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)

Okadaic acid, an inhibitor of serine/threonine protein phosphatases 1 and 2A has been shown to cause mitotic arrest and cell death of HL-60 and K562 cells. HL-60 cells express Bcl-2 and little or no Bcl-X(L), while K562 expresses Bcl-X(L) but not Bcl-2. Since phosphorylation/dephosphorylation reactions have been suggested to be involved in the regulation of Bcl-2, we planned to investigate whether the expression of Bcl-2, Bcl-X(L) and Bax, a protein that antagonizes the antiapoptotic function of Bcl-2, are regulated in myeloid leukemia cell lines (K562, KU812 and HL-60) treated with okadaic acid. Our results indicate that exposure of all three leukemic cell lines to nanomolar concentrations of okadaic acid causes a loss of viability by activation of an apoptotic process accompanied by a marked decrease in the expression of Bcl-2, Bcl-X(L) and Bax at both mRNA and protein level, but not of c-fos, vimentin and epsilon-globin, ruling out a non-specific effect of okadaic acid. Furthermore, constitutive expression of either Bcl-X(L) or Bcl-2 by gene transfer inhibited apoptosis triggered by okadaic acid in K562 cells. Thus, we suggest that protein phosphatases may be involved in maintaining the expression of bcl-2 family genes as part of the survival machinery of the cell.
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PMID:Apoptosis of human myeloid leukemia cells induced by an inhibitor of protein phosphatases (okadaic acid) is prevented by Bcl-2 and Bcl-X(L). 920 72

Erythropoietin (EP) is required by late-stage erythroid progenitor cells to prevent apoptosis. Several lines of evidence suggest that it is this action of EP that regulates erythrocyte production in vivo. To study the control of apoptosis in mouse and human erythroblasts, the expression of members of the Bcl-2 family of proteins and the expression and activation of the apoptosis-linked cysteine protease Yama/CPP32/apopain were examined. These proteins have been implicated as regulators of apoptosis in several cell models. The Bcl-2 family members analyzed were Bcl-2, Bcl-X, Bax, Bad, Bak, A1, and Mcl-1. Bcl-X expression in proerythroblasts was highly EP-dependent. Bcl-X was strongly increased during the terminal differentiation stages of human and mouse erythroblasts, reaching maximum transcript and protein levels at the time of maximum hemoglobin synthesis. This increase in Bcl-X expression led to an apparent level of approximately 50 times the level in proerythroblasts. In contrast, neither mouse nor human erythroblasts expressed Bcl-2 transcript or protein. Bax and Bad proteins remained relatively constant throughout differentiation, but diminished near the time of enucleation. Bak protein was present in early erythroblasts, but diminished progressively during differentiation. EP deprivation in both mouse and human erythroblasts led to activation of the cysteine protease, apopain, as was indicated by cleavage of the proenzyme into its proteolytically active fragments. Apopain activation was detectable within 2 hours of EP deprivation in mouse erythroblasts. These findings suggest an important role for Bcl-X in late erythroid differentiation and for apopain in apoptosis of erythroblasts caused by deprivation of EP.
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PMID:The roles of Bcl-X(L) and apopain in the control of erythropoiesis by erythropoietin. 922 63

Retrograde degeneration of retinal ganglion cells as a consequence of optic nerve lesion has been shown to fulfil the criteria of apoptosis. In the present study, we investigated the time course of ganglion cell apoptosis following intraorbital crushing of the optic nerve in adult rats using morphological criteria and applying a terminal transferase technique (TUNEL) for in situ detection of DNA strand breaks. In addition, we examined expression patterns of the anti-apoptotic proteins Bcl-2 and Bcl-X and the cell death-promoting protein Bax in retinae after crushing the optic nerve. Apoptotic nuclei were detected in the ganglion cell layer in the first 3 weeks after optic nerve crush, with a peak after 6 days. Bcl-2 and Bcl-X proteins were expressed in ganglion cells at low levels. Expression of Bcl-2 decreased further during the days following crush. Bcl-X expression was initially increased, followed by a decline over the following days. In contrast, Bax protein, which was expressed in most ganglion cells at moderate baseline levels, was sharply increased as early as 30 min after crush, reached peak levels after 3 days, and remained up-regulated for at least 1 week thereafter. Double labelling for Bax and TUNEL in retinal sections, however, did not reveal colocalization of the two signals in individual retinal ganglion cells, consistent with the idea that increases in Bax precede apoptosis after optic nerve lesion. Thus, retinal ganglion cell death might be prevented by ablation of Bax protein in these cells, or by up-regulation of Bax-antagonists such as Bcl-2 or Bcl-X.
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PMID:Up-regulation of Bax protein in degenerating retinal ganglion cells precedes apoptotic cell death after optic nerve lesion in the rat. 928 31

The v-Rel oncoprotein belongs to the Rel/NF-kappaB family of transcription factors. It transforms chicken lymphoid cells in vitro and induces fatal lymphomas in vivo. In this study, we used a tetracycline-regulated system to characterize the role of v-Rel in cell transformation. We show that the continued expression of v-Rel is necessary to maintain the viability of transformed lymphoid cells and enables primary spleen cells to escape apoptosis in vitro culture. In agreement with a possible role for v-Rel in the inhibition of programmed cell death, its inducible expression in HeLa cells prevented TNFalpha-induced apoptosis. While the repression of v-Rel was accompanied by the rapid degradation of IkappaBalpha, changes in the steady-state levels of the apoptosis inhibitors Bcl-2 and Bcl-X(L) were only observed following the onset of cell death in transformed lymphoid cells. This suggests that the anti-apoptotic activity of v-Rel may affect other apoptosis inhibitors or other factors in the death pathway. Together, these findings demonstrate that v-Rel blocks apoptosis and suggest that this activity may be an important component of its transforming function.
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PMID:v-Rel prevents apoptosis in transformed lymphoid cells and blocks TNFalpha-induced cell death. 928 92

Galectin-3, a beta-galactoside-binding protein, has been shown to be involved in tumor progression and metastasis. Here, we demonstrate that expression of galectin-3 in human breast carcinoma BT549 cells inhibits cis-diamminedichloroplatinum (cisplatin)-induced poly(ADP-ribose) polymerase degradation and apoptosis, without altering Bcl-2, Bcl-X(L), or Bax expressions. Galectin-3 contains the NWGR amino acid sequence highly conserved in the BH1 domain of the bcl-2 gene family, and a substitution of glycine to alanine in this motif abrogated its antiapoptotic activity. Our findings demonstrate that galectin-3 inhibits apoptosis through a cysteine protease pathway and highlight the functional significance of the NWGR motif in apoptosis resistance of a non-Bcl-2 protein.
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PMID:Galectin-3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family. 939 48

Since apoptosis is observed in tuberculous granulomata, we investigated the molecular mechanisms underlying the apoptotic pathway in an in vitro model of mycobacterial infection of mononuclear phagocytes. We postulated that Mycobacterium tuberculosis could trigger the apoptotic pathway in macrophages, resulting in death of the microorganism by modulating the expression of bcl-2, bax, bcl-xL, and bcl-xS. We found that the mRNA of bcl-2, an inhibitor of apoptosis, was downregulated in peripheral blood monocytes (PBM) between 2 and 6 h following infection with M. bovis BCG or induction with heat-killed M. tuberculosis H37Ra. Western analysis showed a downregulation of the Bcl-2 protein, with a half-life of 24 h. At the same time points, there was no change in the expression of Bax or Bcl-xS, inducers of apoptosis, but Bcl-xL, another inhibitor of apoptosis, was minimally upregulated by BCG. To determine if apoptosis could be a mechanism for growth inhibition in vivo, we obtained alveolar macrophages by bronchoalveolar lavage from involved sites in patients with active pulmonary tuberculosis. Using the TUNEL (terminal deoxynucleotidyltransferase mediated nick end labeling) technique, we observed significantly more apoptosis in involved segments of five tuberculosis patients (14.8 +/- 1.9%) than in those of normal controls (<1%, P = 0.02) or in uninvolved segments (4.3 +/- 0.9%, P < 0.05). We conclude that apoptosis of mononuclear phagocytes induced by M. tuberculosis occurs in vivo and that in an in vitro model of mycobacterial infection, apoptosis may be mediated by downregulation of Bcl-2.
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PMID:Effects of mycobacteria on regulation of apoptosis in mononuclear phagocytes. 939 26

Intact endothelium acts as a sensor and transducer of signals and also provides a nonthrombogenic surface at the blood-vascular wall interface. Hence, mechanisms that maintain the integrity of the endothelium are of interest in physiological and pathological states. In this study we show that apoptosis induced by growth factor and serum deprivation of endothelial cells occurs at all phases of the cell cycle and can be blocked by fibroblast growth factor-2 (FGF-2) independently of its mitogenic activity. As the Bcl-2 family of proteins plays a prominent role in regulating cell survival, we attempted to identify Bcl-2 homologues expressed in endothelial cells. Here we demonstrate that, in addition to the previously identified A1, four other members of the Bcl-2 family, Bcl-2, Mcl-1, Bcl-X(L), and Bax, are expressed in endothelial cells. Of these family members, only Bcl-2 is induced by FGF-2. Overexpression of Bcl-2, using a retroviral vector, protects endothelial cells from serum and growth factor deprivation. There is no difference in FGF-2-induced proliferation between Bcl-2-overexpressing cells and those transduced with the empty retroviral vector. At early time points Bcl-2 is not up-regulated, but FGF-2 still has a protective effect. However, FGF-2 protects only adherent endothelial cells but not those that are cultured in suspension. The early effect of FGF-2 is dependent on tyrosine phosphorylation but not on activation of the MAP kinase pathway. Thus, FGF-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms.
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PMID:Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. 940 28

The BAD protein is a pro-apoptotic member of the Bcl-2 family whose ability to heterodimerize with survival proteins such as Bcl-X(L) and to promote cell death is inhibited by phosphorylation. Monoclonal antibodies were generated against the human BAD protein and used to evaluate its expression by immunoblotting and immunohistochemistry in normal human tissues and by immunoblot analysis of the National Cancer Institute anti-cancer drug screening panel of 60 human tumor cell lines. BAD protein was detectable by immunoblotting in many normal tissues, with testis, breast, colon, and spleen being among those with the highest steady-state levels. Immunostaining of tissues revealed many examples of cell-type-specific expression of BAD, suggesting dynamic regulation of BAD protein levels in vivo. In many types of normal cells, BAD immunoreactivity was associated with cytosolic organelles resembling mitochondria, suggesting that BAD is often heterodimerized with other Bcl-2 family proteins in vivo. The relative levels of BAD protein varied widely among established human tumor cell lines, with colon, lung, and melanomas generally having the highest expression. As a group, hematopoietic and lymphoid lines contained the least BAD protein. The BAD protein derived from 11 of 41 tumor lines that expressed this pro-apoptotic protein migrated in gels as a clear doublet, consistent with the presence of hyperphosphorylated BAD protein. Taken together, these findings define for the first time the normal cell-type-specific patterns of expression and intracellular locations of the BAD protein in vivo and provide insights into the regulation of this pro-apoptotic Bcl-2 family protein in human tumors.
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PMID:Expression and location of pro-apoptotic Bcl-2 family protein BAD in normal human tissues and tumor cell lines. 942 23

Recent evidence demonstrates that the proto-oncogene product, Bcl-2 can protect cells from a variety of cell death-inducing stimuli. Because previous studies have demonstrated that protein kinase (PK) pathways may be involved in the regulation of cell death, we tested various PK inhibitors for their effects on cell death in a dopaminergic neuronal cell line, MN9D, as well as the potential of Bcl-2 family members and structural mutants to block this process. Cells expressing either human Bcl-2 (MN9D/Bcl-2), or neomycin (MN9D/Neo; control cells) were treated with either staurosporine (0.25-2 microM) or trifluoperazine (10-100 microM). In control MN9D/Neo cells, both reagents led to a dose-dependent cell death with morphological features of apoptosis. Overexpression of Bcl-2 rescued cells from staurosporine-induced but not trifluoperazine-induced apoptotic cell death. Cell death induced by the specific PKC inhibitor, calphostin C was also significantly attenuated in MN9D/Bcl-2 cells indicating that a PKC pathway represents one mechanism by which Bcl-2 prevents staurosporine-induced cell death. Similarly, the Bcl-2 family member, Bcl-X(L) also blocked staurosporine-induced cell death in MN9D cells whereas overexpression of Bcl-X(S) or Bax did not. Finally, staurosporine-induced cell death was still blocked by the expression of clones encoding mutations in the Bcl-2 homology domains, BH1 and BH2, as well as C-terminally truncated Bcl-2. These data suggest that in the staurosporine-mediated cell death model Bcl-2 is not heterodimerizing to related proteins through these highly conserved structural domains nor does it need to be membrane-anchored. Thus, in this paradigm, either Bcl-2 functions as a homodimer or essential sequences lie outside of the BH1 or BH2 domains.
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PMID:Regions outside of the Bcl-2 homology domains, BH1 and BH2 protect a dopaminergic neuronal cell line from staurosporine-induced cell death. 942 15

The Bcl-2 family member Bcl-xL has often been correlated with apoptosis resistance. We have shown recently that in peripheral human T cells resistance to CD95-mediated apoptosis is characterized by a lack of caspase-8 recruitment to the CD95 death-inducing signaling complex (DISC) and by increased expression of Bcl-xL (Peter, M. E., Kischkel, F. C., Scheuerpflug, C. G., Medema, J. P., Debatin, K.-M., and Krammer, P. H. (1997) Eur. J. Immunol. 27, 1207-1212). This raises the possibility that Bcl-xL directly prevents caspase-8 activation by the DISC. To test this hypothesis a cell line in which CD95 signaling was inhibited by overexpression of Bcl-xL was used. In these MCF7-Fas-bcl-xL cells Bcl-xL had no effect on the recruitment of caspase-8 to the DISC. It did not affect the activity of the DISC nor the generation of the caspase-8 active subunits p18 and p10. In contrast, cleavage of a typical substrate for caspase-3-like proteases, poly(ADP-ribose) polymerase, was inhibited in comparison with the control-transfected CD95-sensitive MCF7-Fas cells. To test whether Bcl-xL would inhibit active caspase-8 subunits in the cytoplasm, a number of immunoprecipitation experiments were performed. Using monoclonal antibodies directed against different domains of caspase-8, anti-Bcl-xL antibodies, or fusion proteins of glutathione S-transferase with different domains of caspase-8, no evidence for a direct or indirect physical interaction between caspase-8 and Bcl-xL was found. Moreover, overexpression of Bcl-xL did not inhibit the activity of the caspase-8 active subunits p18/p10. Therefore, in this cell line that has become resistant to CD95-induced apoptosis due to overexpression of Bcl-xL, Bcl-xL acts independently and downstream of caspase-8.
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PMID:Bcl-xL acts downstream of caspase-8 activation by the CD95 death-inducing signaling complex. 945 59


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