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)

In t(14;18) (q32;q21) lymphomas, bcl-2 gene is activated by the juxtaposition of immunoglobulin (Ig) gene. The fused bcl-2-Ig gene generates chimeric mRNAs which consist of bcl-2 at 5' portion and Ig at 3' portion. Chimeric mRNA does not disrupt the bcl-2 coding frame of 239 amino acid polypeptide. Bcl-2-Ig transgenic mice demonstrated the extended B cell survival and the follicular lymphoproliferation, but they did not develop a malignancy until 25 weeks. Ten percent of them, however, developed malignant diffuse large-cell lymphomas after a long latency. Forty percent of these malignancies demonstrated the c-myc rearrangement, indicating that multiple step changes are required for malignant transformation in bcl-2 activated cells. Study on the bcl-2 gene rearrangement in Japanese B cell lymphoma and B-CLL revealed that 10 out of 32 cases of follicular lymphoma (31%), 5 out of 56 cases of diffuse lymphoma (9%) and 2 out of 30 cases of B-CLL (7%) were rearranged. Less frequency of B cell lymphoma, particularly follicular lymphoma in Japan might be partly due to the less bcl-2 involvement than in American cases. The ratio of bcl-2 involvement in B-CLL is not significantly different between Japan and U.S.A.. bcl-2 rearrangement at 5' promoter region is noted for Japanese B-CLL which was demonstrated for American cases. The clinical application of polymerase chain reaction for bcl-2 translocation was also discussed.
 ...
PMID:[BCL-2 gene in lymphocytic malignancy]. 205 69

The bcl-2 gene can potentially encode 26- and 22-kDa proteins that differ only in their carboxyl tails because of an alternative splicing mechanism. The larger of these proteins contains a hydrophobic transmembrane domain within its carboxyl terminus, resides (at least in part) in mitochondrial membranes and has been shown to prolong cell survival by blocking programmed cell death (also termed "apoptosis"). To explore the function of the shorter 22-kDa Bcl-2 protein that lacks a transmembrane domain, DNAs encoding p26-Bcl-2-alpha or p22-Bcl-2-beta were expressed in an interleukin-3 (IL-3)-dependent hematopoietic cell line 32D. In contrast to p26-Bcl-2 alpha that markedly prolonged cell survival, p22-Bcl-2-beta did not extend the survival of 32D cells when cultured in the absence of IL-3. Expression in 32D cells of a chimeric DNA that fused portions of the open reading frame common to Bcl-2-alpha and Bcl-2-beta (amino-acids 1-195) with sequences encoding the transmembrane and cytosolic domains of the IL-2 receptor-alpha protein resulted in production of a Bcl-2/IL-2R fusion protein that was capable of prolonging 32D cell survival in the setting of IL-3 withdrawal. Based on fractionation of cells to produce crude heavy membrane, light membrane, nuclei, and cytosolic preparations, much of the p22-Bcl-2-beta protein appeared to reside in the cytosol, whereas Bcl-2-alpha and the Bcl-2/IL-2R chimeric proteins were found exclusively in fractions that also contained the inner mitochondrial membrane protein F1-beta-ATPase. Taken together, these findings demonstrate the importance of membrane association for the function and intracellular targeting of the apoptosis-blocking Bcl-2 protein. Furthermore, despite the strong evolutionary conservation of the carboxyl regions of Bcl-2-alpha proteins observed previously for mammalian and avian species, these data suggest that a heterologous transmembrane domain can be substituted without loss of function.
 ...
PMID:Structure-function analysis of the Bcl-2 oncoprotein. Addition of a heterologous transmembrane domain to portions of the Bcl-2 beta protein restores function as a regulator of cell survival. 849 57

In mammalian cells, the Bcl-2 and Bcl-x(L) proteins suppress programmed cell death whereas the topographically similar Bax protein accelerates the apoptotic process. Recently published data suggest that expression of the human Bax-alpha gene is lethal for the yeast Saccharomyces cerevisiae and that this toxicity can be overcome by co-expressing Bcl-2 or Bcl-x(L). Our findings corroborate these results. However, we find that although Bax induction invariably stops cell growth under all circumstances, it does not lead to death in 'petite' cells. Petites cannot respire because they lack functional mitochondria. It seems that in 'grande' cells, which do possess normal mitochondrial DNA, nutritional limitation is critical for increased mortality. Surprisingly, murine Bcl-2 lacking the membrane anchor of human Bcl-2 has no effect on grande cells, but can efficiently rescue petites in rich medium. It has been suggested that the C-terminal membrane anchor of human Bcl-2 may have a crucial role in rescuing apoptosis in mammalian cells. When murine Bcl-2 is fused to the membrane anchor of yeast mitochondrial Mas70 protein, the Bcl-2 variant mBcl-2-mma rescues not only petites but also grandes, just like human Bcl-x(L). The rescuing ability of Bcl-x(L), which contains its own membrane anchor, surpasses that of mBcl-2-mma. Our results indicate that the process involving Bax-induced growth inhibition followed by possible lethality, and the rescuing effect of Bcl-2 and Bcl-x(L) is linked to yeast mitochondrial function. We propose a model which is consistent with these observations.
 ...
PMID:Role of mitochondria and C-terminal membrane anchor of Bcl-2 in Bax induced growth arrest and mortality in Saccharomyces cerevisiae. 860 30

Bcl-2 is an oncogene associated with prevention of apoptosis in a variety of cell types. Bcl-2 expression in B lymphoid cells prolongs antibody production, in vitro and in vivo. A line of transgenic mice (B6) has been developed that expresses human Bcl-2 in the B cells of SWR/SJL mice. B6 transgenic, nontransgenic littermates, and BALB/c mice were immunized with beta-galactosidase (B-gal) or sheep red blood cells (SRBC). The number of spleen cells recovered from immunized B6 mice was 3-4 times greater than syngeneic, nontransgenic littermates or BALB/c mice. Spleen cells from B-gal or SRBC immune B6, SWR/SJL, and BALB/c mice were fused with P3 myeloma cells to produce hybridomas. Forty-eight percent of the wells plated with fused B6 spleen cells produced B-gal-specific antibodies compared to 14% from BALB/c and 12% from SWR/SJL. Antibody-specific wells were subcloned, resulting in enhanced recovery of antigen-specific subclones with B6-derived fusions compared to controls. In the SRBC fusions, 17% of the wells plated with fused B6 spleen cells produced SRBC-specific antibodies compared to 6% for BALB/c and SWR/SJL spleens. After subcloning, B6-derived clones produced 8% positive subclones compared to 9.5% from SWR/SJL and 3.5% from BALB/c. Comparison of the isotype distribution of subclones showed a higher ratio of IgG antibodies compared to IgM from B6 mice in the B-gal fusions. IgA antibodies were recovered only from B6 mice. These data indicate that B6 transgenic mice that overexpress Bcl-2 in their B cells may be superior to other mouse strains for production of antigen-specific hybridomas.
 ...
PMID:Evaluation of Bcl-2/B cell transgenic mice (B6) for hybridoma production. 891 86

A green fluorescent protein (GFP)-Raf-1 fusion protein was used to show that Bcl-2 can target this kinase to mitochondria. Active Raf-1 fused with targeting sequences from an outer mitochondrial membrane protein protected cells from apoptosis and resulted in phosphorylation of BAD, a proapoptotic Bcl-2 homolog. Plasma membrane-targeted Raf-1 did not protect from apoptosis and resulted in phosphorylation of ERK-1 and ERK-2. Untargeted active Raf-1 improved Bcl-2-mediated resistance to apoptosis, whereas a kinase-inactive Raf-1 mutant abrogated apoptosis suppression by Bcl-2. Bcl-2 can therefore target Raf-1 to mitochondrial membranes, allowing this kinase to phosphorylate BAD or possibly other protein substrates involved in apoptosis regulation.
 ...
PMID:Bcl-2 targets the protein kinase Raf-1 to mitochondria. 892 27

While generating bcl2 alpha transgenic mice, we found some F2 offspring of one of the transgenic lines which were very small and had closed eyes at the time of weaning. These pups died within 1 month after birth. In order to determine the molecular basis of this phenotype, we screened a genomic library of the above transgenic line with a transgene-specific probe and found that the Bmp7 gene, a member of the TGF beta superfamily, was inactivated by insertional mutagenesis due to transgene integration. The Bmp7 homozygous null condition in mice is a postnatal lethal mutation and is associated with various developmental defects: holes in the basisphenoid bone and the xyphoid cartilage, retarded ossification of bones, fused ribs and vertebrae, underdeveloped neural arches of the lumbar and sacral vertebrae, polydactyly of the hind limbs, a kinked tail, a reduced number of nephrons, polycystic kidney, lack of retinal pigmentation, and retarded lens development. These findings indicate that BMP7 is an important signaling molecule for normal development of the mammalian skeleton, kidney, and eye. Academic Press
 ...
PMID:BMP7 null mutation in mice: developmental defects in skeleton, kidney, and eye. 901 3

Suppression of apoptosis appears to contribute to the development of various diseases, including autoimmune disorders and cancer. Numerous genes that encode activators and suppressors of apoptosis have been identified; however, such genes have not been shown to be expressed in all cell types. Furthermore, the sensitivity of different cell types to induction of apoptosis varies widely. We have employed a genetic approach using somatic cell hybridization to determine if apoptosis is a dominant or a recessive process in cells. These studies have utilized cell fusion partners with differing sensitivity to induction of apoptosis. The apoptosis-sensitive cells chosen were BW5147 murine thymoma cells. These cells readily undergo apoptosis in response to glucocorticoids and calcium ionophore. The resistant fusion partners were HTC rat hepatoma cells, which possess an intact glucocorticoid signal transduction pathway but are resistant to induction of apoptosis by either agent. Neither cell type expresses detectable Bcl-2 protein. Heterokaryons were identified by their retention of fluorescent cytosolic dyes and by nuclear morphology and cell size. The three types of heterokaryons observed were intratypic HTC/HTC and BW5147/BW5147 heterokaryons and intertypic BW5147/HTC heterokaryons. Glucocorticoid receptor was shown by immunohistochemistry to undergo hormone-dependent translocation to all nuclei in intertypic heterokaryons. BW5147/BW5147 heterokaryons die after treatment with glucocorticoid and calcium ionophore, whereas both HTC/ HTC and BW5147/HTC hybrids survive. The presence of multiple BW5147 cells fused to a single HTC cell did not affect this outcome. This demonstrates that HTC cells are able to dominantly suppress apoptosis in all BW5147/HTC heterokaryons. Thus, HTC cells contain activities that can suppress apoptosis in lymphocytes.
 ...
PMID:Dominant suppression of lymphocyte apoptosis by hepatoma cells. 901 14

Bax, a member of the Bcl-2 protein family, accelerates apoptosis by an unknown mechanism. Bax has been recently reported to be an integral membrane protein associated with organelles or bound to organelles by Bcl-2 or a soluble protein found in the cytosol. To explore Bcl-2 family member localization in living cells, the green fluorescent protein (GFP) was fused to the NH2 termini of Bax, Bcl-2, and Bcl-XL. Confocal microscopy performed on living Cos-7 kidney epithelial cells and L929 fibroblasts revealed that GFP-Bcl-2 and GFP-Bcl-XL had a punctate distribution and colocalized with a mitochondrial marker, whereas GFP-Bax was found diffusely throughout the cytosol. Photobleaching analysis confirmed that GFP-Bax is a soluble protein, in contrast to organelle-bound GFP-Bcl-2. The diffuse localization of GFP-Bax did not change with coexpression of high levels of Bcl-2 or Bcl-XL. However, upon induction of apoptosis, GFP-Bax moved intracellularly to a punctate distribution that partially colocalized with mitochondria. Once initiated, this Bax movement was complete within 30 min, before cellular shrinkage or nuclear condensation. Removal of a COOH-terminal hydrophobic domain from GFP-Bax inhibited redistribution during apoptosis and inhibited the death-promoting activity of both Bax and GFP-Bax. These results demonstrate that in cells undergoing apoptosis, an early, dramatic change occurs in the intracellular localization of Bax, and this redistribution of soluble Bax to organelles appears important for Bax to promote cell death.
 ...
PMID:Movement of Bax from the cytosol to mitochondria during apoptosis. 938 73

Immunotoxins composed of antibodies linked to plant or bacterial toxins are being evaluated in the treatment of cancer. It is known that the toxin moieties of immunotoxins, including Pseudomonasexotoxin A (PE), diphtheria toxin, and ricin, are capable of inducing apoptosis. Since the efficiency of induction of apoptosis and the apoptosis pathway may have direct effects on the therapeutic usefulness of immunotoxins, we have studied how B3(Fv)-PE38, a genetically engineered immunotoxin in which the Fv fragment of an antibody is fused to a mutated form of PE, induces apoptosis of the MCF-7 breast cancer cell line. We show for the first time that a PE-containing immunotoxin activates ICE/ced-3 proteases, now termed caspases, and causes characteristic cleavage of the "death substrate" poly(ADP)-ribose polymerase (PARP) to an 89 kDa fragment with a time course of cleavage comparable to that induced by TNFalpha. Also the fluorescent substrate, DEVD-AFC, is cleaved 2-4-fold more rapidly by lysates from B3(Fv)-PE38 treated MCF-7 cells than untreated control cells, suggesting that a CPP32-like caspase is involved in B3(Fv)-PE38-mediated apoptosis. B3(Fv)-PE38-induced PARP cleavage is inhibited by several protease inhibitors known to inhibit caspases (zVAD-fmk, zDEVD-fmk, zIETD-fmk) as well as by overexpression of Bcl-2 providing additional evidence for caspase involvement. zVAD-fmk, a broad spectrum inhibitor of most mammalian caspases, prevents the early morphological changes and loss of cell membrane integrity produced by B3(Fv)-PE38, but not its ability to inhibit protein synthesis, arrest cell growth, and subsequently kill cells. Despite inhibition of apoptosis, the immunotoxin is still capable of selective cell killing, which indicates that B3(Fv)-PE38 kills cells by two mechanisms: one requires caspase activation, and the other is due to the arrest of protein synthesis caused by inactivation of elongation factor 2. The fact that an immunotoxin can specifically kill tumor cells without the need of inducing apoptosis makes such agents especially valuable for the treatment of cancers that are protected against apoptosis, e.g., by overexpression of Bcl-2.
 ...
PMID:Role of caspases in immunotoxin-induced apoptosis of cancer cells. 983 86

The effects of L1-Fc and CHL1-Fc fusion proteins on neuronal survival were investigated. Cerebellar granule neurons of mouse and hippocampal neurons of rat embryo undergo apoptosis when cultured in serum-free medium. Treatment with chimeric proteins containing the extracellular domains of the neural adhesion molecules L1 or CHL1 fused to the Fc region of human immunoglobulin significantly enhanced the survival of neurons. Compared to the control, the percentage of surviving neurons increased about 60% and 45% with L1 and CHL1 fusion proteins, respectively. A fusion protein containing the extracellular domain of NCAM had no effect on survival. The L1 and CHL1 fusion proteins were effective both in soluble form or when offered as a substrate, with the maximal effect at about 1 microg/mL. To explore the intracellular events related to the neuronal survival effects of L1-Fc fusion protein, Bcl-2 and c-Jun expression were analyzed by Western blotting. The level of Bcl-2 in cerebellar granule neurons was increased by treatment with L1-Fc at both 1 and 5 days of culture. The level of c-Jun was not significantly affected at the early time point and was reduced by L1-Fc fusion protein after long-term culture. The results demonstrate that the neural adhesion molecule L1 and its relative CHL1 are potential neuronal survival factors for neurons of the central nervous system. Bcl-2 may serve as one of the intracellular mediators of the neuronal survival effects of L1.
 ...
PMID:Prevention of neuronal cell death by neural adhesion molecules L1 and CHL1. 1002 83


1 2 3 4 5 6 7 8 9 Next >>