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 anti-cancer drug taxol is known to bind to and induce the polymerization of tubulin and has recently been shown to bind to the anti-apoptotic protein Bcl-2, but not to its homolog, Bcl-XL. Libraries of random peptides displayed on the surface of a bacteriophage were screened to select those exhibiting affinity for taxol. The sequences of these peptides were compared to sequences of proteins involved in mitosis and apoptosis. No significant similarities were detected between the sequences of tubulins and the taxol-selected peptides. However, a high level of similarity exists between the selected peptides and the disordered loop of Bcl-2. Conversely, there was little similarity between the sequences of the selected peptides and Bcl-XL. These results indicate that peptides displayed on the surface of a bacteriophage can mimic the ligand-binding behavior of a disordered protein loop and that comparison of the sequences of affinity-selected peptides with protein sequences can be predictive for ligand binding.
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PMID:Similarity between the sequences of taxol-selected peptides and the disordered loop of the anti-apoptotic protein, Bcl-2. 1038 Feb 25

Serum deprivation of Ha-ras-transformed brown adipocyte cell line resulted in a dramatic apoptotic cell death, as detected either by DNA laddering or by an increase in the percentage of hypodiploid cells or by nuclei condensation and fragmentation, as compared with immortalized cell line or primary fetal brown adipocytes. Moreover, transient transfection of immortalized brown adipocytes with a constitutively active ras gene (Ha-raslys12) mimics the high rate of apoptosis detected in the transformed cell line. On the other hand, transient transfection of the dominant-negative construct of raf-1 rescued serum-deprived Ha-ras-transformed brown adipocytes from apoptosis, decreasing the percentage of hypodiploid cells, the external display of phosphatidylserine, and the DNA laddering. However, inhibition of mitogen-activated protein kinase with PD098059 did not preclude apoptosis and in fact increased the rate of apoptosis observed in serum-deprived Ha-ras-transformed cells, indicating that the Ras/Raf-1 pathway induced apoptosis throughout a mitogen-activated protein kinase kinase 1 (MEK-1)-independent pathway. Furthermore, apoptosis in Ha-ras-transformed brown adipocytes is concurrent with an up-regulation in the expression of the pro-apoptotic protein Bcl-xS, the expression of the anti-apoptotic protein Bcl-2 being down-regulated. Finally, an association of Ras and Raf with phosphorylated Bcl-2 protein was demonstrated in immunoprecipitates from apoptotic cells. Thus, we propose a mechanism of apoptosis in Ha-ras-transformed adipocytes under serum deprivation involving Raf-1 association with phosphorylated Bcl-2, down-regulation of Bcl-2 expression, and up-regulation of Bcl-xS expression.
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PMID:Activated Ha-ras induces apoptosis by association with phosphorylated Bcl-2 in a mitogen-activated protein kinase-independent manner. 1038 81

Huntington's disease (HD) is a hereditary neurodegenerative disorder presenting with chorea, dementia, and extensive striatal neuronal death. The mechanism through which the widely expressed mutant HD gene mediates a slowly progressing striatal neurotoxicity is unknown. Glutamate receptor-mediated excitotoxicity has been hypothesized to contribute to the pathogenesis of HD. Here we show that transgenic HD mice expressing exon 1 of a human HD gene with an expanded number of CAG repeats (line R6/1) are strongly protected from acute striatal excitotoxic lesions. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neuronal death in wild-type mice, but no damage in transgenic HD littermates. The remarkable neuroprotection in transgenic HD mice occurred at a stage when they had not developed any neurological symptoms caused by the mutant HD gene. At this stage there was no change in the number of striatal neurons and astrocytes in untreated R6/1 mice, although the striatal volume was decreased by 17%. Moreover, transgenic HD mice had normal striatal levels of NMDA receptors, calbindin D28k (calcium buffer), superoxide dismutase activity (antioxidant enzyme), Bcl-2 (anti-apoptotic protein), heat shock protein 70 (stress-induced anti-apoptotic protein), and citrate synthase activity (mitochondrial enzyme). We propose that the presence of exon 1 of the mutant HD gene induces profound changes in striatal neurons that render these cells resistant to excessive NMDA receptor activation.
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PMID:Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. 1041 43

Erythropoietin (Epo) initiates its cellular response by binding to the Epo receptor, which triggers the activation of signal transducer and activator of transcription (Stat) 5 protein. Cell culture studies of erythroid progenitors have suggested that Epo functions as a survival factor by repressing apoptosis at least in part through Bcl-x(L), an anti-apoptotic protein of the Bcl-2 family. In this report, we examine whether Stat5 can induce transactivation of the bcl-x gene in response to Epo. Two Epo-responsive progenitor cell lines, HCD-57 and Bcl-2-transfected Ba/F3-Epo receptor (Ba/F3-EpoR-Bcl-2), were used in this study. After Epo stimulation, we observed a correlation between expression of bcl-x(L) and activation of Stat5 as assessed by the expression of oncostatin M, a direct target of Stat5, and the phosphorylation and nuclear translocation of Stat5. Moreover, a Stat binding element in the bcl-x promoter was found to be active in response to Epo, a finding that was further confirmed because mutagenesis of this sequence motif abrogated its promoter activity and overexpression of a dominant negative Stat5 protein blocked transactivation. When DNA-protein binding analyses were performed, we found that Stat5, not Stat1 or Stat3, was the protein bound to the bcl-x promoter in response to Epo. These data suggest that Epo-dependent activation of Stat5 is a transcriptional pathway that can be used by Epo-responsive progenitor cells to induce the expression of bcl-x(L) and consequently to inhibit apoptosis.
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PMID:Erythropoietin can induce the expression of bcl-x(L) through Stat5 in erythropoietin-dependent progenitor cell lines. 1042 80

Two pro-apoptotic proteases, caspase-1 and caspase-3, have been expressed as full-length proteins in the fission yeast Schizosaccharomyces pombe. Both proteins autoprocess to generate the corresponding active enzyme and both are lethal to the yeast cell. Lethality is due to catalytic activity since the expression of the inactive mutant forms of both caspases does not result in an obvious phenotype. Caspase-expressing yeast can be rescued by co-expression of the baculovirus protein p35, a known inhibitor of the caspase family. Co-expression of Bcl-2, another anti-apoptotic protein, does not prevent the cell death induced by either caspase. However, Bcl-2 is itself cleaved by both caspase-1 and caspase-3 at two adjacent recognition sites, YEWD(31')A and DAGD(34')V respectively, immediately downstream from the N-terminal BH4 domain, a region of Bcl-2 which is essential for its anti-apoptotic activity; similar cleavage of Bcl-2 by caspases has been demonstrated in mammalian cells. Hence, key elements of the apoptotic pathway can be reliably reconstituted in fission yeast, opening the way to exploit yeast in order to study the control of apoptosis. Furthermore, the activity of caspase-3, although not caspase-1, can be demonstrated in vitro using chromogenic substrates. This offers the possibility of using caspase-producing strains of yeast to screen for chemical inhibitors either in vivo or in vitro.
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PMID:Reconstitution of caspase-mediated cell-death signalling in Schizosaccharomyces pombe. 1044 91

The Bcl-2 family of proteins regulates apoptosis, the cell death program triggered by activation of certain proteases (caspases). An attractive model for how Bcl-2 and its closest relatives prevent caspase activation is that they bind to and inactivate an adaptor protein required for procaspase processing. That model has been supported by reports that mammalian prosurvival Bcl-2 relatives bind the adaptor Apaf-1, which activates procaspase-9. However, the in vivo association studies reported here with both overexpressed and endogenous Apaf-1 challenge this notion. Apaf-1 could be immunoprecipitated together with procaspase-9, and the Apaf-1 caspase-recruitment domain was necessary and sufficient for their interaction. Apaf-1 did not bind, however, to any of the six known mammalian prosurvival family members (Bcl-2, Bcl-x(L), Bcl-w, A1, Mcl-1, or Boo), or their viral homologs adenovirus E1B 19K and Epstein-Barr virus BHRF-1. Endogenous Apaf-1 also failed to coimmunoprecipitate with endogenous Bcl-2 or Bcl-x(L), or with two proapoptotic relatives (Bax and Bim). Moreover, apoptotic stimuli did not induce Apaf-1 to bind to these family members. Thus, the prosurvival Bcl-2 homologs do not appear to act by sequestering Apaf-1 and probably instead constrain its activity indirectly.
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PMID:Bcl-2 family members do not inhibit apoptosis by binding the caspase activator Apaf-1. 1044 54

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare and uniformly fatal disorder of early childhood characterized by fever, hepatosplenomegaly, cytopenia and widespread infiltration of vital organs by activated lymphocytes and macrophages. In order to test whether the massive accumulation of immune cells in these patients is associated with a perturbation of apoptosis, lymphocytes were isolated from eight patients and subjected to the chemotherapeutic agent etoposide or agonistic anti-Fas monoclonal antibodies in vitro. These stimuli elicited a normal apoptotic response in FHL patient cells when compared to healthy controls, as determined by phosphatidylserine exposure, DNA fragmentation, in vitro cleavage of the caspase-3-like substrate aspartate-glutamate-valine-aspartate-7-amino-4-methyl-coumarin (DEVD-AMC) and proteolysis of the anti-apoptotic protein Bcl-2. In addition, the degree of constitutive and Fas-triggered apoptosis in freshly isolated neutrophils was monitored in three children, with similar results. These studies indicate that immune cells derived from FHL patients are not inherently resistant to apoptosis induction. Specifically, etoposide-induced and Fas-triggered activation of intracellular caspases appears to remain intact in these individuals. However, the degree of spontaneous activation of caspase-3-like enzymes in activated lymphocytes was attenuated in three of the four patients tested prior to initiation of therapy, suggesting a possible biological deficiency in these individuals.
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PMID:Induction of apoptosis and caspase activation in cells obtained from familial haemophagocytic lymphohistiocytosis patients. 1046 May 99

BAG-1 is an anti-apoptotic protein that interacts with Bcl-2, Bcl-XL, Hsp70/Hsc70, Raf-1 and numerous hormone or growth factor receptors. Recently, BAG-1 has been found to be overexpressed in a variety of human cancer cell lines and some tumors. However, the molecular mechanism of BAG-1 upregulation is still unclear. In this study, we cloned 0.9 kb of human genomic DNA, BGEV, 5' flanking the BAG-1 open reading frame. BGEV subcloned into a promoterless luciferase reporter vector conferred high promoter activity in various human cancer cell lines. Deletion analysis of this sequence localized the region of maximal BAG-1 promoter activity from nucleotide positions -353 to -54, upstream of the first start codon CTG. Sequence analysis of the BAG-1 promoter region showed the absence of a TATA box but identified a CCAAT box, several GC boxes, a CpG island and several transcriptional factor binding sites, which may be important in the regulation of BAG-1 transcription. Most importantly, functional characterization of the BAG-1 promoter in vivo demonstrated that gain-of-function p53 mutants derived from human tumors upregulated the transcription of BAG-1 RNA and the expression of a reporter gene from the BAG-1 promoter. These results indicated that we have isolated the functional constitutive BAG-1 promoter. Furthermore, the data suggested that overexpression of BAG-1 in some tumors may be due to upregulation of the human BAG-1 promoter by mutant p53.
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PMID:Cloning and characterization of the human BAG-1 gene promoter: upregulation by tumor-derived p53 mutants. 1046 99

Retinal ganglion cells of transgenic mice overexpressing the anti-apoptotic protein Bcl-2 in neurons show a dramatic increase of survival rate after axotomy. We used this experimental system to test the regenerative potentials of central neurons after reduction of nonpermissive environmental factors. Survival of retinal ganglion cells 1 month after intracranial crush of the optic nerve was found to be 100% in adult bcl-2 mice and 44% in matched wild-type (wt) mice. In the optic nerve, and particularly at the crush site, fibers regrowing spontaneously or simply sprouting were absent in both wt and bcl-2 mice. We attempted to stimulate regeneration implanting in the crushed nerves hybridoma cells secreting antibodies that neutralize central myelin proteins, shown to inhibit regeneration (IN-1 antibodies) (Caroni and Schwab, 1988). Again, we found that regeneration of fibers beyond the site of crush was virtually absent in the optic nerves of both wt and bcl-2 mice. However, in bcl-2 animals treated with IN-1 antibodies, fibers showed sprouting in the proximity of the hybridoma implant. These results suggest that neurons overexpressing bcl-2 are capable of surviving axotomy and sprout when faced with an environment in which inhibition of regeneration has been reduced. Nevertheless, extensive regeneration does not occur, possibly because other factors act by preventing it.
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PMID:Optic nerve crush: axonal responses in wild-type and bcl-2 transgenic mice. 1049 38

Activation of the N-ras gene by point mutation occurs in about 15% of all human melanomas. In recently established severe combined immunodeficiency (SCID) mouse xenotransplantation models for human melanoma, we demonstrated that mutated N-ras not only contributes to tumour growth by enhancing cellular proliferation, but also by blocking apoptosis. Mutated N-ras overexpression protected human melanomas from naturally occurring apoptosis and, in a more pronounced way, from chemotherapy-induced apoptosis in vitro and in vivo. Given the potential clinical importance of these findings we sought to determine the underlying mechanism. We found that mutated N-ras specifically upregulates the expression of the anti-apoptosis gene bcl-2 in two human melanoma cell lines in vitro and in SCID mice. Neither the expression of the anti-apoptotic protein Bcl-xL nor that of the pro-apoptotic proteins Bax and Bak were altered in cells expressing mutated N-Ras. The increase in Bcl-2 expression mediated by mutated ras therefore qualifies as a rational explanation for the enhanced chemoresistance of human melanoma expressing mutated N-Ras.
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PMID:Mutated N-ras upregulates Bcl-2 in human melanoma in vitro and in SCID mice. 1050 52


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