bid, Noxa, Puma/Bbc3, Bmf, BNip3 and BNip3L), BNip3 and Bmf mRNAs increase markedly during differentiation. These results provide basic information to guide further studies on the roles for Bcl-2-related family proteins in OLC death.
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PMID:Bcl-2-related protein family gene expression during oligodendroglial differentiation. 1278 69

Prosurvival Bcl-2-like proteins, like Bcl-w, are thought to function on organelles such as the mitochondrion and to be targeted to them by their hydrophobic COOH-terminal domain. We unexpectedly found, however, that the membrane association of Bcl-w was enhanced during apoptosis. In healthy cells, Bcl-w was loosely attached to the mitochondrial membrane, but it was converted into an integral membrane protein by cytotoxic signals that induce binding of BH3-only proteins, such as Bim, or by the addition of BH3 peptides to lysates. As the structure of Bcl-w has revealed that its COOH-terminal domain occupies the hydrophobic groove where BH3 ligands bind, displacement of that domain by a BH3 ligand would displace the hydrophobic COOH-terminal residues, allowing their insertion into the membrane. To determine whether BH3 ligation is sufficient to induce the enhanced membrane affinity, or to render Bcl-w proapoptotic, we mimicked their complex by tethering the Bim BH3 domain to the NH2 terminus of Bcl-w. The chimera indeed bound avidly to membranes, in a fashion requiring the COOH-terminal domain, but neither promoted nor inhibited apoptosis. These results suggest that ligation of a proapoptotic BH3-only protein alters the conformation of Bcl-w, enhances membrane association, and neutralizes its survival function.
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PMID:Proapoptotic BH3-only proteins trigger membrane integration of prosurvival Bcl-w and neutralize its activity. 1295 38

Kainic acid induces excitotoxicity and nerve cell degeneration in vulnerable regions of rat brain, most markedly in hippocampus and amygdala. Part of the cell death following kainic acid is apoptotic as shown by caspase 3 activation and chromatin condensation. Here we have studied the regulation of pro- and anti-apoptotic proteins belonging to the Bcl-2 family in rat hippocampus and amygdala by kainic acid in relationship to ensuing neuronal death. The pro-apoptotic protein Bax was up-regulated in hippocampus 6 h after kainic acid administration. The increase in Bax was followed by the appearance of TdT-mediated dUTP nick end labelling-positive cells which were prominent at 24 h. Immunohistochemistry for active Bax revealed a punctuated labelling of neurons in the CA3 and hilar regions of hippocampus as well as in amygdala. Double staining for NeuN, a marker for nerve cells, and TdT-mediated dUTP nick end labelling showed that mainly neurons undergo degeneration after kainic acid treatment. In contrast to Bax, the pro-apoptotic BH3-only Bcl-2 proteins Bim and Harakiri/DP5 were down-regulated by kainic acid. This was also observed for the anti-apoptotic proteins Bcl-x and Bcl-w. Immunoreactive Bcl-2 was up-regulated in hippocampus after kainic acid together with an increase in the phosphorylation of serine-87 in Bcl-2, suggesting a post-transcriptional modification of the protein. This was confirmed using immunoprecipitation of total Bcl-2 from hippocampus and amygdala which revealed an increase in serine-87 phospho-Bcl-2 after kainic acid. Inhibition of the c-jun N-terminal protein kinase pathway reduced both serine-87 phosphorylation and cell death after kainic acid. This indicates an important role of Bcl-2 phosphorylation in controlling neuronal death after kainic acid. In contrast to the situation in trophic factor-deprived neurons, no up-regulation of Bim or Harakiri/DP5 proteins occurred after kainic acid, suggesting alternative pathways for regulation of cell death in excitotoxicity. The results indicate that not only the relative levels of Bcl-2 family proteins but also conformation changes and post-translational modifications contribute to neuronal death following kainic acid.
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PMID:Increase in Bcl-2 phosphorylation and reduced levels of BH3-only Bcl-2 family proteins in kainic acid-mediated neuronal death in the rat brain. 1295 12

CED-4, a pro-apoptotic factor in Caenorhabditis elegans, activates the cell death protease CED-3. CED-9 directly binds to CED-4 and represses this. However, it has remained unclear whether a mammalian CED-9 homologue, Bcl-XL, inhibits the function of the mammalian CED-4 homologue, Apaf-1, by direct binding. To analyze the interaction, we adopted a yeast two-hybrid system. Since Bcl-XL and the CED-4-like portion of Apaf-1 failed to exhibit a positive result in the assay, we prepared "fragment libraries" of bcl-XL or apaf-1 cDNA. By screening of the apaf-1 "fragment library," we obtained nine clones interacting with Bcl-XL, all containing the same region within the ATPase domain, designated BBR: the Bcl-XL binding region. Binding of BBR to Bcl-XL was also confirmed by immunoprecipitation assays. Bcl-2, Bcl-w, A1/Bfl-1, and Boo/Diva failed to show the same capacity for binding to BBR as Bcl-XL. These results indicate that Bcl-XL directly binds to a specific region in Apaf-1.
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PMID:Identification of a Bcl-XL binding region within the ATPase domain of Apaf-1. 1296 20

Bcl-2-family members (Bcl-2, Bax, Bcl-w and Bcl-x(L)) are crucial integrators of signals for cell survival and death; the pro- or antiapoptotic activities of these proteins are regulated by their subcellular localization. Bcl-2 directly inserts into the membranes, where it acts; however, Bax requires a stimulus-dependent translocation from an inactive cytosolic to an active membrane-inserted state. Recently, a novel mechanism is described for the survival factor Bcl-w, which is active while weakly associated with mitochondria. In apoptotic cells, a BH3-only protein neutralizes the survival activity of Bcl-w by binding to its "hydrophobic pockets", thereby releasing its C-terminal domain and allowing its insertion into the membrane. Here, we discuss the importance of this finding for a better understanding of the action mode of Bcl-w and other Bcl-2-family members.
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PMID:Bcl-w(edding) with mitochondria. 1472 75

Ceramide is a lipid mediator in cell proliferation, differentiation, and apoptosis in many cell lines. However, the molecular mechanisms for ceramide have not been clarified in HC11 mouse mammary epithelial cells. Under phase contrast microscope, C2-ceramide-treated cells clearly showed morphological changes, which were characteristic features of apoptosis. Treatment with C2-ceramide at 10 microM specifically resulted in the death of 50% of the cells after 48 h as assessed by MTT assay. To further investigate which genes contribute to cell death in C2-ceramide-treated cells, we used the reverse transcription-polymerase chain reaction to assess mRNA levels for five genes in the Bcl-2 family and five genes in the caspases family. The steady-state mRNA levels of Bax, Bad and Bak were not significantly changed for 48 h of C2-ceramide treatment. The increases of mRNA levels of Bcl-2 and Bcl-w were observed for the first 3 h of C2-ceramide treatment and the last 24 h between 24 and 48 h. We also found that in HC11 cells, C2-ceramide increased mRNA levels of the caspases family from 6 to 24 h. These results suggest that in the HC11 cells, C2-ceramide promote cell death by mediating the induction of caspases and that HC11 mouse mammary epithelial cells paradoxically up-regulate the expression of Bcl-2 and Bcl-w to prevent C2-ceramide-mediated cell death.
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PMID:C2-ceramide as a cell death inducer in HC11 mouse mammary epithelial cells. 1473 27


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