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)

Certain members of the Bcl-2 family inhibit apoptosis while others facilitate this physiological process of cell death. An expression screen for proteins that bind to Bcl-2 yielded a small novel protein, denoted Bim, whose only similarity to any known protein is the short (nine amino acid) BH3 motif shared by most Bcl-2 homologues. Bim provokes apoptosis, and the BH3 region is required for Bcl-2 binding and for most of its cytotoxicity. Like Bcl-2, Bim possesses a hydrophobic C-terminus and localizes to intracytoplasmic membranes. Three Bim isoforms, probably generated by alternative splicing, all induce apoptosis, the shortest being the most potent. Wild-type Bcl-2 associates with Bim in vivo and modulates its death function, whereas Bcl-2 mutants that lack survival function do neither. Significantly, Bcl-xL and Bcl-w, the two closest homologues of Bcl-2, also bind to Bim and inhibit its activity, but more distant viral homologues, adenovirus E1B19K and Epstein-Barr virus BHRF-1, can do neither. Hence, Bim appears to act as a 'death ligand' which can only neutralize certain members of the pro-survival Bcl-2 sub-family.
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PMID:Bim: a novel member of the Bcl-2 family that promotes apoptosis. 943 Jun 30

We identified and cloned a novel murine member of the pro-apoptotic Bcl-2 family. This protein, designated Blk, is structurally and functionally related to human Bik and localized to the mitochondrial membrane. Blk contains a conserved BH3 domain and can interact with the anti-apoptotic proteins Bcl-2 and Bcl-xL. Ectopic expression of Blk in mammalian cells induces apoptosis, which can be inhibited by mutations in the BH3 domain and by overexpression of Bcl-2 or Bcl-xL but not by CrmA. The apoptotic activity of Blk is also inhibited by a dominant negative caspase-9, suggesting that Blk induces apoptosis through activation of the cytochrome c-Apaf-1-caspase-9 pathway.
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PMID:Blk, a BH3-containing mouse protein that interacts with Bcl-2 and Bcl-xL, is a potent death agonist. 952 67

The Bcl-2 family of proteins consists of both antagonists (e.g. Bcl-2) and agonists (e.g. Bax) that regulate apoptosis and compete through dimerization. In the present study we cloned the cDNA encoding the rat brain BAD, a distant member of the Bcl-2 family that was shown to promote cell death. The cloned cDNA encoded a protein of 205 amino acids, containing three putative Bcl-2 homology domains (BH1, BH2 and BH3) and no C-terminal signal-anchor sequence. The predicted amino acid sequence was identical to the Bad-cDNA recently cloned from the rat ovary with the exception of a stretch of six amino acids, thus indicating the existence of two Bad alternative splice variants or a sequence artifact in the rat ovary Bad-cDNA. Immunohistochemical analysis in the rat brain revealed the exclusive expression of Bad in the epithelial cells of the choroid plexus, a result which is consistent with a very specialized function of Bad in the brain.
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PMID:Cloning and expression of the programmed cell death regulator Bad in the rat brain. 953 32

We have identified and characterized Mtd, a novel regulator of apoptosis. Sequence analysis revealed that Mtd is a member of the Bcl-2 family of proteins containing conserved BH1, BH2, BH3, and BH4 regions and a carboxyl-terminal hydrophobic domain. In adult tissues, Mtd mRNA was predominantly detected in the brain, liver, and lymphoid tissues, while in the embryo Mtd mRNA was detected in the liver, thymus, lung, and intestinal epithelium. Expression of Mtd promoted the death of primary sensory neurons, 293T cells and HeLa cells, indicating that Mtd is a proapoptotic protein. Unlike all other known death agonists of the Bcl-2 family, Mtd did not bind significantly to the survival-promoting proteins Bcl-2 or Bcl-XL. Furthermore, apoptosis induced by Mtd was not inhibited by Bcl-2 or Bcl-XL. A Mtd mutant with glutamine substitutions of highly conserved amino acids in the BH3 domain retained its ability to promote apoptosis, further indicating that Mtd does not promote apoptosis by heterodimerizing with Bcl-2 or Bcl-XL. Mtd-induced apoptosis was not blocked by broad range synthetic caspase inhibitors z-VAD-fmk or a viral protein CrmA. Mtd is the first example of a naturally occurring Bcl-2 family member that can activate apoptosis independently of heterodimerization with survival-promoting Bcl-2 and Bcl-XL.
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PMID:Mtd, a novel Bcl-2 family member activates apoptosis in the absence of heterodimerization with Bcl-2 and Bcl-XL. 953 47

Bax is a pro-apoptotic member of the Bcl-2 protein family that resides in the outer mitochondrial membrane. It is controversial whether Bax promotes cell death directly through its putative function as a channel protein versus indirectly by inhibiting cellular regulators of the cell death proteases (caspases). We show here that addition of submicromolar amounts of recombinant Bax protein to isolated mitochondria can induce cytochrome c (Cyt c) release, whereas a peptide representing the Bax BH3 domain was inactive. When placed into purified cytosol, neither mitochondria nor Bax individually induced proteolytic processing and activation of caspases. In contrast, the combination of Bax and mitochondria triggered release of Cyt c from mitochondria and induced caspase activation in cytosols. Supernatants from Bax-treated mitochondria also induced caspase processing and activation. Recombinant Bcl-XL protein abrogated Bax-induced release of Cyt c from isolated mitochondria and prevented caspase activation. In contrast, the broad-specificity caspase inhibitor benzyloxycarbonyl-valinyl-alaninyl-aspartyl-(0-methyl)- fluoromethylketone (zVAD-fmk) and the caspase-inhibiting protein X-IAP had no effect on Bax-induced release of Cyt c from mitochondria in vitro but prevented the subsequent activation of caspases in cytosolic extracts. Unlike Ca2+, a classical inducer of mitochondrial permeability transition, Bax did not induce swelling of mitochondria in vitro. Because the organellar swelling caused by permeability transition causes outer membrane rupture, the findings, therefore, dissociate these two events, implying that Bax uses an alternative mechanism for triggering release of Cyt c from mitochondria.
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PMID:Bax directly induces release of cytochrome c from isolated mitochondria. 956 Feb 17

To search for a Bcl-2 family homologue in the posterior silk gland of Bombyx mori, Western blot analysis was performed with the anti-rat Bcl-XL antiserum preabsorbed with a XL1-Blue MRF' lysate. The antiserum was shown to cross-react specifically with a silkworm protein of 80000 mol. wt (BmP80). The level of BmP80 increased dramatically during the spinning stage and decreased rapidly after the formation of a cocoon, implying that the silkworm protein was involved in histolysis of posterior silk gland as a stimulator. Screening a B. mori cDNA library with the same preabsorbed antiserum, a cDNA clone contaiing a cDNA fragment that is presumably large enough to encode the entire BmP80 protein was identified. The cDNA fragment contained 127 nucleotides (nt) of untranslated sequence at the 5' end, 2895nt of presumptive coding sequence and 625nt of untranslated sequence including a poly(A) tail at the 3' end. The calculated mol. wt of the presumptive protein (BmP109) was 108800. BmP109 shared sequence homology with the antiapoptotic proteins within the four conserved regions, BH1, BH2, BH3 and BH4, which were located at the C-terminal half of the protein and resided in the same characteristic order as Bcl-2 family proteins. Comparison of amino acid content revealed that BmP109 contained much more cysteine and lysine but less glycine and arginine than the antiapoptotic proteins. Northern blot analysis indicated that the mRNA for BmP109 is about 4.0kb. Reverse transcription-polymerase chain reaction experiments showed that the mRNA level for BmP109 increased dramatically during the spinning stage and decreased rapidly after formation of a cocoon, suggesting the involvement of transcriptional regulation.
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PMID:Molecular cloning of a cDNA encoding a silkworm protein that contains the conserved BH regions of Bcl-2 family proteins. 961 Dec 71

Bax is a member of the Bcl-2 protein family with proapoptotic properties. The proteins of this family contain three highly conserved regions termed BH1, BH2, and BH3 as well as a hydrophobic COOH-terminal domain, which is responsible for the membrane attachment of the proteins. We have expressed human Bax truncated of the 20 amino acid COOH-terminal hydrophobic domain to obtain large amounts of soluble protein suitable for biochemical and structural studies. The truncated protein was expressed as a glutathione S-transferase (GST) fusion protein in Escherichia coli. The GST-Bax fusion protein was bound to glutathione-Sepharose, and Bax was released by thrombin cleavage and further purified by sequential chromatography on heparin-Sepharose and DEAE-Sepharose. The purified protein was present in solution as a heptamer and multimers of the heptamer complex. Limited tryptic digestion cleaved the protein in the region preceding the BH3 domain and produced a specific stable protein fragment of 15 kDa. Phosphorylation has been proposed as a possible regulatory mechanism of the bcl-2 proteins. The Bax protein was an in vitro substrate for specific serine/threonine protein kinases.
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PMID:Purification and biochemical properties of soluble recombinant human Bax. 963 24

Bcl-2-related proteins have come to occupy a prominent position in the realm of programmed cell death. Members of this fast-growing family are highly related in one or more specific regions, commonly referred to as Bcl-2 homology (BH) domains. BH domains contribute at multiple levels to the function of these proteins in cell death and survival. Particularly intriguing is the emergence of the BH3 domain as a potent 'death domain' and of a growing subclass of pro-apoptotic proteins with no similarity to Bcl-2 beyond their BH3 homology. Here, the authors classify proteins of the Bcl-2 family on the basis of function and domain organization, discuss the importance of the BH3 domain in protein-protein interactions and in cell death and provide possible explanations for the perceived redundancy in the expression of this subclass of death promoters.
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PMID:Bcl-2-family proteins: the role of the BH3 domain in apoptosis. 970 9

Bok (Bcl-2-related ovarian killer) is a proapoptotic Bcl-2 family protein identified in the ovary based on its dimerization with the antiapoptotic protein Mcl-1. In addition to the Bcl-2 homology (BH) domains 1 and 2 and the transmembrane sequence, Bok also has a BH3 domain believed to be important for dimerization with selective antiapoptotic Bcl-2 proteins and cell killing. We identified a splicing variant of Bok mRNA with a deletion of 43 residues from the full-length protein (Bok-L), leading to the fusion of the N-terminal-half of its BH3 domain to the C-terminal-half of the BH1 domain. Genomic analysis indicated that the Bok has five exons, and the short form of Bok (Bok-S) represents the splicing out of exon three during transcription. Although Bok-S retains the apoptosis-inducing activity in transfected cells, it has lost the ability to dimerize with antiapoptotic proteins in vitro. Additional BH3 domain mutations of Bok-L also led to defective heterodimerization without affecting its proapoptotic action. Furthermore, similar deletions for the related channel-forming proapoptotic Bax and Bak did not impair their cell killing ability. Thus, the naturally occurring Bok-S variant represents a new form of proapoptotic protein that induces cell killing without heterodimerization with antiapoptotic Bcl-2 proteins. This variant appears to contain the minimal module spanning BH1 and BH2 domains and the transmembrane sequence for apoptosis induction by channel-forming Bcl-2 proteins.
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PMID:A splicing variant of the Bcl-2 member Bok with a truncated BH3 domain induces apoptosis but does not dimerize with antiapoptotic Bcl-2 proteins in vitro. 980 69

We have identified and characterized Diva, which is a novel regulator of apoptosis. Sequence analysis revealed that Diva is a member of the Bcl-2 family of proteins containing Bcl-2 homology domain 1, 2, 3, and 4 (BH1, BH2, BH3, and BH4) regions and a carboxyl-terminal hydrophobic domain. The expression of Diva mRNA was detected in multiple embryonic tissues but was restricted to the ovary and testis in adult mice. The expression of Diva promoted the death of 293T, Ramsey, and T47D cells as well as that of primary sensory neurons, indicating that Diva is a proapoptotic protein. Significantly, Diva lacks critical residues in the conserved BH3 region that mediate the interaction between BH3-containing proapoptotic Bcl-2 homologues and their prosurvival binding partners. Consistent with this, Diva did not bind to cellular Bcl-2 family members including Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1/Bfl-1. Furthermore, mutants of Diva lacking the BH3 region fully retained their proapoptotic activity, confirming that Diva promotes apoptosis in a BH3-independent manner. Significantly, Diva interacted with a viral Bcl-2 homologue (vBcl-2) encoded by the Kaposi's sarcoma-associated herpesvirus. Consistent with these associations, apoptosis induced by Diva was inhibited by vBcl-2 but not by Bcl-XL. Importantly, Diva interacted with Apaf-1, an adapter molecule that activates caspase-9, a central death protease of the apoptotic pathway. The expression of Diva inhibited the binding of Bcl-XL to Apaf-1, as determined by immunoprecipitation assays. Thus, Diva represents a novel type of proapoptotic Bcl-2 homologue that promotes apoptosis independently of the BH3 region through direct binding to Apaf-1, thus preventing Bcl-XL from binding to the caspase-9 regulator Apaf-1.
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PMID:Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell death. 982 80


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