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Query: UNIPROT:P06889 (Mol)
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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

There is increasing evidence that cell cycle transit is potentially lethal, with survival depending on the activation of metabolic pathways which block apoptosis. However, the identities of those pathways coupling cell cycle transit to survival remain undefined. Here we show that the eukaryotic translation initiation factor 4E (eIF4E) can mediate both proliferative and survival signaling. Overexpression of eIF4E completely substituted for serum or individual growth factors in preserving the viability of established NIH 3T3 fibroblasts. An eIF4E mutant (Ser-53 changed to Ala) defective in mediating its growth-factor-regulated functions was also defective in its survival signaling. Survival signaling by enforced expression of eIF4E did not result from autocrine release of survival factors, nor did it lead to increased expression of the apoptosis antagonists Bcl-2 and Bcl-XL. In addition, the execution apparatus of the apoptotic response in eIF4E-overexpressing cells was found to be intact. Increased expression of eIF4E was sufficient to inhibit apoptosis in serum-restricted primary fibroblasts with enforced expression of Myc. In contrast, activation of Ha-Ras, which is required for eIF4E proliferative signaling, did not suppress Myc-induced apoptosis. These data suggest that the eIF4E-activated pathways leading to survival and cell cycle progression are distinct. This dual signaling of proliferation and survival might be the basis for the potency of eIF4E as an inducer of neoplastic transformation.
Mol Cell Biol 1996 Nov
PMID:Translational control of programmed cell death: eukaryotic translation initiation factor 4E blocks apoptosis in growth-factor-restricted fibroblasts with physiologically expressed or deregulated Myc. 888 86

Inactivation of resorbing osteoclasts by calcitonin is associated with typical morphological changes and alteration of the specific organization of osteoclast cytoskeleton. Here we show that calcitonin also promotes the survival of rat osteoclasts in vitro, cultured either on glass or bone, by delaying the onset of apoptosis. Parathyroid hormone had no effect on osteoclasts cultured on glass but it slightly increased apoptosis index of osteoclasts cultured on bone. Calcitonin was also able to rescue osteoclasts in calvarial explant cultures. The survival effect of calcitonin was mimicked by dibutyryl cAMP and could not be blocked by various metabolic inhibitors known to affect the apoptotic pathway. However, clodronate-induced apoptosis of osteoclasts could not be reversed by calcitonin and neither could calcitonin rescue osteoclasts already committed to apoptosis. It did not alter the distribution of Bcl-2 in osteoclasts. Our results show that at least in vitro calcitonin protects osteoclasts from apoptosis and suggest that it regulates the onset of apoptosis.
Mol Cell Endocrinol 1996 Sep 18
PMID:Calcitonin promotes osteoclast survival in vitro. 890 42

Bisphosphonates (BPs), such as clodronate and pamidronate, are inhibitors of bone resorption and are used on a widespread basis in the treatment of hyper-resorptive bone diseases. At the cellular level, BPs inhibit osteoclasts, but the precise molecular mechanisms are unclear. BPs have also been shown to affect the survival of macrophages, cells ontogenetically related to osteoclasts. We show that both clodronate and pamidronate induce apoptosis in isolated osteoclasts. Clodronate, when administered in liposomes, also induced apoptosis in rat peritoneal macrophages in vitro and in liver macrophages of mice in vivo but not in murine macrophage-like RAW-264 cells. The subcellular localization and staining intensity of Bcl-2, an anti-apoptotic protein known to protect several cell types against drug-induced apoptosis, were similar in RAW-264 and peritoneal macrophage cells, as revealed by immunofluorescence. The clodronate-induced apoptotic pathway was further characterized in isolated osteoclasts cultured on glass coverslips through the use of clodronate-containing liposomes and several inhibitors of the apoptotic cascade. None of the agents tested could totally prevent clodronate-induced osteoclast death. Partial protection was, however, obtained by the addition of staurosporine or homocysteine. The results suggest that primarily cytoplasmic, protein kinase C-activated mechanisms are involved in the execution of clodronate-induced apoptosis of osteoclasts.
Mol Pharmacol 1996 Nov
PMID:Characteristics of clodronate-induced apoptosis in osteoclasts and macrophages. 891 44

Using in situ hybridization, Northern blotting and RT-PCR we studied the post-ischemic expression of bcl-2, bcl-x, bax and ICE. One day following 5 min or 10 min of global ischemia bcl-2 and bcl-x mRNAs were induced in CA1 hippocampal pyramidal neurons while bax was unchanged. By 72 h after ischemia the expression of bcl-2, bcl-x and bax mRNAs decreased in CA1. The large isoform of bcl-x (bcl-xL), detected using RT-PCR, decreased in whole hippocampus by 24-72 h after ischemia relative to the putative short (bcl-xS) and transmembrane deleted (bcl-x delta TM) forms. Oligonucleotides to interleukin-1 beta convertase (ICE), which detected the expected 2-kb transcript and two lesser 1.5- and 3-kb hybridizing species, demonstrated slight mRNA induction in the CA1 region at 72 h following ischemia. DNA nick end-labeling at 3 days following ischemia showed DNA fragmentation in neurons limited to the CA1 region of hippocampus following 5 min ischemia, while DNA fragmentation was detected in CA1, CA3, dentate gyrus and cortical neurons following 10 min ischemia. The data support the view that hippocampal neurons might undergo an apoptosis-like death after global ischemia. Since global ischemia decreases total protein synthesis especially in the CA1 region, the increases in bcl-2 mRNA levels may not necessarily lead to increased Bcl-2 protein levels. This may explain why the CA1 neurons die despite the prominent induction of the protective bcl-2 gene. The observed decrease by 24 h in the bcl-xL/bcl-xS ratio which preceded DNA fragmentation may participate in the cell death produced by ischemia. However, because of the ischemia-induced decrease in total protein synthesis, the decreased bcl-xL/bcl-xS ratio does not necessarily lead to a changed ratio in the amount of the appropriate proteins. Since ICE-like mRNA was induced at 72 h when the CA1 neurons were dead, the significance of this ICE-like mRNA induction remains unclear.
Brain Res Mol Brain Res 1996 Nov
PMID:Global ischemia induces apoptosis-associated genes in hippocampus. 891 83

In vivo measurement of human somatic mutations may be a valuable biodosimeter of exposure to carcinogens and of cancer risk. We have surveyed translocations at the bcl2 locus in B lymphocytes, and mutations at hprt in T lymphocytes, in 120 individuals with varying exposure to radon and cigarette smoke. bcl2 t(14:18) translocation is the commonest chromosomal alteration observed in non-Hodgkins lymphoma (NHL). We observed a significantly larger range of bcl2 translocation frequency (range: 0-372 x 10(-6), median: 1.9 x 10(-6)) than of hprt mutation frequency (range: 0-76.4 x 10(-6), median: 11.1 x 10(-6)), which is likely the result of clonal proliferation of deathless B cell mutants. We observed that the frequencies of these two distinct lymphocytic mutations are significantly correlated. Although some of the correlated variation is explained by age, a significant correlation of bcl2 mutagenesis persists after age adjustment. Correlated mutagenesis at distinct loci in distinct cell types could be explained by the existence of a mutator phenotype or by variation in exposure to environmental mutagens. NHL is commoner in men than in women, and our data indicate a trend toward higher bcl2 mutagenesis in males than females. There is mounting epidemiological evidence for a worldwide increase in NHL, which may have an environmental basis; molecular epidemiological analysis of bcl2 mutagenesis in exposed populations might be especially relevant to the identification of putative environmental causes. Given the relative ease of the bcl2 assay versus the hprt assay, and the consistency with which data are reproduced from laboratory to laboratory, it is likely that the bcl2 assay will be soon added to the array of assays used in human mutational surveillance.
Environ Mol Mutagen 1997
PMID:Correlated mutagenesis of bcl2 and hprt loci in blood lymphocytes. 902 Mar 5

Mutations in the retinoblastoma (pRb) tumor suppressor pathway including its cyclin-cdk regulatory kinases, or cdk inhibitors, are a hallmark of most cancers and allow unrestrained E2F-1 transcription factor activity, which leads to unregulated G1-to-S-phase cell cycle progression. Moderate levels of E2F-1 overexpression are tolerated in interleukin 3 (IL-3)-dependent 32D.3 myeloid progenitor cells, yet this induces apoptosis when these cells are deprived of IL-3. However, when E2F activity is augmented by coexpression of its heterodimeric partner, DP-1, the effects of survival factors are abrogated. To determine whether enforced E2F-1 expression selectively sensitizes cells to cytotoxic agents, we examined the effects of chemotherapeutic agents and radiation used in cancer therapy. E2F-1 overexpression in the myeloid cells preferentially sensitized cells to apoptosis when they were treated with the topoisomerase II inhibitor etoposide. Although E2F-1 alone induces moderate levels of p53 and treatment with drugs markedly increased p53, the deleterious effects of etoposide in E2F-1-overexpressing cells were independent of p53 accumulation. Coexpression of Bcl-2 and E2F-1 in 32D.3 cells protected them from etoposide-mediated apoptosis. However, Bcl-2 also prevented apoptosis of these cells upon exposure to 5-fluorouracil and doxorubicin, which were also cytotoxic for control cells. Pretreating E2F-1-expressing cells with ICRF-193, a second topoisomerase II inhibitor that does not damage DNA, protected the cells from etoposide-induced apoptosis. However, ICRF-193 cooperated with DNA-damaging agents to induce apoptosis. Therefore, topoisomerase II inhibition and DNA damage can cooperate to selectively induce p53-independent apoptosis in cells that have unregulated E2F-1 activity resulting from mutations in the pRb pathway.
Mol Cell Biol 1997 Mar
PMID:E2F-1 cooperates with topoisomerase II inhibition and DNA damage to selectively augment p53-independent apoptosis. 903 31

6-Mercaptopurine and related purine antimetabolites are used in the treatment of several B cell disorders. These drugs inhibited the proliferation of mature splenic B cells after being triggered with polyclonal mitogens. In addition to the antiproliferative effects, 6-mercaptopurine, 2-mercaptopurine, and aminoguanidine evoked a rapid apoptotic cell death in activated B cells that started at 6 hr after drug treatment and therefore preceded DNA synthesis. Incubation of activated B lymphocytes with 6-mercaptopurine blocked the low but sustained nitric oxide release observed in these cells that contributes to the prevention of apoptotic cell death; the addition of chemical nitric oxide donors significantly antagonized the apoptosis elicited by these drugs. The inhibition of nitric oxide synthesis elicited by mercaptopurines correlated with a decrease in the release of nitric oxide-derived species to the culture medium and in the intracellular levels of cGMP. The ratio between the amounts of Bcl-2 and Bax, two proteins involved in the control of apoptosis in mature B cells, markedly decreased as result of mercaptopurine treatment.
Mol Pharmacol 1997 Mar
PMID:6-Mercaptopurine decreases the Bcl-2/Bax ratio and induces apoptosis in activated splenic B lymphocytes. 2887 8

BCR-ABL is a chimaeric oncogene generated by translocation of sequences from the c-ABL protein-tyrosine kinase gene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, p210(BCR-ABL) and p190(BCR-ABL), are produced that are characteristic of chronic myelogenous leukemia and acute lymphoblastic leukemia, respectively. Their role in the aetiology of human leukemia remains to be defined. We have previously shown that the tumorigenic effect of BCR-ABL oncogenes is mediated by Bcl-2. In addition to Bcl-2, is a protein essential for transformation by BCR-ABL. However, it is not known how Bcl-2 and Ras fit together in cell transformation by BCR-ABL. The data presented here establish that Bcl-2 is a downstream target gene of the Ras signalling pathway in cells transformed by BCR-ABL, and that constitutive Ras activation results in constitutive expression of the gene. Conversely, a truncated form of the BCR-ABL, which lacks a critical BCR region required for activation of the Ras signalling pathway, failed to induce Bcl-2 expression. These results indicate that BCR-ABL prevents apoptosis by inducing Bcl-2 through a signalling pathway involving Ras and links constitutive Ras activation and Bcl-2 gene regulation. Hence, these results further imply that Ras is involved in both mitogenic signals and survival signals.
J Mol Biol 1997 Mar 28
PMID:Regulation of Bcl-2 gene expression by BCR-ABL is mediated by Ras. 909 20

We report the isolation and characterization of a chicken testis bcl-XL cDNA coding for a long bcl-x protein with a hydrophobic tail, and the expression of bcl-2 and bcl-x during chicken spermatogenesis. Bcl-2 is highly expressed in embryonic and immature testes enriched in spermatogonia and barely detectable in mature testes, where most of the cells are meiotic and postmeiotic. Bcl-x is expressed in both mature and immature testes, but in a lesser amount in mature testes. Differential expression of bcl-2 and bcl-x during spermatogenesis is consistent with the reported different susceptibility to apoptosis of spermatogonia, and meiotic and postmeiotic cells.
Mol Reprod Dev 1997 May
PMID:Differential expression of bcl-2 and bcl-x during chicken spermatogenesis. 911 Mar 11


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