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 regulation of cell death in activated naive T cells is not well understood. We examined the expression of A1, an antiapoptotic member of the Bcl-2 family, following activation of naive mouse splenocytes. A1 gene expression was strongly but transiently induced during the first day of activation, with a peak at 2 to 6 hours, whereas Bcl-2 mRNA was simultaneously transiently down-regulated. Transgenic (Tg) overexpression of A1-a in T cells via the lck distal promoter resulted in decreased apoptosis following activation either with concanavalin A or with antibodies to CD3 and CD28 and led to a doubling of T-cell yield by 5 days. Tg A1-a also partially protected thymocytes from several proapoptotic stimuli but did not protect T-cell blasts from cell death induced by reactivation via the T-cell receptor. Tg Bcl-2 and Tg A1-a showed a similar ability to reduce apoptosis in both resting and activated T cells. However, in activated splenocyte cultures, the increase in 5-day T-cell yield observed with Tg Bcl-2 was only half that produced by Tg A1-a. This difference could be attributed at least in part to the fact that A1, unlike Bcl-2, did not inhibit S-phase entry of activated cells. The A1 protein may represent an adaptation of the Bcl-2 gene family to the need for survival regulation in the context of a proliferative stimulus.
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PMID:A1 is a growth-permissive antiapoptotic factor mediating postactivation survival in T cells. 1240 3

Nuclear factor-kappaB (NF-kappaB) is a transcription factor with a pivotal role in neuronal homeostasis. Indeed, NF-kappaB trans-activates several antiapoptotic genes in neurons and inhibition of NF-kappaB transcriptional activity triggers neuronal apoptosis. However, the exact mechanisms by which neurons undergo apoptosis in conditions of NF-kappaB inhibition are poorly understood. To further clarify how NF-kappaB operates in neurons, and to gather information on the molecular events occurring during NF-kappaB inhibition-dependent neuronal apoptosis, this study evaluated the effects of recently identified NF-kappaB inhibitors such as parthenolide, SN50, BAY 11-7082 and helenalin on primary cultures of rat cortical neurons. Data show that NF-kappaB was constitutively activated in neurons, and demonstrate for the first time that drug-dependent NF-kappaB inhibition induced rapid mitochondrial release of cytochrome c, caspase-9 and -3 activation, poly(ADP-ribose) polymerase-1 cleavage, membrane blebbing and nuclear fragmentation, without evidence of procaspase-8 and Bid processing. Interestingly, a burst of Akt activation occurred in neurons exposed to NF-kappaB inhibitors. These events were preceded by selective reduction of mRNAs of NF-kappaB-dependent, antiapoptotic Bcl-2 family members such as Bcl-x(L), Bcl-2 and, in particular, A1/Bfl-1. The present study reports a novel, detailed temporal analysis of the molecular events following impairment of NF-kappaB-driven transcription in neurons and demonstrates that inhibition of constitutive neuronal NF-kappaB activity triggers selective activation of the intrinsic apoptotic program.
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PMID:Characterization of the molecular events following impairment of NF-kappaB-driven transcription in neurons. 1253 27

Expression of the prosurvival Bcl-2 homologue Bfl-1/A1 is induced by NF-kappa B-activating stimuli, while B and T cells from c-rel knockout mice show an absolute defect in bfl-1/a1 gene activation. Here, we demonstrate NF-kappa B-dependent assembly of an enhanceosome-like complex on the promoter region of bfl-1. Binding of NF-kappa B subunit c-Rel to DNA nucleated the concerted binding of transcription factors AP-1 and C/EBP beta to the 5'-regulatory region of bfl-1. Optimal stability of the complex was dependent on proper orientation and phasing of the NF-kappa B site. Chromatin immunoprecipitation analyses demonstrated that T-cell activation triggers in vivo binding of endogenous c-Rel, c-Jun, C/EBP beta, and HMG-IC to the bfl-1 regulatory region, coincident with selective recruitment of coactivators TAFII250 and p300, SWI/SNF chromatin remodeling factor component BRG-1, and basal transcription factors TATA-binding protein (TBP) and TFIIB, as well as hyperacetylation of histones H3 and H4. These results highlight a critical role for NF-kappa B in bfl-1 transcription and point to the need for a complex and precise regulatory network to control bfl-1 expression. To our knowledge, this is the first demonstration of enhanceosome-mediated regulation of a cell death inhibitor.
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PMID:NF-kappa B-dependent assembly of an enhanceosome-like complex on the promoter region of apoptosis inhibitor Bfl-1/A1. 1266 76

The Bfl-1 gene, which was isolated from human fetal liver and only recently described, is a member of the Bcl-2 gene family. Reverse transcriptase-polymerase chain reaction was performed on RNA drawn from 30 breast cancer tissues to compare the expression of the Bfl-1 gene with other prognostic factors. The median relative ratio was 3.0 (range, 0.12-26.83) and the Bfl-1 gene expression rate was 36.7% (11/30). There was no statistically significant relationship between the clinicopathologic parameters of patients and the expression value of Bfl-1 gene. The level of Bfl-1 gene expression was higher in more advanced breast cancers than in early cancers. There was no significant relationship between the expression values and currently acknowledged prognostic factors, but a higher expression pattern was noticed in the groups of positive hormone receptors and negative p53 and negative c-erbB2, albeit statistically not significant. It seems that the increased expression of the Bfl-1 gene serves as a contributory factor in breast cancer, in the same way that another group of genes, the Bcl-2 family, contributes to apoptosis.
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PMID:Bfl-1 gene expression in breast cancer: its relationship with other prognostic factors. 1269 20

Bfl-1 is an antiapoptotic Bcl-2 family member and a mouse A1 homologue. The mouse A1 has been reported to have three isoforms, but little is known about human Bfl-1. By reverse-transcriptase polymerase chain reaction analysis, we have identified Bfl-1S (short form), an alternative splice variant of Bfl-1. The Bfl-1S primary sequence contains four conserved Bcl-2 homology (BH) domains and a positive-charged C-terminus containing KKRK amino acids. The expression of Bfl-1S mRNA was detected predominantly in normal lymph nodes and in B-lymphoid leukemia cells. Confocal microscopic analysis using green fluorescence protein fusion proteins demonstrated that Bfl-1S is localized in the nucleus by its C-terminus as an intrinsic nuclear localization sequence. Bfl-1S acts as an antiapoptotic agent in coexpression experiments with Bax, a proapoptotic molecule. The expression of Bfl-1S provided significant resistance against staurosporine (STS) treatments in Molt-4 human T-leukemia cells. Bfl-1S also significantly inhibited the cleavage of Bid, and of caspases 3 and 8 against STS treatment. These results indicate that Bfl-1S is a novel human Bcl-2 family member that possesses antiapoptotic function.
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PMID:Bfl-1S, a novel alternative splice variant of Bfl-1, localizes in the nucleus via its C-terminus and prevents cell death. 1271 23

We analyzed regulation of the prosurvival Bcl-2 homologue A1, following T-cell receptor (TCR) or cytokine receptor engagement. Activation of CD4(+) or CD8(+) T cells by antigenic peptides induced an early but transient IL-2-independent expression of A1 and Bcl-xl mRNA and proteins, whereas expression of Bcl-2 was delayed and required IL-2. Cytokines such as IL-2, IL-4, IL-7 or IL-15 prevented apoptosis of activated T cells that effect being associated with the maintenance of Bcl-2, but not of A1 expression. However, restimulation of activated or posteffector T cells with antigenic peptide strongly upregulated A1 mRNA and maintained A1 protein expression. IL-4, IL-7 or IL-15 also prevented cell death of naive T cells. In those cells, cytokines upregulated Bcl-2, but not A1 expression. Therefore, in naive, activated and posteffector T cells, expression of A1 is dependent on TCR but not on cytokine receptor engagement, indicating that A1 is differently regulated from Bcl-xl and Bcl-2.
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PMID:A1/Bfl-1 expression is restricted to TCR engagement in T lymphocytes. 1293 80

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

Human Bfl-1 is an anti-apoptotic Bcl-2 family member. Here, we found that Bfl-1 was converted into a potent death-promoting protein by green fluorescent protein (GFP) fusion with its N-terminus. The transient expression of GFP-Bfl-1 induced cytochrome c release and triggered apoptosis in 293T cells, which depended on the mitochondrial localization of GFP-Bfl-1. Apoptosis induced by GFP-Bfl-1 was significantly blocked by the pan-caspase inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone, but was not blocked by either Bcl-xL or Bfl-1. Our findings provide a useful model for understanding the structural basis of Bcl-2 family proteins that act in an opposite way despite sharing structural similarity between anti-apoptotic and pro-apoptotic proteins.
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PMID:Conversion of Bfl-1, an anti-apoptotic Bcl-2 family protein, to a potent pro-apoptotic protein by fusion with green fluorescent protein (GFP). 1296

After antigen-driven expansion, the majority of T cells involved in an immune response die rapidly by apoptosis dependent on the Bcl-2 related proteins, Bim and Bax or Bak. The details of how these proteins are activated and interact are still unclear. The crystal structure of mouse Bcl-x(L) bound to a long helical fragment of Bim indicates that the structure of Bim is very different from proteins with a Bcl-2-like fold and may leave the BH3 region of Bim constitutively exposed. Based on the structural homology between Bcl-x(L) and Bax, we predicted that binding of Bim to Bax would require displacement of the Bax penultimate alpha helix. Consistent with this prediction, truncation of this short helix was required for Bim/Bax interaction and led to spontaneous activation of Bax. Our results suggest a way in which both Bim and Bax/Bak might be required for activated T cell apoptosis.
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PMID:The structure of a Bcl-xL/Bim fragment complex: implications for Bim function. 1449 10

In our search for NF-kappaB inhibitors from natural resources, we have previously identified two structurally related dilignans, manassantin A and B as specific inhibitors of NF-kappaB activation from Saururus chinensis. However, their molecular mechanism of action remains unclear. We here demonstrate that manassantins A and B are potent inhibitors of NF-kappaB activation by the suppression of transciptional activity of RelA/p65 subunit of NF-kappaB. These compounds significantly inhibited the induced expression of NF-kappaB reporter gene by LPS or TNF-alpha in a dose-dependent manner. However, these compounds did not prevent the DNA-binding activity of NF-kappaB assessed by electrophoretic mobility shift assay as well as the induced-degradation of IkappaB-alpha protein by LPS or TNF-alpha. Further analysis revealed that manassantins A and B dose-dependently suppressed not only the induced NF-kappaB activation by overexpression of RelA/p65, but also transactivation activity of RelA/p65. Furthermore, treatment of cells with these compounds prevented the TNF-alpha-induced expression of anti-apoptotic NF-kappaB target genes Bfl-1/A1, a prosurvival Bcl-2 homologue, and resulted in sensitizing HT-1080 cells to TNF-alpha-induced cell death. Similarly, these compounds also suppressed the LPS-induced inducible nitric oxide synthase expression and nitric oxide production. Taken together, manassantins A and B could be valuable candidate for the intervention of NF-kappaB-dependent pathological condition such as inflammation and cancer.
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PMID:Suppression of RelA/p65 transactivation activity by a lignoid manassantin isolated from Saururus chinensis. 1459 50


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