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)

A random library of phage displayed peptides was screened for binding to a biotinylated derivative of paclitaxel (Taxol). Affinity-selected peptides were analyzed for similarity to human proteins. There was no significant similarity between the paclitaxel-selected peptides and tubulin. However, a subset of the peptides was identified that exhibits significant similarity to a non-conserved region of the anti-apoptotic human protein Bcl-2: ELISA assays confirmed binding of paclitaxel to Bcl-2, and circular dichroism spectroscopy demonstrated that a substantial conformational change accompanies this binding. In vivo, treatment with paclitaxel has been shown to lead to Bcl-2 inactivation with concomitant phosphorylation of residues in a disordered, regulatory loop region of the protein. Similarity between paclitaxel-selected peptides and this loop region implicate these residues in drug binding, and suggest that the apoptotic action of paclitaxel may involve the binding of paclitaxel to Bcl-2. These results demonstrate that peptides displayed on the surface of bacteriophage particles can mimic the ligand-binding properties of disordered regions of proteins.
J Mol Biol 1999 Jan 08
PMID:Screening of a library of phage-displayed peptides identifies human bcl-2 as a taxol-binding protein. 987 99

The cytosolic factor Cif (cytochrome c-efflux inducing factor) was activated by the apoptosis inducers staurosporine and anti-Fas antibodies and rapidly induced the efflux of cytochrome c from purified human mitochondria. HL-60 cells that stably overexpressed a bcl-2 cDNA transgene (Bcl-2:HL-60 cells) contained mitochondria and a cytosol that were resistant to exogenous Cif and that lacked detectable endogenous Cif activity, respectively. Therefore, Bcl-2 overexpression negated Cif activity and suggested that the requirement for Cif resides upstream of Bcl-2 on the apoptotic signal transduction pathway. The addition of purified caspase 3, caspase 7, or caspase 8 to the cytosolic extract from Bcl-2:HL-60 cells, however, restored Cif activity, demonstrating that the inhibition of Cif by Bcl-2 overexpression could be overcome by activated caspases. Moreover, the addition of purified caspases to cytosolic extracts prepared from parental HL-60 cells was also sufficient to cause Cif activation, suggesting that caspases might be required for Cif activation. Consistent with these observations, Fas-induced apoptosis in Jurkat cells resulted in caspase 8 activation and subsequently in activation of Cif. Finally, we demonstrate that the activation of Cif correlated with the activation of the Bcl-2 family member Bid by caspases and that Cif activity was selectively neutralized by anti-Bid antibodies. Taken together, these results indicate that Cif is identical to Bid and that it can be inhibited by Bcl-2 and activated by caspases. Thus, Cif (Bid) is an important biological regulator for the transduction of apoptotic signals.
Mol Cell Biol 1999 Feb
PMID:Cif (Cytochrome c efflux-inducing factor) activity is regulated by Bcl-2 and caspases and correlates with the activation of Bid. 989 Oct 71

Although p53 has been shown to directly activate transcriptional bax gene and to inhibit expression of bcl-2 gene during radiation-induced apoptosis, it is poorly understood how the Bcl-2 family changes in p53-deficient cells during radiation-induced apoptosis. The present work describes the effect of X-irradiation on the apoptosis of p53-deficient HL-60 cells as assessed by means of several methods. Apoptosis of HL-60 cells was induced by X-irradiation in a dose- and time-dependent manner. 18 h after 5 Gy irradiation, G2 cells underwent apoptosis, while 15 Gy X-irradiation induced the death of G1/S cells by 6 h. After X-irradiation, expression of Bcl-2 was elevated, while Bax expression was unchanged. We have isolated a clonal HL-60 variant following twice 5 Gy irradiation of HL-XR3 cells. These cells highly expressed Bcl-2 (about 2-fold), showed a reduced activation of caspase-3, and were not only more resistant to X-irradiation-induced apoptosis but also more radioresistant. These results suggest that HL-60 cells may resist apoptosis and radiation by increasing Bcl-2 expression, and that this elevated Bcl-2 expression might be one of the causes of the phenomenon, often seen clinically, that tumor cells gradually acquire radioresistance during fractionated radiation therapy.
Int J Mol Med 1999 Feb
PMID:X-irradiation enhances the expression of Bcl-2 in HL-60 cells: the resulting effects on apoptosis and radiosensitivity. 991 21

Apoptosis is an active cell 'suicide' essential for the elimination of superfluous cells during diverse physiological processes in essentially all animal species. Although regulation of apoptosis by extracellular mediators is cell type-specific, new insights based on characterization of conserved intracellular effectors have suggested that intracellular pathways leading to apoptosis in diverse organisms is regulated by a group of evolutionarily conserved genes including ced-9/Bcl-2, ced-4/Apaf-1 and ced3/caspases gene families. To study whether the Bcl-2 family proteins are important in the regulation of ovarian cell apoptosis, we have used transgenic mice and yeast 2-hybrid protein protein interaction assay to characterize the roles of Bcl-2 family proteins in ovarian atresia. The use of 2-hybrid analysis resulted in the isolation of a novel pro-apoptotic Bcl-2 protein, Bcl-2-related ovarian killer (Bok) and the identification of upstream mediators for ovarian cell apoptosis.
Mol Cell Endocrinol 1998 Oct 25
PMID:Intracellular mechanisms of ovarian cell apoptosis. 992 95

Loss of the Epstein-Barr virus (EBV) genome from Akata Burkitt lymphoma (BL) cells is coincident with a loss of malignant phenotype, despite the fact that Akata and other EBV-positive BL cells express a restricted set of EBV gene products (type I latency) that are not known to overtly affect cell growth. Here we demonstrate that reestablishment of type I latency in EBV-negative Akata cells restores tumorigenicity and that tumorigenic potential correlates with an increased resistance to apoptosis under growth-limiting conditions. The antiapoptotic effect of EBV was associated with a higher level of Bcl-2 expression and an EBV-dependent decrease in steady-state levels of c-MYC protein. Although the EBV EBNA-1 protein is expressed in all EBV-associated tumors and is reported to have oncogenic potential, enforced expression of EBNA-1 alone in EBV-negative Akata cells failed to restore tumorigenicity or EBV-dependent down-regulation of c-MYC. These data provide direct evidence that EBV contributes to the tumorigenic potential of Burkitt lymphoma and suggest a novel model whereby a restricted latency program of EBV promotes B-cell survival, and thus virus persistence within an immune host, by selectively targeting the expression of c-MYC.
Mol Cell Biol 1999 Mar
PMID:Epstein-barr virus regulates c-MYC, apoptosis, and tumorigenicity in Burkitt lymphoma. 1002 53

Several cardioprotective proteins are induced during myocardial ischemia, such as heat shock proteins and anti-apoptotic Bcl-2-related proteins which, when experimentally overexpressed, have been shown to prevent ischemia-induced myocyte loss. As this pathophysiological induction is obviously not sufficient to prevent losses of myocytes, we analysed whether it could occur under moderate myocardial ischemia with hibernation, thus potentially contributing to myocyte protection under these conditions. Therefore, using anesthetized pigs with documented myocardial hypoperfusion and short-term hibernation, we investigated the left ventricular mRNA expression of the inducible heat shock protein Hsp70 and of the anti-apoptotic Bcl-XL in comparison with the pro-apoptotic Bak and Fas expression. For transcriptional analyses, the porcine cDNA sequences of Bcl-XL, Bak and Fas were identified by polymerase chain reaction (PCR) or by screening of a porcine heart cDNA library and cloned. Using reverse transcription polymerase chain reaction (RT-PCR), we observed an unchanged mRNA expression of inducible Hsp70, Bcl-XL, Bak and Fas after 85 min of hypoperfusion in the short-term hibernating myocardium, as well as after 30 min of subsequent reperfusion in the stunned myocardium, compared with transcription in a non-hypoperfused control area of the same ventricle. In conclusion, the mRNA expression of inducible Hsp70 and of several apoptosis-modulating proteins is not altered during moderate myocardial ischemia resulting in short-term hibernation of the affected area and during subsequent stunning.
J Mol Cell Cardiol 1999 Jan
PMID:Quantification of cardioprotective gene expression in porcine short-term hibernating myocardium. 1007 23

Bcl-xL, a member of the Bcl-2 family, inhibits apoptosis, and its expression is regulated at the transcriptional level, yet nothing is known about the transcription factors specifically activating this promoter. The bcl-x promoter contains potential Ets binding sites, and we show that the transcription factor, Ets2, first identified by its sequence identity to v-ets of the E26 retrovirus, can transactivate the bcl-x promoter. Transient expression of Ets2 results in the upregulation of Bcl-xL but not of Bcl-xS, an alternatively spliced gene product which induces apoptosis. Ets2 is ubiquitously expressed at low levels in a variety of cell types and tissues but is specifically induced to abundant levels during macrophage differentiation. Since Bcl-xL is also upregulated during macrophage differentiation, we asked whether the bcl-x could be a direct downstream target gene of Ets2 in macrophages. BAC1.2F5 macrophages, which are dependent on macrophage colony-stimulating factor 1 (CSF-1) for their growth and survival, were used in these studies. We show that CSF-1 stimulation of BAC1.2F5 macrophages results in the upregulation of expression of ets2 and bcl-xL with similar kinetics of induction. In the absence of CSF-1, these macrophages undergo cell death by apoptosis, whereas constitutive expression of Ets2 rescues these cells from cell death, and bcl-xL is upregulated. These results strongly suggest a novel role of Ets2 in affecting apoptosis through its regulation of Bcl-xL transcription.
Mol Cell Biol 1999 Apr
PMID:The Ets2 transcription factor inhibits apoptosis induced by colony-stimulating factor 1 deprivation of macrophages through a Bcl-xL-dependent mechanism. 1008 28

The Bcl-2 family has been shown to be vital regulators of programmed cell death in numerous systems. To investigate the role of such proteins in the regulation of apoptosis of eosinophils, the expression of Bcl-2 and homologues Bcl-xL (death antagonists), Bax, and Bcl-xS (death agonists) were examined by immunoblot, flow cytometry, and reverse transcriptase-polymerase chain reaction analysis. Potential modulation of apoptosis-associated molecules during spontaneous apoptosis and in the presence of interleukin (IL)-5 was also investigated. Peripheral blood eosinophils were found to express constitutively Bax and Bcl-x, but Bcl-2 was absent. Analysis of mRNA revealed that the bcl-xL isoform predominated, although bcl-xS was also detectable. Spontaneous apoptosis due to culturing in the absence of cytokines for 24 h did not result in modulation of any of the Bcl-2 homologues examined. Culturing eosinophils in the presence of 100 pg/ml IL-5 for 24 h significantly reduced apoptosis (P < 0.01) to 10.7 +/- 2.6% compared with 46.8 +/- 7.4% in the absence of IL-5, and induced Bcl-2 mRNA and protein expression, with no detectable change in Bax, Bcl-x, or beta-actin as a control. This investigation indicates a specific profile of apoptotic molecules in eosinophils distinct from that of neutrophils, and indicates that survival-enhancing IL-5 modulates the expression of Bcl-2 in vitro.
Am J Respir Cell Mol Biol 1999 Apr
PMID:Expression of Bcl-2 and its homologues in human eosinophils. Modulation by interleukin-5. 1010 Oct 4

Retinal ganglion cells die by apoptosis following axotomy. The molecular mechanisms of the retinal ganglion cell death are not well understood. In the present study using RT-PCR and in situ hybridization techniques we demonstrated that levels of mRNA for Bcl-2 and Bcl-x decreased after axotomy. Bax levels remained high until 4 days after axotomy, decreased by day 7 and remained low up to day 10. CPP32 levels increased at day 7 and remained high after optic nerve cut. We studied whether inhibitors of CPP32/caspase would save the axotomy induced ganglion cell death. DEVD-CHO (Ac-Asp-Glu-Val-aspartic acid aldehyde) and DEVD-FMK (Z-Asp-Glu-Val-Asp-FMK), caspase inhibitors, when administered intraocularly at the time of optic nerve cut, at days 3 and 7 protect about 30-35% the ganglion cells from death. We further demonstrated that the number of reactive microglia decrease in the retina when the inhibitors were given as compared with retina where no inhibitors were given. The present data offers new avenues for studying the complex interactions between the retinal ganglion cell death and the activation of resident microglia/macrophages.
Brain Res Mol Brain Res 1999 Apr 06
PMID:Caspase inhibitors block the retinal ganglion cell death following optic nerve transection. 1010 Dec 30

Bcl-2 family members that have only a single Bcl-2 homology domain, BH3, are potent inducers of apoptosis, and some appear to play a critical role in developmentally programmed cell death. We examined the regulation of the proapoptotic activity of the BH3-only protein Bim. In healthy cells, most Bim molecules were bound to LC8 cytoplasmic dynein light chain and thereby sequestered to the microtubule-associated dynein motor complex. Certain apoptotic stimuli disrupted the interaction between LC8 and the dynein motor complex. This freed Bim to translocate together with LC8 to Bcl-2 and to neutralize its antiapoptotic activity. This process did not require caspase activity and therefore constitutes an initiating event in apoptosis signaling.
Mol Cell 1999 Mar
PMID:The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. 1019 31


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