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)

Purkinje cell degeneration (pcd) is an autosomal recessive mutation in the mouse characterized by an almost complete loss of cerebellar Purkinje neurons between postnatal days 22 and 28. The pcd gene has not been identified, however, a relationship between activation of specific genes and cell death has been suggested in other models of neuronal cell death. In the present study we analyzed the expression of several candidate cell death effector genes (bax, c-fos, junB, krox-24) and a cell death repressor gene (bcl-2) in the cerebellum of pcd homozygotes and wild-type mice. At postnatal day 22, when Purkinje cells start to degenerate, levels of c-fos, junB, and krox-24 mRNA increased about 5-fold in mutants. To the contrary, the amount of bcl-2 mRNA declined and bax transcripts remained unchanged compared to wild-type animals. Immunoreactivity for c-Fos and Jun could be detected exclusively in cerebellar Purkinje neurons of pcd mice but not in wild-types, whereas the number of Bcl-2 immunopositive Purkinje cells decreased significantly in mutants. Both double labeling experiments and immunostaining of consecutive sections revealed lack of colocalization of Jun with Bcl-2. These results demonstrate an induction of members of the fos and jun family and a downregulation of antiapoptotic bcl-2 in cerebellar Purkinje neurons that are destined to die. Fos and Jun transcription factor proteins may be implicated in the regulation of bcl-2 expression and in the signal cascade leading to Purkinje cell death.
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PMID:Differential regulation of bcl-2, bax, c-fos, junB, and krox-24 expression in the cerebellum of Purkinje cell degeneration mutant mice. 756 51

The process of programmed cell death is frequently attenuated by inhibitors of protein and RNA synthesis. This implies that gene expression is necessary for the active elimination of some cell types. Genes such as bcl-2 and bax have been implicated in the direct control of cell death, while cellular immediate-early genes (cIEGs), such as c-fos and c-jun have been repeatedly associated with neuronal degeneration. We are using the olfactory neuroepithelium as a model system to investigate the role that expression of such genes might play in cell death. The advantages of this system is that even in the adult, there is spontaneous degeneration of olfactory receptor neurons followed by their replacement by the division and differentiation of precursors. Furthermore, the receptor neurons can be induced to die synchronously by removal of the olfactory bulb or intranasal administration of toxic agents. We have generated fos-lacZ and jun-lacZ transgenic mice that can be used to assess expression of c-fos and c-jun following these various manipulations. In addition, a line of transgenic mice has been derived that express Bcl-2 under the control of the olfactory receptor protein promoter. These mice have high levels of Bcl-2 selectively in receptor neurons of the primary neuro-epithelium and vomeronasal organ. Since in some circumstances, Bcl-2 can protect against programmed cell death these mice are being assessed for neuronal turnover under basal conditions and following olfactory bulbectomy.
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PMID:The olfactory system as a model for the analysis of the contribution of gene expression to programmed cell death. 758 21

Mechanisms of etoposide (VP-16) resistance have been evaluated in a human promyelocytic leukemia HL60 cell line. HL60 resistant (HL60/AR) cells were selected for resistance with adriamycin and were 250-fold resistant to VP-16. We have found that while a significantly higher (10 to 15-fold more) dose of VP-16 was required to induce similar amounts of SDS-KCI-precipitable DNA-protein complex formation in the resistant cell line, there was no difference in the repair of VP-16-induced DNA damage, indicating that differential DNA repair was not involved in VP-16 resistance in HL60 cells. VP-16 treatment significantly inhibited c-myc expression and induced c-jun and c-fos expressions in sensitive cells. In contrast, VP-16 had no effect on c-myc, c-jun or c-fos expressions in resistant cells. The level of bcl2 oncogene was similar in both cell lines; however, treatment with VP-16 resulted in a time- and dose-dependent degradation of the genomic DNA into oligo-sized DNA only in the sensitive cells, indicating that differential expressions of oncogenes (c-myc, c-jun, and c-fos) and susceptibility to apoptosis may play important roles in the sensitivity and resistance to VP-16 in HL60 cells.
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PMID:Differential oncogene expression and susceptibility to apoptosis in the human leukemia HL60 cell lines: implications for etoposide resistance. 764 49

Systemic administration of kainate induces cell death in vulnerable regions of the rodent brain. Neuronal degeneration is associated with internucleosomal DNA fragmentation and induction of presumptive cell death effector genes (e.g. p53, c-fos) suggesting that kainate activates an apoptotic pathway. In the present study, kainate-induced DNA damage has been demonstrated at the cellular level by in situ nick translation in the mouse hippocampus and neocortex at 24 h and 48 h after intraperitoneal injections. In the same regions, the intensity of Bcl-2 immunoreactivity decreased by about 45% as measured by digital image analysis. Most important, kainate treatment evoked a nearly 3-fold increase in bax mRNA levels within the mouse brain. The down-regulation of bcl-2, which promotes cell survival, and the up-regulation of bax, which promotes programmed cell death, may have functional significance in kainate-mediated excitotoxicity and in the selective vulnerability of specific brain regions.
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PMID:Up-regulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain. 767 27

Two interleukin-2 receptor-dependent signaling pathways have thus far been identified: the c-fos/c-jun induction pathway mediated by src family protein-tyrosine kinases and the c-myc induction pathway. Here, we provide evidence for the existence of a third, rapamycin-sensitive pathway, which results in the induction of another proto-oncogene, bcl-2. In the hematopoietic cell line BAF-B03, the expression of any two of lckF505 (an active form of p56lck), Bcl-2, or c-Myc is sufficient to promote transit of the cell cycle, regardless of the activation state of the third pathway. We also provide evidence that epidermal growth factor receptor signaling may act through the same pathway that involves p56lck. These studies demonstrate a novel approach to dissecting signaling pathways regulating cellular proliferation.
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PMID:Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. 773 74

Etoposide (VP-16) is one of several DNA-damaging agents that induce subcellular structural changes associated with apoptosis. VP-16 exerts its DNA-damaging and cytotoxic effects subsequent to interference with DNA topoisomerase II activity. VP-16 also stimulates c-jun and c-fos mRNA expression in some cell lines, including human leukemia K562 and HL-60 cells. To compare the temporal relationship between drug-induced c-jun expression and apoptosis, we examined cell morphology, cell viability, DNA integrity, and c-jun induction during VP-16 treatment of K562 and HL-60 cells. VP-16 (10 microM)-induced internucleosomal DNA damage and nuclear fragmentation were readily apparent within 6 hr in HL-60 cells but were absent in K562 cells treated for up to 24 hr. Some internucleosomal DNA damage was observed in K562 cells but only after treatment with 100 microM VP-16 for 24 hr. In contrast, VP-16-induced DNA single-strand breaks, VP-16-induced topoisomerase II/DNA covalent complex formation, and VP-16-mediated growth inhibition were similar in K562 and HL-60 cells. Also, the time course of VP-16-induced c-jun mRNA expression was comparable for both K562 and HL-60 cell lines. Western blot analysis of whole-cell lysates showed that Bcl-2 protein levels were 13-fold greater in HL-60 cells than in K562 cells. Thus, the resistance of VP-16-treated K562 cells to apoptosis was not attributable to protection by Bcl-2. Furthermore, the relatively high levels of Bcl-2 in HL-60 cells were not sufficient to protect these cells against apoptosis. Together, our results indicate that the temporal coupling of VP-16-induced DNA damage, c-jun expression, and apoptosis is cell type specific and suggest that different signaling pathways for apoptosis are operating in these two human leukemia cell lines.
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PMID:Differential induction of etoposide-mediated apoptosis in human leukemia HL-60 and K562 cells. 796 39

The proto-oncogene product c-Fos, a component of the transcription factor AP-1, is induced in early B lineage cells. To investigate a role of c-Fos in early B cell development, fetal liver (FL) cells from transgenic mice carrying an IFN-alphabeta (IFN)-inducible c-fos gene (Mx-c-fosD) were cultured on a stromal cell layer with IL-7. Although B lineage cells normally developed in the Mx-c-fosD FL cell culture, the development was perturbed by the addition of IFN at the beginning of culture. When IFN was added in the FL culture after B lineage cells developed, pro-B (B220+,CD43+) cells were selectively dying by apoptosis within 48 h after IFN stimulation. This apoptosis was intrinsically induced in the pro-B cells that overexpressed c-fos when the Mx-c-fosD FL (H-2Kb) cells were cocultured with the normal C3H FL (H-2Kk) cells. The molecular basis of the apoptosis was investigated by examining expression of the genes that regulate apoptosis. The IFN stimulation did not modulate expression of Bcl-2 and Fas in early B lineage cells from the Mx-c-fosD FL culture. However, Rag-2 was down-regulated in these cells within 12 h after IFN stimulation. These results suggest that the c-Fos plays a causal role in deletion of pro-B cells with nonfunctional Ag receptor.
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PMID:Overexpression of c-Fos induces apoptosis of CD43+ pro-B cells. 889 9

RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) treatment of murine EL4 T lymphoma cells induced the cells to undergo apoptosis. After 48 hours of VES treatment at 20 micrograms/ml, 95% of cells were apoptotic. Evidence for the induction of apoptosis by VES treatments is based on staining of DNA for detection of chromatin condensation/fragmentation, two-color flow-cytometric analyses of DNA content, and end-labeled DNA and electrophoretic analyses for detection of DNA ladder formation. VES-treated EL4 cells were blocked in the G1 cell cycle phase; however, apoptotic cells came from all cell cycle phases. Analyses of mRNA expression of genes involved in apoptosis revealed decreased c-myc and increased bcl-2, c-fos, and c-jun mRNAs within three to six hours after treatment. Western analyses showed increased c-Jun, c-Fos, and Bcl-2 protein levels. Electrophoretic mobility shift assays showed increased AP-1 binding at 6, 12, and 24 hours after treatment and decreased c-Myc binding after 12 and 24 hours of VES treatment. Treatments of EL4 cells with VES+RRR-alpha-to-copherol reduced apoptosis without effecting DNA synthesis arrest. Treatments of EL4 cells with VES+rac-6-hydroxyl-2, 5,7,8-tetramethyl-chroman-2-carboxylic acid, butylated hydroxytoluene, or butylated hydroxyanisole had no effect on apoptosis or DNA synthesis arrest caused by VES treatments. Analyses of bcl-2, c-myc, c-jun, and c-fos mRNA levels in cells receiving VES + RRR-alpha-tocopherol treatments showed no change from cells receiving VES treatments alone, implying that these changes are correlated with VES treatments but are not causal for apoptosis. However, treatments with VES + RRR-alpha-tocopherol decreased AP-1 binding to consensus DNA oligomer, suggesting AP-1 involvement in apoptosis induced by VES treatments.
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PMID:RRR-alpha-tocopheryl succinate inhibits EL4 thymic lymphoma cell growth by inducing apoptosis and DNA synthesis arrest. 897 Jan 89

Apoptosis (programmed cell death) is a distinct form of controlled cell degeneration, different from necrosis. It serves multiple physiological functions, such as the control of cell numbers during development, the maintenance of tissue homeostasis and the deletion of abnormal cells. Apoptosis has unique morphological and biochemical features, especially at the nuclear level, in keeping with the idea of the active participation of the cell in its own demise. Gene regulation of apoptosis shows variability among different tissues, particularly regarding the signals that trigger cell death, but shares an effector phase highly conserved accross species. In the nervous system, genes have been identified which either i) promote apoptosis: Bax, Bcl-xS, c-fos, c-jun, p75NGFR and ICE-like proteases, or ii) block apoptosis: Bcl-2 and Bcl-xL. In addition, availability of trophic factors and expression of Trk membrane receptors allow for the fine adjustement of viable cells in each neuronal population. In some diseases, neuron loss takes place via apoptosis, whether exclusively or associated with necrosis, especially when cellular insults are of moderate intensity or death occurs in areas of the brain adjacent to necrotic foci. This has been shown in excitotoxicity, X-ray injury and hypoxia-ischemia. Activation of apoptosis occurs also in some neurodegenerative diseases. Infantile spinal muscular atrophy can be the first example of a pediatric hereditary disease where a deletion in the gene of a protein which inhibits neuron apoptosis has a pathogenic role. Last, some central nervous system infections produce abnormal activation of apoptosis.
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PMID:[Apoptosis in the nervous system]. 897 37

The ability of the protein synthesis inhibitor cycloheximide (CHX) to prevent neuronal death in different paradigms has been interpreted to indicate that the cell death process requires synthesis of "killer" proteins. On the other hand, data indicate that neurotrophic factors protect neurons in the same death paradigms by inducing expression of neuroprotective gene products. We now provide evidence that in embryonic rat hippocampal cell cultures, CHX protects neurons against oxidative insults by a mechanism involving induction of neuroprotective gene products including the antiapoptotic gene bcl-2 and antioxidant enzymes. Neuronal survival after exposure to glutamate, FeSO4, and amyloid beta-peptide was increased in cultures pretreated with CHX at concentrations of 50-500 nM; higher and lower concentrations were ineffective. Neuroprotective concentrations of CHX caused only a moderate (20-40%) reduction in overall protein synthesis, and induced an increase in c-fos, c-jun, and bcl-2 mRNAs and protein levels as determined by reverse transcription-PCR analysis and immunocytochemistry, respectively. At neuroprotective CHX concentrations, levels of c-fos heteronuclear RNA increased in parallel with c-fos mRNA, indicating that CHX acts by inducing transcription. Neuroprotective concentrations of CHX suppressed accumulation of H2O2 induced by FeSO4, suggesting activation of antioxidant pathways. Treatment of cultures with an antisense oligodeoxynucleotide directed against bcl-2 mRNA decreased Bcl-2 protein levels and significantly reduced the neuroprotective action of CHX, suggesting that induction of Bcl-2 expression was mechanistically involved in the neuroprotective actions of CHX. In addition, activity levels of the antioxidant enzymes Cu/Zn-superoxide dismutase, Mn-superoxide dismutase, and catalase were significantly increased in cultures exposed to neuroprotective levels of CHX. Our data suggest that low concentrations of CHX can promote neuron survival by inducing increased levels of gene products that function in antioxidant pathways, a neuroprotective mechanism similar to that used by neurotrophic factors.
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PMID:Neuroprotective action of cycloheximide involves induction of bcl-2 and antioxidant pathways. 906 Apr 77


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