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)

Bcl-2 is the best characterized inhibitor of apoptosis, although the molecular basis of this action is not fully understood. Using a protein interaction cloning procedure, we identified a human gene designated as bis (mapped to chromosome 10q25) that encoded a novel Bcl-2-interacting protein. Bis protein showed no significant homology with Bcl-2 family proteins and had no prominent functional motif. Co-immunoprecipitation analysis confirmed that Bis interacted with Bcl-2 in vivo. DNA transfection experiments indicated that Bis itself exerted only weak anti-apoptotic activity, but was synergistic with Bcl-2 in preventing Bax-induced and Fas-mediated apoptosis. These results suggest that Bis is a novel modulator of cellular anti-apoptotic activity that functions through its interaction with Bcl-2.
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PMID:Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death. 1059 16

Here, we describe the isolation of adenine nucleotide translocase-1 (ANT-1) in a screen for dominant, apoptosis-inducing genes. ANT-1 is a component of the mitochondrial permeability transition complex, a protein aggregate connecting the inner with the outer mitochondrial membrane that has recently been implicated in apoptosis. ANT-1 expression led to all features of apoptosis, such as phenotypic alterations, collapse of the mitochondrial membrane potential, cytochrome c release, caspase activation, and DNA degradation. Both point mutations that impair ANT-1 in its known activity to transport ADP and ATP as well as the NH(2)-terminal half of the protein could still induce apoptosis. Interestingly, ANT-2, a highly homologous protein could not lead to cell death, demonstrating the specificity of the signal for apoptosis induction. In contrast to Bax, a proapoptotic Bcl-2 gene, ANT-1 was unable to elicit a form of cell death in yeast. This and the observed repression of apoptosis by the ANT-1-interacting protein cyclophilin D suggest that the suicidal effect of ANT-1 is mediated by specific protein-protein interactions within the permeability transition pore.
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PMID:Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis. 1061 7

Transcription of the human polyomavirus JC virus (JCV) genome is regulated by cellular proteins and the large tumour (T) antigen. Earlier studies led to the identification of nuclear factor-1 (NF-1)-binding sites in the JCV enhancer by DNase I protection assays of extracts from retinoic acid (RA)-differentiated P19 embryonal carcinoma (EC) cells. In this study, a cDNA clone that encodes a protein capable of binding to the JCV NF-1 sites was isolated from an RA-differentiated EC cell cDNA library. Sequence analysis revealed that the cDNA isolated was identical to the previously described Bcl-2-interacting protein BAG-1 (Bcl-2-associated athano gene-1). Results from RNA studies indicated that BAG-1 is expressed in several cell types. Co-transfection of a recombinant BAG-1 expression plasmid with JCV promoters indicated that BAG-1 stimulates transcription of the JCV(E) promoter and to a lesser extent the JCV(L) promoter. Mutations in the NF-1 sites in the JCV(E) promoter eliminated the activation by BAG-1. Thus, BAG-1 is a novel transcription factor that may play a role in JCV expression.
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PMID:BAG-1, a novel Bcl-2-interacting protein, activates expression of human JC virus. 1064 33

An increasing number of proteins are implicated in apoptosis and several of them have been shown to be altered in Alzheimer's disease (AD) brain. Because of this apoptosis is thought to be the underlying mechanism of neuronal cell loss in AD. To further substantiate this hypothesis we investigated the expression of a recently identified apoptosis related proteins and other apoptosis regulators in frontal cortex and cerebellum of AD by Western blot and enzyme-linked immunsorbent assay technique. Quantitative analysis revealed unaltered levels of Bax and RAIDD (Receptor interacting protein associated ICH-1 (caspase-2)/CED-3 (Caenorhabditis elegans death protease-3)-homologous protein with death domain) in both regions. ZIP (Zipper interacting protein) kinase, Bim/BOD (Bcl-2 interacting mediator of cell death/Bcl-2 related ovarian death gene) and p21 were significantly increased only in AD frontal cortex (P < 0.05, in all cases). Cerebellar Bcl-2 levels were significantly increased in AD (P < 0.01) while in AD frontal cortex, although the levels tended to increase did not reach significance level. The results indicate that apoptosis indeed account for the neuronal loss in AD. However, it does not seem to involve Bax and RAIDD.
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PMID:Expression of apoptosis related proteins in brains of patients with Alzheimer's disease. 1131 97

Solid tumors contain regions of hypoxia, a physiological stress that can activate cell death pathways and, thus, result in the selection of cells resistant to death signals and anticancer therapy. Bcl2/adenovirus EIB 19kD-interacting protein 3 (BNIP3) is a cell death factor that is a member of the Bcl-2 proapoptotic family recently shown to induce necrosis rather than apoptosis. Using cDNA arrays and serial analysis of gene expression, we found that hypoxia induces up-regulation of BNIP3 and its homologue, Nip3-like protein X. Analysis of human carcinoma cell lines showed that they are hypoxically regulated in many tumor types, as well as in endothelial cells and macrophages. Regulation was hypoxia inducible factor-1-dependent, and hypoxia inducible factor-1 expression was suppressed by von Hippel-Lindau protein in normoxic cells. Northern blotting and in situ hybridization analysis has revealed that these factors are highly expressed in human tumors compared with normal tissue and that BNIP3 is up-regulated in perinecrotic regions of the tumor. This study shows that genes regulating cell death can be hypoxically induced and are overexpressed in clinical tumors.
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PMID:HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. 1155 32

Down syndrome (DS) is a genetic disease that exhibits significant neuropathological parallels with Alzheimer's disease (AD). One of the features of DS, neuronal loss, has been hypothesized to occur as a result of apoptosis. An increasing number of proteins are implicated in apoptosis and several of them were shown to be altered in AD, however, the knowledge in DS is far from complete. To further substantiate the hypothesis that apoptosis is the underlying mechanism for neuronal loss and contribute towards the current knowledge of apoptosis in DS, we analyzed the expression of apoptosis related proteins in frontal cortex and cerebellum of DS by western blot and ELISA techniques. Quantitative analysis revealed a significant increase in DS frontal (P < 0.0001) and cerebellar (P < 0.05) Bim/BOD (Bcl-2 interacting mediator of cell death/Bcl-2 related ovarian death gene), cerebellar Bcl-2 (P < 0.01) as well as p21 (P < 0.05) levels compared to controls. No significant change was detected in Bax, RAIDD (receptor interacting protein (RIP)-associated ICH-1/CED-3-homologus protein with death domain), ZIP (Zipper interacting protein) kinase and NF-kappaB p65 levels in both regions, although frontal cortex levels of RAIDD, Bcl-2 and p21 levels tended to increase. In addition, a 45 kDa truncated form of NF-kappaB p65 displayed a significant elevation (P < 0.05) in DS cerebellum. No significant correlation had been obtained between postmortem interval and level of the proteins analyzed. With regard to age, it was only NF-kappaB p65 that showed significant correlation (r = -0.8964, P = 0.0155, n = 9) in frontal cortex of controls. These findings provide further evidence that apoptosis indeed accounts for the neuronal loss in DS but Bax and RAIDD do not appear to take part in this process.
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PMID:Expression of apoptosis related proteins: RAIDD, ZIP kinase, Bim/BOD, p21, Bax, Bcl-2 and NF-kappaB in brains of patients with Down syndrome. 1177 42

We cloned mouse ING1 homologue (mINGh), an A1/Bfl-1-interacting protein, from mouse mammary glands using a yeast two-hybrid assay and unexpectedly found four splicing variants of mINGh by reverse transcription-PCR assay and sequence analysis. The alternative splicing variants were mINGh-S, mINGh-M, mINGh-L, and mINGh-L2 encoding 171, 248, 166, and 227 amino acids, respectively. Cell death of HC11 cells, induced by serum starvation, was enhanced by mINGhs, and the action of mINGhs was inhibited by A1 protein. These results indicate that A1 can inhibit cell death not only via the well known pathway related to the Bcl-2 family but also through direct interaction with mINGh in mammary epithelial cells.
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PMID:Mouse ING1 homologue, a protein interacting with A1, enhances cell death and is inhibited by A1 in mammary epithelial cells. 1188 90

Following caspase-8 mediated cleavage, a carboxyl-terminal fragment of the BH3 domain-only Bcl-2 family member Bid transmits the apoptotic signal from death receptors to mitochondria. In a screen for possible regulators of Bid, we defined Bfl-1/A1 as a potent Bid interacting protein. Bfl-1 is an anti-apoptotic Bcl-2 family member, whose preferential expression in hematopoietic cells and endothelium is controlled by inflammatory stimuli. Its mechanism of action is unknown. We find that Bfl-1 associates with both full-length Bid and truncated (t)Bid, via the Bid BH3 domain. Cellular expression of Bfl-1 confers protection against CD95- and Trail receptor-induced cytochrome c release. In vitro assays, using purified mitochondria and recombinant proteins, demonstrate that Bfl-1 binds full-length Bid, but does not interfere with its processing by caspase-8, or with its mitochondrial association. Confocal microscopy supports that Bfl-1, which at least in part constitutively localizes to mitochondria, does not impede tBid translocation. However, Bfl-1 remains tightly and selectively bound to tBid and blocks collaboration between tBid and Bax or Bak in the plane of the mitochondrial membrane, thereby preventing mitochondrial apoptotic activation. Lack of demonstrable interaction between Bfl-1 and Bak or Bax in the mitochondrial membrane suggests that Bfl-1 generally prevents the formation of a pro-apoptotic complex by sequestering BH3 domain-only proteins.
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PMID:Bcl-2 family member Bfl-1/A1 sequesters truncated bid to inhibit is collaboration with pro-apoptotic Bak or Bax. 1192 71

Bis (also called Bag-3), identified as a novel Bcl-2-interacting protein, has been shown to enhance anti-cell death activity of Bcl-2. Because ischemia/reperfusion induces expression of Bcl-2, we examined the changes in the pattern of Bis expression in the adult rat hippocampus after transient forebrain ischemia. Western blot analysis with protein extracts from the hippocampus showed that, compared with controls, levels of Bis were markedly increased seven days after ischemia. An immunohistochemical study showed that the expression of Bis increased preferentially in the CA1 and the dentate hilar regions, and peaked at 3-7 days after reperfusion. The temporal and spatial patterns of expression for both Bis and glial fibrillary acidic protein (GFAP) were very similar, and double immunofluorescence histochemistry showed that Bis was expressed in reactive astrocytes, which express GFAP. Immunolabeling of adjacent sections with anti-Bcl-2 and anti-Hsp70 antibodies revealed that the pattern of Bis expression closely correlates with that of Bcl-2, but clearly differs from that of Hsp70. Coexpression of Bis and Bcl-2 in reactive astrocytes was confirmed by double immunofluorescence histochemistry. Our results demonstrate that reactive astrocytes transiently up-regulate Bis after ischemia/reperfusion in the adult rat hippocampus. However, the precise role of Bis in the astrocytic response to ischemia/reperfusion in relation to Bcl-2 remains to be determined.
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PMID:Reactive astrocytes express bis, a bcl-2-binding protein, after transient forebrain ischemia. 1206 64

Myeloid cell leukemia 1 protein (MCL1) is an anti-apoptotic protein that is structurally related to Bcl-2. Unlike other Bcl-2 family proteins that are constitutively expressed, MCL1 is inducibly expressed in cells that are recently exposed to growth and differentiation stimuli. Here, we report the identification of fortilin as a novel MCL1-interacting protein by screening of a yeast two-hybrid library with MCL1 as bait. Fortilin specifically interacted with MCL1 both in vitro and in vivo. The intracellular localization of fortilin was predominantly nuclear and identical to that of MCL1, as shown by immunostaining and confocal microscopy analysis. Fortilin, like MCL1, was rapidly inducible in serum-stimulated human aortic vascular smooth muscle cells. Although the depletion of intracellular fortilin by small interfering RNA (siRNA) against fortilin (siRNA-fortilin) did not affect intracellular MCL1 level, the depletion of intracellular MCL1 by siRNA-MCL1 was associated with the significant reduction of the fortilin protein level, without affecting the fortilin transcript numbers. In addition, a pulse-chase experiment showed that the depletion of MCL1 by siRNA-MCL1 was associated with the rapid degradation of fortilin protein, which was found quite stable in the presence of MCL1. Furthermore, the half-life of fortilin(R21A), a point mutant of fortilin lacking the binding to MCL1, was significantly shorter than that of wild-type fortilin as shown by a pulse-chase experiment. These data suggest that MCL1, in addition to being an anti-apoptotic molecule, serves as a chaperone of fortilin, binding and stabilizing fortilin in vivo. Taken together with our previous observation that fortilin overexpression prevents cells from undergoing apoptosis (Li, F., Zhang, D., and Fujise, K. (2001) J. Biol. Chem. 276, 47542-47549), it is likely that MCL1, an anti-apoptotic protein inducible by growth and differentiation stimuli, stabilizes another anti-apoptotic protein fortilin maximizing the prosurvival environment in cells.
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PMID:Physical and functional interaction between myeloid cell leukemia 1 protein (MCL1) and Fortilin. The potential role of MCL1 as a fortilin chaperone. 1214 73


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