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)

Here we demonstrate that open reading frame 16 (ORF16) of the oncogenic herpesvirus saimiri protects cells from heterologous virus-induced apoptosis. The BH1 and BH2 homology domains are highly conserved in ORF16, and ORF16 heterodimerizes with Bcl-2 family members Bax and Bak. However, ORF16 lacks the core sequence of the conserved BH3 homology domain, suggesting that this region is not essential for anti-apoptotic activity. Conservation of a functional bcl-2 homolog among gammaherpesviruses suggests that inhibition of programmed cell death is important in the biology of these viruses.
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PMID:Herpesvirus saimiri encodes a functional homolog of the human bcl-2 oncogene. 909 93

Bcl-2 inhibits apoptosis induced by a wide variety of stimuli. In contrast, the Bcl-2 homologue, Bax, antagonizes Bcl-2's death protecting function. Bcl-2 forms protein-protein homodimers with itself and heterodimers with Bax, and previous experiments have shown that point mutations in Bcl-2 can abrogate Bax binding while leaving homodimerization intact. These mutagenesis results can be interpreted to suggest that Bcl-2 has separate binding sites that are responsible for homodimer and heterodimer formation. Results from yeast two-hybrid studies have also suggested that homodimerization and heterodimerization reflect distinct modes of interaction. However, using quantitative plate binding assays, we now show that Bax as well as peptides derived from the BH3 domains of Bax and Bak block both Bcl-2/Bax binding and Bcl-2/Bcl-2 binding. Similar assays demonstrate that Bcl-xL can form both homodimers and heterodimers and that these interactions are also inhibited by Bax and the BH3-derived peptides. These results demonstrate that the same binding motifs are responsible for both homodimerization and heterodimerization of Bcl-2 family members.
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PMID:A common binding site mediates heterodimerization and homodimerization of Bcl-2 family members. 911 Oct 42

Apoptosis as a form of programmed cell death (PCD) in multicellular organisms is a well-established genetically controlled process that leads to elimination of unnecessary or damaged cells. Recently, PCD has also been described for unicellular organisms as a process for the socially advantageous regulation of cell survival. The human Bcl-2 family member Bak induces apoptosis in mammalian cells which is counteracted by the Bcl-x(L) protein. We show that Bak also kills the unicellular fission yeast Schizosaccharomyces pombe and that this is inhibited by coexpression of human Bcl-x(L). Moreover, the same critical BH3 domain of Bak that is required for induction of apoptosis in mammalian cells is also required for inducing death in yeast. This suggests that Bak kills mammalian and yeast cells by similar mechanisms. The phenotype of the Bak-induced death in yeast involves condensation and fragmentation of the chromatin as well as dissolution of the nuclear envelope, all of which are features of mammalian apoptosis. These data suggest that the evolutionarily conserved metazoan PCD pathway is also present in unicellular yeast.
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PMID:Human Bak induces cell death in Schizosaccharomyces pombe with morphological changes similar to those with apoptosis in mammalian cells. 911 15

The function of the African swine fever virus (ASFV) bcl-2 homologue, gene A179L, in the regulation of apoptosis was investigated using as a model system the human myeloid leukemia cell line K562 induced to die by apoptosis with inhibitors of macromolecular synthesis, a process that is prevented by overexpression of human bcl-2. It is shown that transfection of K562 cells with the ASFV A179L gene protects these cells from apoptotic cell death induced by a combination of cycloheximide and actinomycin D or by treatment with cytosine arabinoside. To test the functional role of the highly conserved BH1 domain present in the A179L protein, the Gly residue at position 85 was mutated to Ala, since it has been shown that substitution of the corresponding Gly in human Bcl-2 abrogates its death-repressor activity. It was found that the Gly-to-Ala mutation in the BH1 domain of the viral protein abolished its capacity to protect the K562 cells from apoptosis, indicating that this Gly is essential for A179L action. This finding stresses the functional similarity of the BH1 domains of the viral protein and cellular Bcl-2.
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PMID:Inhibition of apoptosis by the African swine fever virus Bcl-2 homologue: role of the BH1 domain. 912 49

Programmed cell death is essential in organ development and tissue homeostasis and its deregulation is associated with the development of several diseases in mice and humans. The precise mechanisms that control cell death have not been elucidated fully, but it is well established that this form of cellular demise is regulated by a genetic program which is activated in the dying cell. Here we report the identification, cloning and characterization of harakiri, a novel gene that regulates apoptosis. The product of harakiri, Hrk, physically interacts with the death-repressor proteins Bcl-2 and Bcl-X(L), but not with death-promoting homologs, Bax or Bak. Hrk lacks conserved BH1 and BH2 regions and significant homology to Bcl-2 family members or any other protein, except for a stretch of eight amino acids that exhibits high homology with BH3 regions. Expression of Hrk induces cell death which is inhibited by Bcl-2 and Bcl-X(L). Deletion of 16 amino acids including the conserved BH3 region abolished the ability of Hrk to interact with Bcl-2 and Bcl-X(L) in mammalian cells. Moreover, the killing activity of this mutant form of Hrk (Hrk deltaBH3) was eliminated or dramatically reduced, suggesting that Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by Bcl-2 and Bcl-X(L). Because Hrk lacks conserved BH1 and BH2 domains that define Bcl-2 family members, we propose that Hrk and Bik/Nbk, another BH3-containing protein that activates apoptosis, represent a novel class of proteins that regulate apoptosis by interacting selectively with survival-promoting Bcl-2 and Bcl-X(L).
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PMID:harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). 913 Jul 13

Of six prostatic carcinoma cell lines examined (ALVA31, DU145, JCA1, LNCaP, ND1, and PC3) by flow cytometric analysis, all were found to be positive for Fas antigen. Furthermore, of the prostate tissue specimens studied (six cases), all revealed Fas expression in benign and malignant epithelial cells. The agonistic anti-Fas monoclonal antibody (IPO-4) induced apoptosis in only two of six cell lines investigated, PC3 and ALVA31. PCR analysis indicated that all cell lines expressed normal transmembrane and death domains of Fas antigen. Using Western blot analysis, we found abundant expression of p53 in the cytoplasm of two Fas-resistant cell lines, DU145 and ND1, and did not find p53 in two Fas-sensitive cell lines, PC3 and ALVA31. Western blot and PCR analysis did not show consistent differences between cell lines examined in the expression of Bcl-2, Bcl-X(L), Bcl-X(S), and Bak. In contrast, Bax protein was not detected in two Fas-resistant cell lines, DU145 and ND1. We also showed that three Fas-resistant cell lines, DU145, ND1, and JCA1, expressed CD40, whereas the two Fas-sensitive cell lines, PC3 and ALVA31, were CD40 negative. Fas-sensitive cell lines were transfected with the cDNA encoding CD40, and the CD40-positive transfectant became more resistant to growth inhibition mediated by treatment with TNF-alpha and anti-Fas monoclonal antibody. Treatment with cycloheximide converted the phenotype of resistant cell lines from Fas resistant to Fas sensitive. Moreover, anti-Fas treatment of both resistant and sensitive cell lines induced rapid tyrosine phosphorylation or dephosphorylation of multiple proteins. These results suggest that the apoptotic machinery involved in DNA fragmentation is already in place in Fas-resistant cell lines, and thus, Fas-mediated apoptosis could be a target for therapeutic intervention.
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PMID:Fas-mediated apoptosis in human prostatic carcinoma cell lines. 913 20

Induction of Bcl-2 and Bcl-x has been demonstrated in mitogen-stimulated lymphocytes in vitro, suggesting that these two apoptosis modulators may also play a role during proliferation. To explore this possibility in a physiological setting, mRNA expression of various Bcl-2 family members was examined during liver regeneration induced by partial hepatectomy, a well characterized in vivo model of cell cycle progression. After a 60% partial hepatectomy in C3H/HeN mice, the steady-state levels of Bcl-x mRNA exhibited a cyclical pattern, with peaks at 4 hours (early G1) and 48 to 72 hours (G1 phase of the second hepatocyte cell cycle). A1 and Bcl-2 mRNA were not detected, and the levels of two Mcl-1 mRNA species remained low without significant changes. The three pro-apoptotic members of the family, Bak, Bad, and Bax, all showed an early decline in mRNA levels when Bcl-x transcripts increased, followed by later peaks at 12, 24, and 48 to 72 hours, respectively. Experiments were subsequently conducted in C3H/HeJ mice, an endotoxin-resistant strain with slower liver regeneration marked by a protracted G1 phase. Even though immediate-early gene responses measured by c-myc induction remained intact, the timing of Bcl-x mRNA expression was delayed in C3H/HeJ mice. When C3H/HeN mice were pretreated with cycloheximide before hepatectomy, the early peak of Bcl-x mRNA at 4 hours was essentially abrogated whereas the immediate-early gene c-myc was hyperinduced, thus implicating Bcl-x as a delayed early response gene during liver regeneration. Bcl-x was localized in hepatocytes and by both immunohistochemistry and Western blot analysis, Bcl-xL protein reached highest levels at 12 hours (mid-G1), consistent with the expression of a delayed early gene. In summary, the expression profiles of Bcl-2 family members during liver regeneration suggest a cell-cycle-dependent regulation as well as a physiological role for these apoptosis-modulating genes during growth and proliferation.
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PMID:Expression of Bcl-2 family during liver regeneration and identification of Bcl-x as a delayed early response gene. 917 92

Bcl-2 family members are regulators of cell death. The precise biochemical properties of these proteins are unclear although intrafamily protein-protein association is thought to be involved. To elucidate structure-activity relationships among Bcl-2 proteins and identify the pathways in which they act, an inducible death suppressor assay was developed in yeast. Only Bax and Bak killed yeast via a process that did not require interleukin-1beta-converting enzyme-like proteases. Bax/Bak lethality was suppressed by coexpression of Bcl-2 family members that are anti-apoptotic in vertebrates, namely Bcl-xL, Bcl-2, Mcl-1, and A1. Furthermore, Bcl-xL and Bcl-2 suppressed Bax toxicity by distinct mechanisms in yeast. Bad, Bcl-xS, and Ced-9 lacked suppressor activity. These inactive proteins bound to anti-apoptotic members of the Bcl-2 family but not to Bax or Bak. In contrast, most Bcl-2 family proteins that attenuated death bound to Bax and Bak. However, two mutants of Bcl-xL suppressed Bax-induced cell death while having no Bax binding activity. Therefore, Bcl-xL functions independently of Bax binding, perhaps by interacting with a common target or promoting a pathway that antagonizes Bax. Thus, the pathways downstream of Bax and Bcl-xL may be conserved between vertebrates and yeast. This suppressor assay could be used to isolate components of these pathways.
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PMID:Modulation of cell death in yeast by the Bcl-2 family of proteins. 918 91

The effects of the expression of the human Bcl-2 family proteins Bax, Bak, Bcl-2, and Bcl-XL were examined in the fission yeast Schizosaccharomyces pombe and compared with Bax-induced cell death in mammalian cells. Expression of the proapoptotic proteins Bax and Bak conferred a lethal phenotype in this yeast, which was strongly suppressed by coexpression of the anti-apoptotic protein Bcl-XL. Bcl-2 also partially abrogated Bax-mediated cytotoxicity in S. pombe, whereas a mutant of Bcl-2 (Gly145Ala) that fails to heterodimerize with Bax or block apoptosis in mammalian cells was inactive. However, other features distinguished Bax- and Bak-induced death in S. pombe from animal cell apoptosis. Electron microscopic analysis of S. pombe cells dying in response to Bax or Bak expression demonstrated massive cytosolic vacuolization and multifocal nuclear chromatin condensation, thus distinguishing this form of cell death from the classical morphological features of apoptosis seen in animal cells. Unlike Bax-induced apoptosis in 293 cells that led to the induction of interleukin-1 beta-converting enzyme (ICE)/CED-3-like protease activity, Bax- and Bak-induced cell death in S. pombe was accompanied neither by internucleosomal DNA fragmentation nor by activation of proteases with specificities similar to the ICE/CED-3 family. In addition, the baculovirus protease inhibitor p35, which is a potent inhibitor of ICE/CED-3 family proteases and a blocker of apoptosis in animal cells, failed to prevent cell death induction by Bax or Bak in fission yeast, whereas p35 inhibited Bax-induced cell death in mammalian cells. Taken together, these findings suggest that Bcl-2 family proteins may retain an evolutionarily conserved ability to regulate cell survival and death but also indicate differences in the downstream events that are activated by overexpression of Bax or Bak in divergent cell types.
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PMID:Bax- and Bak-induced cell death in the fission yeast Schizosaccharomyces pombe. 919 Feb 11

Interleukin-13 (IL-13) is a novel T-cell-derived cytokine with IL-4-like effects on many cell types. In human B lymphocytes, IL-13 induces activation, stimulates proliferation in combination with anti-IgM or anti-CD40 antibodies, and directs Ig isotype switching towards IgE and IgG4 isotypes. We show here that IL-13 also regulates human B-cell apoptosis. IL-13 reduced spontaneous apoptosis of peripheral blood B cells in vitro, as shown by measurement of DNA fragmentation using the TUNEL and Nicoletti assays. The inhibition of cell death by IL-13 alone was significant but modest, but was potently enhanced in combination with CD40 ligand (CD40L), a survival stimulus for B cells by itself. Interestingly, IL-13 increased the expression of CD40 on peripheral blood B cells, providing a possible mechanism for the observed synergy. IL-13 alone was a less potent inhibitor of apoptosis than IL-4. Moreover, there was no additive effect of combining IL-4 and IL-13 at supraoptimal concentrations, which is consistent with the notion that the IL-4 and IL-13 binding sites share a common signaling subunit. The combination of IL-13 with CD40L augmented the expression of the Bcl-2 homologues Bcl-xL and Mcl-1, suggesting this as a possible intracellular mechanism of induced survival. By contrast, levels of Bcl-2, and two other Bcl-2 family members, Bax and Bak, remained unaltered. Given the importance of the CD40-CD40L interaction in B-cell responses, these results suggest a significant role of IL-13 in the regulation of B-cell apoptosis.
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PMID:Interleukin-13 in combination with CD40 ligand potently inhibits apoptosis in human B lymphocytes: upregulation of Bcl-xL and Mcl-1. 919 66


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