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)

The authors recently reported that CD2 ligation rescues B cells from antigen-induced apoptosis by upregulation of intracellular Bcl-2 levels. However, the characterization of the early signals involved in apoptosis rescue by CD2 ligation has not been well established. In this context, CD2 does not promote either phosphatidylinositol turnover or CA2+ mobilization in B cells. In this paper the authors show that CD2 interaction with its ligand CD48 also reduces the apoptosis induced by forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and, to a much lesser extent, the apoptosis induced by cholera toxin in murine B splenocytes. Using a cAMP detection system sensitive to the picomolar range, the authors demonstrate that CD2-CD48 interaction decreases the intracellular cAMP concentrations induced by forskolin but not by cholera toxin. In comparison with the CD2-CD48 interaction, CD40-CD40 ligand interaction completely inhibits the apoptosis induced by cAMP increases without affecting the intracellular cAMP levels promoted by forskolin or cholera toxin. These results indicate that CD2 can also control the apoptosis at the very early steps after receptor signalling, such as the adenylate cyclase activity. Given that heterotrimeric G-proteins can mediate the adenylate cyclase activity the authors suggest that CD2 signalling could act through these small proteins, which would explain the inability of CD2 signalling to rescue from the apoptosis induced by cholera toxin, a Gs-protein activator. Conversely, CD40 seems to control apoptosis further downstream of the cAMP-PKA pathway where the survival and apoptotic signals are confluent, which might therefore render it a more efficient system to block apoptosis.
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PMID:Decrease in cAMP levels promoted by CD48-CD2 interaction correlates with inhibition of apoptosis in B cells. 866 20

The Janus kinase, JAK3 plays an important role in interleukin-2 (IL-2)-dependent signal transduction and proliferation of T lymphocytes. Our findings show that prostaglandin E2 (PGE2) can inhibit upregulation of JAK3 protein in naive T cells and can downregulate its expression in primed cells. Reduction in JAK3 was selective because expression of other tyrosine kinases (JAK1, p56(lck), and p59(fyn)) and signal transducer and activator of transcription (STAT)5, which are linked to IL-2 receptor (IL-2R) signaling pathway, were not affected. Inhibition of JAK3 may be controlled by intracellular cyclic adenosine monophosphate (cAMP) levels, as forskolin, a direct activator of adenylate cyclase and dibutyryl cAMP (dbcAMP), a membrane permeable analogue of cAMP suppressed JAK3 expression. Moreover, 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of cAMP phosphodiesterase, potentiated PGE2-induced suppression of JAK3. In naive T cells, but not primed T cells, PGE2 and other cAMP elevating agents also caused a modest reduction in surface expression of the common gamma chain (gammac) that associates with JAK3. The absence of JAK3, but not IL-2R in T cells correlated with impaired IL-2-dependent signal transduction and proliferation. The alteration in IL-2 signaling included decreased tyrosine phosphorylation and DNA binding activity of STAT5 and poor induction of the c-Myc and c-Jun pathways. In contrast, IL-2-dependent induction of Bcl-2 was unaffected. These findings suggest that suppression of JAK3 levels may represent one mechanism by which PGE2 and other cAMP elevating agents can inhibit T-cell proliferation.
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PMID:Downregulation of JAK3 protein levels in T lymphocytes by prostaglandin E2 and other cyclic adenosine monophosphate-elevating agents: impact on interleukin-2 receptor signaling pathway. 1009 Sep 41

Nerve growth factor (NGF) binds to the TrkA tyrosine kinase and the p75 neurotrophin receptors. Depending upon which receptor is activated, NGF can induce differentiation or apoptosis. C6-2B glioma cells express the p75 receptor, but NGF decreases their growth only when TrkA is introduced (C6trk). It is unclear, however, whether TrkA reduces C6-2B cell growth by apoptosis or differentiation. To examine which mechanisms account for the anti-proliferative effect of NGF in these cells, we first analyzed whether NGF causes apoptosis by flow cytometry, two-site immunoassay and in situ TUNEL. None of these methods indicated that C6trk undergo apoptosis. Additional apoptotic markers, such as Bcl-2, Bax, Bad, p53, caspase 3, and NF-kappaB were also used. C6trk cells exhibited lower levels of Bcl-2 compared with the parental C6 mock cells, but no changes in the levels of other apoptotic proteins. Moreover, NGF increased AP-1 binding activity in C6trk cells, suggesting that NGF may induce differentiation. We then examined whether TrkA changes the glioma phenotype. In C6trk cells, but not in C6mock cells, NGF enhanced the levels of neuron-specific enolase as well as the levels of A2B5 and 2', 3'-cyclic nucleotide 3'-phosphodiesterase, markers for oligodendrocytes, without affecting the expression of other neuronal markers. Our data suggest that the antiproliferative properties of TrkA may rely on its ability to induce differentiation of C6 cells from undifferentiated glioma to oligodendrocytes.
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PMID:TrkA induces differentiation but not apoptosis in C6-2B glioma cells. 1139 88

B cell chronic lymphocytic leukemia (B-CLL) is an incurable clonal disease which shows initial responsiveness to a number of chemotherapeutic drugs. However, in most patients the disease becomes resistant to treatment. Rolipram, a specific inhibitor of phosphodiesterase (PDE) type 4, the PDE predominantly expressed in B-CLL cells, has been shown to induce cAMP-dependent apoptosis in these cells. In the present study, we demonstrate that the extent of rolipram-induced apoptosis is similar to fludarabine-induced apoptosis in vitro. The combination of rolipram and fludarabine results in an enhancement in the number of apoptotic cells compared to apoptosis induced by either agent alone. Second, rolipram suppresses the expression of anti-apoptotic members of the Bcl-2 family and induces the pro-apoptotic protein Bax, thereby shifting the balance between pro- and anti-apoptotic members of the Bcl-2 family towards a pro-apoptotic direction. Finally rolipram-induced apoptosis is caspase-dependent. PDE 4 inhibitors are currently under investigation for chronic obstructive pulmonary disease and asthma in phase III clinical trials showing promising results with tolerable side-effects. In conclusion, by inducing apoptosis, by enhancing apoptosis induced by fludarabine, by suppressing Bcl-2, Bcl-X and by inducing Bax expression, PDE 4 inhibitors may add a new therapeutic option for patients with B-CLL.
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PMID:Phosphodiesterase type 4 inhibitor suppresses expression of anti-apoptotic members of the Bcl-2 family in B-CLL cells and induces caspase-dependent apoptosis. 1158 14

Glucocorticoids or increases in cellular cAMP promote apoptosis in many cell types, including murine S49 cells. We examined the impact of Bcl-2, an antiapoptotic protein, on S49 cell growth and death promoted by the glucocorticoid dexamethasone or agents that increase cAMP: isoproterenol (a beta-adrenergic agonist) + 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor) and forskolin (diterpene). These agents promoted apoptosis (i.e., increased expression of annexin V) of wild-type (WT) S49 cells, but Bcl-2-overexpressing S49 cells were protected from this response. Bcl-2 overexpression did not protect cells from G(1) growth arrest but did allow cells to grow longer in culture and protected cells from culture-dependent necrosis. Commitment to and reversal from apoptosis vs. G(1) growth arrest by isoproterenol + 3-isobutyl-1-methylxanthine showed different kinetics. Although both processes required several hours to develop, removal of agonists readily reversed growth arrest, but not apoptosis. Thus commitment to apoptosis is less reversible than G(1) growth arrest. The findings also indicate that glucocorticoid- and cAMP-mediated G(1) growth arrest is unaffected by Bcl-2 overexpression, even though increased Bcl-2 allows these lymphoma cells to resist necrosis and apoptosis.
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PMID:Bcl-2 protects lymphoma cells from apoptosis but not growth arrest promoted by cAMP and dexamethasone. 1160 Apr 28

It has been shown that expression of the RIalpha subunit of cyclic AMP (cAMP)-dependent protein kinase is enhanced in human cancer cell lines, primary tumors, and cells after transformation. Using an antisense strategy, we have shown that RIalpha has a role in neoplastic cell growth in vitro and in vivo. In the present study, we have investigated the sequence- and target-specific effects of exogenous RIalpha antisense oligodeoxynucleotides (ODNs) and endogenous antisense gene on tumor growth, apoptosis, and cAMP signaling in androgen-insensitive prostate cancer cells, both in vitro and in nude mice. Here, we show that an RIalpha antisense, RNA/DNA mixed backbone ODN exerts a reduction in RIalpha expression at both the mRNA and protein levels, up-regulation of both the RIIbeta subunit of cAMP-dependent protein kinase or protein kinase A and c-AMP-phosphodiesterase IV expression, and inhibition of cell growth. Growth inhibition was accompanied by changes in cell morphology and the appearance of apoptotic nuclei. In addition, Bcl-2 hyperphosphorylation; increase in the proapoptotic proteins Bax, Bak, and Bad; and Bad hypophosphorylation occurred in the antisense-treated cells. These effects of exogenously supplied antisense ODN mirrored those induced by endogenous antisense gene overexpression. The RIalpha antisense ODNs, which differed in sequence or chemical modification, promoted a sequence- and target-specific reduction in RIalpha protein levels and inhibited tumor growth in nude mice. These results demonstrate that in a sequence-specific manner, RIalpha antisense, via efficient depletion of the growth stimulatory molecule RIalpha, induces growth inhibition, apoptosis, and phenotypic (cell morphology) changes, providing an innovative approach to combat hormone-insensitive prostate cancer cell growth.
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PMID:Protein kinase A RIalpha antisense inhibition of PC3M prostate cancer cell growth: Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation. 1183 45

The aim of this study was to investigate whether and how phosphodiesterase (PDE) inhibitors modulate the proliferation, cell cycle and apoptosis in lymphoma cells. The effects of aminophylline (AM), a non-specific PDE inhibitor, on Raji cells were explored in vitro. MTT assay, light and transmission electron microscopy and annexin V staining were used to observe cell proliferation, morphologic changes and apoptosis rate in AM-treated cells, and FCM and RT-PCR techniques were adopted to detect the effect on cell cycle, the expression of cyclin B1 and Bcl-2 and mitochondrial transmembrane potential in AM-treated cells. The results showed that AM inhibited the growth of Raji cells in a concentration-dependent manner. Morphologic observations showed apoptosis changes in AM-treated cells, including cytoplamic shrinkage, cytoplasmic bubbling, karyopyknosis and nuclear fragmentation. FCM and RT-PCR detection showed that AM intervention increased the fraction of annexin V(+) cells, reduced the value of mitochondrial transmembrane potential, induced S phase arrest, and down-regulated the expression of Bcl-2 at both mRNA and protein level and cyclin B1 protein in a concentration-dependent manner. It is concluded that PDE inhibitor aminophylline may induce Raji cell growth inhibition, S phase arrest, apoptosis via down-regulation of Bcl-2 and reduction of mitochondrial transmembrane potential.
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PMID:[Effects of aminophylline on proliferation and apoptosis in Raji lympho-blastoid cell line]. 1266 89

1. Theophylline possesses anti-inflammatory activities in asthma. We examined whether theophylline and agents that modulate cyclic AMP can determine the survival and proliferation of progenitor cells. 2. Progenitor cells from the blood of normal and asthmatic subjects were cultured for 14 days in methylcellulose with GM-CSF, stem cell factor, IL-3 and IL-5. Apoptosis was measured by flow cytometry of propidium-iodide-stained cells. 3. A greater number of colonies with a higher proportion of cells of eosinophil lineage from asthmatics compared to normal subjects were grown. Theophylline (at 5 and 20 micro g ml(-1)) significantly inhibited colony formation and increased apoptotic cells in asthmatics compared to control. Salbutamol (0.1, 1, 10 micro M), dibutyryl-cAMP (0.1, 1 mM) and rolipram (0.1, 1 mM), a phosphodiesterase IV inhibitor, also dose-dependently decreased colony numbers and increased apoptosis of progenitor cells from asthmatics. 4. There was no significant effect of theophylline, db-cAMP, salbutamol or rolipram on colony formation or the survival of progenitor cells from normal subjects. AMP did not affect the colony formation and apoptosis. Expression of Bcl-2 protein on progenitor cells of asthma was downregulated by theophylline, salbutamol, db-cAMP and rolipram. 5. Theophylline and rolipram decreased colony formation committed to the eosinophil lineage, together with an increase in apoptosis through an inhibition of Bcl-2 expression effects that may occur through cAMP. The anti-inflammatory properties of theophylline include an inhibition of circulating progenitor cells.
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PMID:Effect of theophylline and specific phosphodiesterase IV inhibition on proliferation and apoptosis of progenitor cells in bronchial asthma. 1268 71

Gemcitabine and cisplatin are commonly used in chemotherapy, however, these drugs may cause severe cytotoxic side effects. Theophylline and aminophylline are commonly used as anti-asthma drugs and can block anti-phosphodiesterase activity. We examined whether these methylxanthins could effect lung cancer cell survival and synergise with gemcitabine and cisplatin to induce apoptosis. We found that theophylline induced apoptosis in the cultured H1299 cell line already at concentrations of 30 microg/ml, reaching an ED50% at 100 microg/ml. In contrast, aminophylline induced apoptosis at concentrations of 300 microg/ml and 17% apoptosis was evident at concentrations as high as 900 microg/ml, which is a lethal dose for in vivo treatment. Cisplatin induced apoptosis with ED50% of 0.8 microg/ml, while gemcitabine induced apoptosis with ED50% of 20 ng/ml. Using a combination of 20 microg/ml of theophylline (calculated as an effective but not toxic anti-asthma drug) with 10 ng/ml gemcitabine or with 0.3 microg/ml cisplatin significantly elevated incidence of apoptosis compared to gemcitabine or cisplatin alone at similar concentrations. In contrast, an observed synergistic effect between aminophylline and gemcitabine was evident only at concentrations of 80 microg/ml and 10 ng/ml respectively. However, no effect was apparent in combination doses of aminophylline (80 microg/ml) with cisplatin (0.3 microg/ml). The combined treatments involved reduction in the intracellular level of the anti-apoptotic Bcl-2 gene product. This corresponded with the extent of apoptosis induced by the various drug combinations. Thus, theophylline is significantly more effective than aminophylline in increasing the sensitivity of the H1299 lung cancer cells to the induction of cell death by gemcitabine and cisplatin. Thus, combination of theophylline with these drugs may permit a reduction in the effective dose needed in chemotherapy treatment of lung cancer patients.
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PMID:Induction of apoptosis in non-small lung carcinoma cell line (H1299) by combination of anti-asthma drugs with gemcitabine and cisplatin. 1564 33

We investigated the effect of sildenafil in protection against necrosis or apoptosis in cardiomyocytes. Adult mouse ventricular myocytes were treated with sildenafil (1 or 10 microM) for 1 h before 40 min of simulated ischemia (SI). Necrosis was determined by trypan blue exclusion and lactate dehydrogenase release following SI alone or plus 1 or 18 h of reoxygenation (RO). Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling assay and mitochondrial membrane potential measured using a fluorescent probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1). Sildenafil reduced necrosis as indicated by decrease in trypan blue-positive myocytes and leakage of lactate dehydrogenase compared with untreated cells after either SI or SI-RO. The number of terminal deoxynucleotidyl transferase-mediated nick end labeling-positive myocytes or loss of JC-1 fluorescence following SI and 18 h of RO was attenuated in the sildenafil-treated group with concomitant inhibition of caspase 3 activity. An early increase in Bcl-2 to Bax ratio with sildenafil treatment was also observed in myocytes after SI-RO. The increase of Bcl-2 expression by sildenafil was inhibited by nitric-oxide synthase (NOS) inhibitor, L-nitro-amino-methyl-ester. The drug also enhanced mRNA and protein content of inducible NOS (iNOS) and endothelial NOS (eNOS) in the myocytes. Sildenafil-induced protection against necrosis and apoptosis was absent in the myocytes derived from iNOS knock-out mice and was attenuated in eNOS knock-out myocytes. The up-regulation of Bcl-2 expression by sildenafil was also absent in iNOS-deficient myocytes. Reverse transcription-PCR, Western blots, and immunohistochemical assay confirmed the expression of phosphodiesterase-5 in mouse cardiomyocytes. These data provide strong evidence for a direct protective effect of sildenafil against necrosis and apoptosis through NO signaling pathway. The results may have possible therapeutic potential in preventing myocyte cell death following ischemia/reperfusion.
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PMID:Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. 1566 44


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