Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenovirus E1B 19-kDa protein (19K) is a member of the Bcl-2 family of suppressors of apoptosis. The suppressors function through heterodimerization with the death promoters, Bax and related proteins, thus establishing a set point within the cell that determines whether or not apoptosis is executed in response to a death signal. Sequence similarities between 19K and Bcl-2 are largely restricted to short Bcl-2 homology (BH) domains that mediate interaction with Bax. The BH1 sequence in 19K is degenerate but nevertheless contains a conserved glycine residue found in all family members that when mutated to alanine in Bcl-2 results in loss of Bcl-2 function and ability to dimerize with Bax (Yin, X.-M., Oltvai, Z. N., and Korsmeyer, S. J. (1994) Nature 369, 321-323). Here, we show that the analogous mutation in BH1 of 19K also abrogates the anti-apoptotic properties of 19K and its ability to interact with Bax, thus establishing the critical importance of this residue within BH1 and the likely similarity of Bcl-2 and 19K function. In distinct contrast to Bcl-2, however, 19K interaction was not detected with Bad, a Bcl-2/Bcl-XL dimerizing protein that can potentially regulate a Bax middle dotBcl-2/Bcl-XL survival set point and reinstate susceptibility to a death signal. Furthermore, the anti-apoptotic function of 19K was not overcome by enforced expression of Bad in transfected cells. This feature of 19K may provide adenovirus with a selective advantage in evading premature induction of apoptosis by the host cell.
J Biol Chem 1996 Sep 27
PMID:Adenovirus E1B 19-kDa death suppressor protein interacts with Bax but not with Bad. 879 65

The retroviral oncoprotein v-Rel is a member of the Rel/ NF-kappa B family of transcription factors. We have previously characterized two v-Rel mutants (v-G37E and v-R273H) that are temperature-sensitive (ts) for transformation and immortalization of chicken spleen cells in vitro. We have now constructed vectors for the co-expression of wild-type or ts mutant v-Rel proteins and the anti-apoptosis proteins Bcl-2 or CrmA. The formation of v-Rel-transformed colonies is enhanced in the presence of overexpressed Bcl-2. Moreover, co-expression of Bcl-2 suppresses apoptosis that is induced when ts v-Rel-transformed cells are shifted to the non-permissive temperature. However, co-expression of Bcl-2 in these cells does not affect ts functions of v-Rel, such as DNA binding and stabilization of I kappa B-alpha. In contrast, co-expression of CrmA does not suppress apoptosis, but does block an amino-terminal proteolysis of I kappa B-alpha that occurs in ts v-G37E-transformed cells shifted to the nonpermissive temperature, indicating that an ICE-like protease activity is not involved in apoptosis in these cells but is involved in proteolysis of I kappa B-alpha. In addition, CrmA can block cycloheximide-induced amino-terminal processing of I kappa B-alpha in spleen cells transformed by wild-type v-Rel. In summary, these results suggest that v-Rel immortalizes chicken spleen cells through a pathway that involves the Bcl-2 family of proteins, and suggest that one pathway of proteolysis of I kappa B-alpha involves an ICE-like protease.
Oncogene 1996 Sep 05
PMID:Bcl-2 and CrmA have different effects on transformation, apoptosis and the stability of I kappa B-alpha in chicken spleen cells transformed by temperature-sensitive v-Rel oncoproteins. 880 78

The proto-oncogene c-myc has been implicated in both cellular proliferation and apoptosis, and we have shown that overexpression of c-myc can induce polycystic kidney disease in transgenic mice. To elucidate the molecular and cellular defects underlying cystogenesis, we have investigated the potential roles of cell proliferation and apoptosis as they relate to c-myc and modulators of c-myc function in human autosomal dominant polycystic kidney disease (ADPKD). Renal c-myc expression was consistently elevated, up to 15-fold, in ADPKD. High levels of c-myc expression correlated with 10- to 100-fold increased proliferation index in cystic epithelium. Interestingly, steady-state levels of bcl-2 mRNA were also increased up to 20-fold and Bcl-2 protein was markedly elevated. In contrast, the expression of bax and p53 was virtually unchanged. However, apoptosis was consistently and significantly increased in ADPKD kidneys, unchecked by high levels of Bcl-2. Together with proliferation, apoptosis may thus represent a general mechanism for cyst growth and tissue remodeling. We conclude that both epithelial cell proliferation and apoptosis required for normal kidney homeostasis are deregulated in ADPKD, recapitulating the renal developmental program. Furthermore, abnormal expression of proto-oncogenes regulating these processes is an important mediator of cystogenesis in human ADPKD.
Oncogene 1996 Sep 19
PMID:Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD). 880 89

Activation-induced apoptosis is a primary mechanism for downmodulation of an immune response leading to immune homeostasis and deletion of T cells with specificities which may be harmful. These include deletion of T cells with self-specificities (autospecific) and excessively high affinity for foreign antigen which may lead to an excessively heightened immune response and septic shock. Surface molecules involved in activation-induced apoptosis involve Fas and Fas ligand (FasL), as well as the T-cell receptor (TCR) which modulates the expression and function of these molecules. Fas signaling mechanisms include the hematopoietic cell phosphatase (HCP) and sphingomyelinase, while TCR-signaling mechanisms include Nur77 and fyn kinase and unknown molecules that modulate expression of FasL. Apoptosis signals are further modulated by inhibitors or inducers of apoptosis including Bcl-2, p53, and interleukin-1 beta converting enzyme (ICE). Further understanding of the interaction of these molecules in autoimmune disease may lead to more specific therapies for immunosuppression tailored to the genetic or environmentally induced, activation-induced apoptosis defect in patients.
Clin Immunol Immunopathol 1996 Sep
PMID:The role of programmed cell death as an emerging new concept for the pathogenesis of autoimmune diseases. 881 Oct 58

This study investigates the main functional features of subepithelial (SE) B cells and compares them with those of purified germinal center (GC) and follicular mantle (FM) B cells isolated from the same tonsils. Unlike FM B cells, SE B cells failed to produce polyspecific antibodies in vitro; unlike GC B cells, SE B cells expressed high levels of Bcl-2 and failed to undergo spontaneous apoptosis in vitro. The most striking function of SE B cells was their ability to produce IgM antibodies to T cell-independent type-2 (TI-2) (but not to TI-1) antigens (Ag). These antibodies could not be detected when both FM and GC B cells were stimulated with TI-2 Ag in vitro. Moreover, B cells isolated from peripheral blood were unable to mount a response to TI-2 Ag. The latter finding is consistent with the observation that B cells with the phenotypic features of SE B cells were virtually absent in the peripheral blood and emphasizes the notion that SE B cells belong to a subset of non-recirculating B cells. SE B cells were by far superior to FM B cells in mixed lymphocyte reaction (MLR) stimulation of allogeneic T cells in vitro, although they were not as efficient as dendritic cells (DC). In order to stimulate T cells efficiently, SE B cells had to be exposed to anti-mu antibody, a treatment which induced expression of activation markers such as CD80, CD86, CD69 and CD39, usually absent in resting SE B cells. CD80 and CD86 molecules expressed by SE B cells participated in the chain of events required to promote the proliferation of allogeneic T cells as demonstrated by inhibition tests with the appropriate mAb. The expression of CD80 and CD86 by anti-mu-treated SE B cells was not, however, the sole explanation for their good antigen presenting capacities since the exposure of FM B cells to anti-mu antibody also induced expression of these surface structures. Nevertheless, these cells failed to become good MLR stimulators. Collectively, the above data contribute further to the characterization of a distinct subset of tonsillar B cells which resemble, both phenotypically and functionally, the B cells of the splenic marginal zone.
Eur J Immunol 1996 Sep
PMID:Subepithelial B cells in the human palatine tonsil. II. Functional characterization. 881 44

The capacity to be recognized and engulfed by phagocytes is an important characteristic of cells dying by apoptosis. Phagocytosis of apoptotic cells occurs rapidly in vivo, probably prior to plasma membrane breakdown. While the molecular mechanisms mediating phagocytosis of apoptotic cells are beginning to be defined, little is yet known of the relationship between the cell-death program itself and the surface changes on the dying cells that signal for engulfment. Here, we investigate to what extent the apoptosis repressor Bcl-2 can modulate the recognition and phagocytosis of human B cells exposed to triggers of apoptosis. Burkitt lymphoma (BL)-derived, Bcl-2- B cells were induced into apoptosis either by the Ca(2+)-ionophore ionomycin or by the inhibitor of protein synthesis cycloheximide. Apoptotic BL cells, but not viable BL cells, were recognized and phagocytosed by monocyte-derived macrophages. bcl-2-transfected BL populations showed a reduced capacity both to undergo apoptosis in response to these inducing agents and to interact with macrophages. Like their Bcl-2- counterparts, Bcl-2+ BL cells interacted with macrophages only after activation of their apoptotic program as assessed by changes in nuclear morphology. These results demonstrate not only that continued protein synthesis in B cells undergoing apoptosis is not essential for their recognition by macrophages, but also that macrophage recognition of apoptotic B cells cannot be uncoupled from the cell-death program that is controlled by Bcl-2. In this respect, the behavior of B cells contrasts markedly with that of neutrophils in which Bcl-2 has been reported to inhibit apoptosis without affecting phagocytic clearance.
Eur J Immunol 1996 Sep
PMID:Bcl-2 delays macrophage engulfment of human B cells induced to undergo apoptosis. 881 73

This study further investigated the mechanisms that control apoptosis in leukaemic CD5+ B cells, and focused on the Bcl-2 gene family. The pattern of expression of Bcl-2, Bcl-xL, Bcl-xS and Bax genes, selected because of their interrelated role in the control of apoptosis, was analysed in a series of CD5+ B-cell chronic lymphoid leukaemias. Cells from 34 patients with chronic lymphoid leukaemia of B-cell type (23 B-chronic lymphocytic leukaemia (B-CLL) and 11 mantle cell lymphoma (MCL) in leukaemic phase) were investigated. High levels of Bcl-2 mRNA were observed by Northern blot and high levels of Bcl-2 protein were detected by cytofluorograph analysis with a specific monoclonal antibody (MAb) in all cases. Strong Bax expression was detected by RT-PCR in 20/23 B-CLL cases; Bax was also observed in 8/11 MCL in leukaemic phase with variable degree of intensity. In both B-CLL and MCL samples the presence of Bax protein was confirmed by cytofluorograph analysis. RT-PCR detected high levels of Bcl-xL in 16/23 B-CLL and in 8/11 MCL in leukaemic phase, whereas Bcl-xS was detectable in low to trace amounts respectively in 13/23 B-CLL and in 6/11 MCL in leukaemic phase. According to the functional role of Bcl-2, Bcl-xL, Bcl-xS and Bax, these data indicate that the pattern of Bcl-2 family genes expression in leukaemic CD5+ B cells is skewed toward prevention of apoptosis and may thus favour the relentless accumulation of CD5+ leukaemic B cells.
Br J Haematol 1996 Sep
PMID:In leukaemic CD5+ B cells the expression of BCL-2 gene family is shifted toward protection from apoptosis. 882 82

Permanent occlusion of the middle cerebral artery in rats was used to assess the effects of focal ischemia on the expression of members of the bcl-2 family which have been implicated in the regulation of programmed cell death. Intraluminal occlusion of one middle cerebral artery for 6 h resulted in histologically detectable brain damage within the ipsilateral caudate putamen, basolateral cortex and parts of the thalamus. In the infarcted basolateral cortex and thalamus fragmentation of DNA was detected in many nuclei using in-situ end-labeling of DNA breaks by terminal transferase, whereas only scattered labeled nuclei were visible in the infarcted caudate putamen. Immunohistochemical analysis revealed activation of c-Fos in the infarcted cortex and thalamus and in the non-infarcted cingulate cortex as has been shown by others. A decrease in immunoreactivity for Bcl-2, and Bcl-X and an increase in immunostaining for Bax was observed exclusively in neurons within the ischemic cortex and thalamus. Within the infarcted caudate putamen, however, protein levels of all bcl-2 family members declined and c-Fos remained absent. By reverse transcription and polymerase chain reaction it was demonstrated that levels of bcl-2 mRNA markedly decreased in the ipsilateral hemisphere, whereas the amount of bax mRNA was elevated. These findings suggest that a shift in the ratio of cell death repressor Bcl-2 to cell death effector Bax and a concomitant activation of c-Fos may contribute to neuronal apoptosis in the infarcted thalamus and cortex.
Brain Res Mol Brain Res 1996 Sep 01
PMID:Altered expression of Bcl-2, Bcl-X, Bax, and c-Fos colocalizes with DNA fragmentation and ischemic cell damage following middle cerebral artery occlusion in rats. 887 9

The role of oxidative stress in mercuric chloride (HgCl2)-induced nephrotoxicity is uncertain and controversial. We demonstrate that I.L.C-PK1 cells, exposed to HgCl2, generate massive amounts of hydrogen peroxide, the latter completely quenched by the hydrogen peroxide scavenger, pyruvate. HgCl2 exerts a dose-dependent cytotoxicity which is attenuated by pyruvate and catalase. Cellular generation of hydrogen peroxide arises, at least in part, from mitochondria since mitochondrial rates of generation of hydrogen peroxide increase in response to HgCl2; HgCl2 also provokes a shift in absorbance spectra in rhodamine 123 loaded-mitochondria and stimulates mitochondrial state 4 respiration. HgCl2, applied for one hour, impairs cellular vitality as demonstrated by the MTT assay, an assay dependent in part on mitochondrial function. HgCl2 impairs function in other organelles such as lysosomes that maintain a transmembrane proton gradient; these latter effects are partially attenuated by pyruvate. We complement these in vitro findings with in vivo evidence demonstrating that HgCl2 stimulates renal generation of hydrogen peroxide. The functional significance of such generation of hydrogen peroxide was evaluated in rats deficient in selenium and vitamin E, a nutrient deficiency that impairs the scavenging of hydrogen peroxide and promotes the toxicity of this oxidant. In these rats serum creatinine values were significantly higher on sequential days following the administration of HgCl2. To probe the renal response to oxidative stress induced by HgCl2, we examined hydrogen peroxide-scavenging enzymes and redox-sensitive genes. Catalase activity was unaltered whereas glutathione peroxidase activity was decreased, effects that may contribute to the net renal generation of hydrogen peroxide. The redox sensitive enzyme, heme oxygenase, was markedly up-regulated in the kidney in response to HgCl2. HgCl2 also induced members of the bcl family, bcl2 and bclx, genes that protect against apoptosis and oxidant injury. In another model of oxidant-induced renal injury, the glycerol model, bcl2 mRNA was not induced at 6 and 24 hours after the administration of glycerol. In summary, we demonstrate that HgCl2 potently stimulates renal generation of hydrogen peroxide in vitro and in vivo and such generation of peroxide contributes to renal dysfunction in vitro and in vivo. We also demonstrate that in response to HgCl2, redox sensitive genes are expressed including heme oxygenase and members of the bcl family.
Kidney Int 1996 Sep
PMID:Renal oxidant injury and oxidant response induced by mercury. 887 81

To investigate the involvement of reactive oxygen species (ROS) in neuronal apoptosis, we performed confocal and flow cytometric analysis with a ROS-specific fluorogen, 6-carboxy-2', 7'-dichorodihydrofluorescein diacetate, di(acetoxymethyl ester) (C-DCDHF-DA). Serum deprivation significantly increased the level of ROS in PC12 cells and rat cortical neurons. N,N'-diphenyl-p-phenylenediamine (DPPD), an antioxidant, reduced ROS production induced by serum deprivation and recovered cell survival. However, some survival factors such as nerve growth factor and Bcl-2, which prevented the apoptosis of PC12 cells, did not affect the up-regulation of ROS induced by serum deprivation. Epidermal growth factor which prevented the apoptosis of cortical neurons, did not affect the increase of ROS. These data suggest that survival factors rescue the serum deprivation induced apoptosis independently of ROS production.
Brain Res 1996 Sep 09
PMID:Survival factor-insensitive generation of reactive oxygen species induced by serum deprivation in neuronal cells. 889 Dec 42


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>