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)

Serum starvation has recently been shown to cause cell death of cardiac fibroblasts and increased synthesis of extracellular matrix proteins in the surviving cells. In the present study, events occurring in the dying cells were investigated. Cultured adult rat cardiac fibroblasts were exposed to serum-free medium. Cell number was measured using a Coulter Counter Channelyzer. The activity of the extracellular signal-regulated or mitogen-activated protein kinases (ERK1/2, p42/p44(MAPK)), the p38 kinase (p38(MAPK)), the c-Jun N-terminal kinases (p46/p54(JNK)), and Akt kinase was assessed by Western blotting and phospho-specific antibodies. Caspase 7-cleavage was investigated by Western blotting and specific antibodies. Caspase 3 activity was measured by detection of its cleaved substrate. The appearance of necrosis was studied by inclusion of trypan blue. Apoptosis was assessed by DNA ladder formation. The mRNA expression of Bax and Bcl-2 was investigated by quantitative real-time PCR. Serum withdrawal led to the death of 26% of cultured isolated cardiac fibroblasts during the first 5 h. The activity of the p42/ p44(MAPK) as well as of Akt kinase was partially reduced. For p46/p54(JNK) and p38(MAPK), elevated phosphorylation was measured. Inhibition of p46/p54(JNK) and p38(MAPK) activity by SB202190 did not affect the decrease in cell number. Cleavage of caspase 7 was detected after 90 min. However, no activation of caspase 3 was measured. DNA fragmentation was not found after serum depletion. Trypan blue staining, however, was observed in 16% of the cells after 5 h. The mRNA levels of both Bax and Bcl-2 were increased after 30 min. These results indicate the appearance of necrosis during serum starvation in cardiac fibroblasts. However, some processes typical of apoptosis were also detected.
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PMID:Mechanism of cell death of rat cardiac fibroblasts induced by serum depletion. 1457 13

We have recently demonstrated that glucocorticoids protect against serum-deprivation, cAMP-, TNFalpha-, and p53-induced apoptosis in ovarian follicular cells involved in up-regulation of Bcl-2. We demonstrated that dexamethasone, which enhances steroidogenesis by up-regulation of the p450scc enzyme system, stimulates the MAPK cascade by phosphorylation of ERK1, ERK2 as well as by Akt phosphorylation within 1-5min with no effect on p38 MAPK phosphorylation. Moreover, glucocorticoids enhance expression of connexin 43, formation of gap junctions, expression of cadherins, and formation of adherence junctions within 24h of hormone stimulation of ovarian granulosa cells. It is suggested that the protective effects of glucocorticoids against apoptosis are mediated by both genomic and non-genomic mechanisms. Moreover, for the first time we show that protein phosphorylation, cell-cell contact, and intracellular communication are important mediators in glucocorticoid protection against apoptosis in ovarian follicular cells.
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PMID:Activation of multiple signal transduction pathways by glucocorticoids: protection of ovarian follicular cells against apoptosis. 1462 88

We employed potent and selective c-Src inhibitors to investigate the functional and molecular consequences of inhibited c-Src tyrosine kinase activity in osteoclasts. These pyrrolopyrimidine derivatives reduced osteoclast numbers and induced osteoclast disruption in vivo. In vitro, they inhibited resorption pit formation and osteoclastogenesis, impaired adhesion ability and actin ring organization, and induced programmed cell death in mature osteoclasts. The cell death receptor Fas and p53 were insensitive to c-Src modulation. The expression of the cyclin-dependent kinase (CDK)-inhibitor p21WAF1/CIP1 was markedly reduced, but neither Bcl-2 nor Bcl-xL or Bax were modulated by c-Src inhibition. Caspase-9, and to a lesser extent caspase-3, but not caspase-8, were transiently cleaved (activated) by treatment with the c-Src inhibitors. c-Src inhibition stabilized p38 mitogen-activated protein kinase (MAPK), whereas the c-Jun N-terminal kinase (JNK) pathway did not appear to be modulated by our compounds. Most interestingly, transient extracellular signal regulated kinase (ERK1/2) dephosphorylation followed by sustained remarkable rephosphorylation overwhelming control levels was observed in response to c-Src inhibition. Blockade of ERK1/2 rephosphorylation by PD98059 reduced osteoclast nuclear disruption, suggesting the involvement of this pathway in apoptosis. Collectively, these data demonstrate that small pyrrolopyrimidine derivatives impair osteoclast function and induce cell damage suggestive of apoptosis in vivo and in vitro, with mechanisms presumably involving selective sustained ERK1/2 phosphorylation.
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PMID:Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK1/2 pathway. 1475 64

ZBP-89 induces apoptosis in human gastrointestinal cancer cells through a p53-independent mechanism. To understand the apoptotic pathway regulated by ZBP-89, we identified downstream signal transduction targets. Ectopic expression of ZBP-89 induced apoptosis through the mitochondrial pathway and was accompanied by activation of all three MAP kinase subfamilies: JNK1/2, ERK1/2 and p38 MAP kinase. ZBP-89-induced apoptosis was markedly enhanced by ERK inhibition with U0126. In contrast, inhibiting JNK with a JNK1-specific peptide inhibitor or dominant-negative JNK2 expression abrogated ZBP-89-mediated apoptosis. The p38 inhibitor SB202190 had no effect on ZBP-89-induced cell death. Protein dephosphorylation assays revealed that ZBP-89 activates JNK via repression of JNK dephosphorylation. Oligonucleotide microarray analyses revealed that ectopic expression of ZBP-89 downregulated expression of the dual-specificity phosphatase MKP6. Overexpression of MKP6 blocked ZBP-89-induced JNK phosphorylation and PARP cleavage. In addition, ectopic expression of ZBP-89 repressed Bcl-xL and Mcl-1 expression, but had no effect on Bcl-2. Silencing ZBP-89 with small interfering RNA enhanced both Bcl-xL and Mcl-1 expression. Taken together, ZBP-89-mediated apoptosis occurs via a p53-independent mechanism that requires JNK activation.
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PMID:ZBP-89-induced apoptosis is p53-independent and requires JNK. 1496 12

Basic fibroblast growth factor (bFGF) serves as a modulator of survival in breast cancer cells. The mechanisms by which bFGF transduces the anti-apoptotic signal and interacts with COX inhibitors were investigated. bFGF reduced apoptosis in MCF-7 breast cancer cells and up-regulated the expression of mitocondrial Bcl-2, whereas COX inhibitors meloxicam (selective COX-2) and aspirin (non-selective), induced apoptosis. bFGF up-regulated survivin protein expression and induced cdc-2 phosphorylation moderately at early (2-6 h), and substantially at late (24 h), time-points. Survivin mRNA expression was up-regulated only at the later time-point. COX inhibitors prevented up-regulation of survivin protein expression at both 2 and 24 h and prevented early modest increases in cdc-2 phosphorylation. Up-regulation of survivin mRNA was not found to be modulated by the COX-2 inhibitor meloxicam. bFGF regulation of survivin expression was found to be ERK1/2 kinase dependent and bFGF-induced phosphorylation of c-raf was prevented by the COX-2 inhibitor. bFGF was, however, unable to induce COX-2 protein expression or modulate COX-2 activity in MCF-7 cells as evidenced by unaltered PGE(2) production. These results indicate that bFGF regulates survivin expression in MCF-7 breast cancer cells by signaling through an ERK1/2 dependent pathway. COX-2 inhibitors can modulate bFGF-induced survivin expression in a COX-2 independent manner.
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PMID:COX inhibitors modulate bFGF-induced cell survival in MCF-7 breast cancer cells. 1499 71

Human and animal models have evidenced how estrogen insufficiency is associated with abnormal spermatogenesis and male infertility. We previously demonstrated that estradiol is able to influence both capacitation and acrosome reaction in human ejaculated spermatozoa. It remains to be elucidated whether the biochemical changes induced by estradiol, in a rapid nongenomic way, are mediated by a single estrogen receptor (ER) or by the two ER subtypes, ER alpha and ER beta. In the present study, we have first demonstrated the concomitant expression of ER beta and ER alpha in human ejaculated spermatozoa. By RT-PCR and Southern blot, transcripts of both ERs were detected. Western blot analysis showed ER alpha and ER beta proteins at the same size as the "classical" ERs. The localization of ER alpha and ER beta with the immunocytochemistry shows a differential distribution of the two ER subtypes, the former being prevalently located in the midpiece, but the latter being in the tail. Estradiol has been associated with sperm longevity; however, the mechanism through which estradiol acts in sperm survival was never investigated. Upon estradiol exposure, we observed an enhanced phosphorylation of the proteins involved in the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway like PDK1, Akt, GSK-3, Bcl-2, together with ERK1/2, which was also involved in cell survival signals. Moreover, such phosphorylations were reduced in the presence of ICI 182, 780, addressing the role of estradiol and ERs in sperm survival. For instance we have provided, for the first time, a different interaction of the two ERs with the PI3K/Akt pathway, because ER alpha interacts with the p55 regulatory subunit of PI3K, whereas ER beta interacts with Akt1. However, it still remains to be elucidated whether the functional role of each of the ER subtypes in sperm survival signaling is redundant or distinct.
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PMID:Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa: evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway. 1500 46

Candida albicans, the most common opportunistic fungal pathogen of humans is a part of the normal microbial flora. To investigate host-parasite interaction related to the commensal-pathogen switch of this yeast we compared the response of macrophages to C. albicans and to the non-pathogenic yeast Saccharomyces cerevisiae. In contrast to S. cerevisiae, C. albicans survived within macrophages. This escape from macrophages was associated with qualitative differences in the sequential phosphorylation of MEK, ERK1/2, and p90RSK during phagocytosis. Decreased activation of this pathway was observed with C. albicans and was associated with a species-specific overexpression of the MEK phosphatase, MKP-1. Dysregulation of the ERK1/2/p90RSK signal transduction pathway by C. albicans was associated downstream with reduction in Bad phosphorylation, specifically at Ser-112, and disappearance of free Bcl-2. This ended at apoptosis of cells that have ingested C. albicans, as revealed by staining of phosphatidylserine exposure in the macrophage outer membrane. The role of phospholipomannan (PLM), a phylogenetically unique glycolipid with a phytoceramide moiety expressed at the surface of and shed by C. albicans, was examined. Addition of PLM to macrophages led to dysregulation similar to that observed with live C. albicans and promoted the survival of the sensitive S. cerevisiae within the cells. Evidence of externalization of membranous phosphatidylserine, loss of mitochondrial integrity, and DNA fragmentation after incubation of macrophages with PLM suggest that this molecule supported the activities observed with C. albicans yeast cells.
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PMID:Role of phospholipomannan in Candida albicans escape from macrophages and induction of cell apoptosis through regulation of bad phosphorylation. 1503 94

We previously reported that hypoxia followed by reoxygenation (hypoxia/reoxygenation) rapidly activated intracellular signaling such as mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated protein kinase (ERK) 1/2, p38MAPK, and stress-activated protein kinases (SAPKs). To investigate the humoral factors which mediate cardiac response to hypoxia/reoxygenation, we analyzed the conditioned media from cardiac myocytes subjected to hypoxia/reoxygenation by two-dimensional electrophoresis and mass spectrometry. We identified cyclophilin A (CyPA) as one of the proteins secreted from cardiac myocytes in response to hypoxia/reoxygenation. Hypoxia/reoxygenation induced the expression of CyPA and its cell surface receptor CD147 on cardiac myocytes in vitro. This was also confirmed by ischemia/reperfusion in vivo. Recombinant human (rh) CyPA activated ERK1/2, p38MAPK, SAPKs, and Akt in cultured cardiac myocytes. Furthermore, CyPA significantly increased Bcl-2 in cardiac myocytes. These data strongly suggested that CyPA is released from cardiac myocytes in response to hypoxia/reoxygenation and may protect cardiac myocytes from oxidative stress-induced apoptosis.
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PMID:Hypoxia followed by reoxygenation induces secretion of cyclophilin A from cultured rat cardiac myocytes. 1504 62

Apoptosis is implicated in the progressive cell loss and fibrosis both at glomerular and tubulointerstitial level. In this study, we examined the potential mechanisms by which persistent proteinuria (protein-overload model) could induce apoptosis. After uninephrectomy (UNX), Wistar rats received daily injections of 0.5 g of bovine serum albumin (BSA)/100 g body weight or saline. Both at day 8 and day 28, rats receiving BSA had proteinuria and renal lesions characterized by tubular atrophy and/or dilation and mononuclear cell infiltration. In relation to control-UNX rats, renal cortex of nephritic rats showed an increment in AT2 mRNA (reverse transcriptase-polymerase chain reaction) and protein (Western blot) expression. In both groups, AT2 receptor immunostaining was mainly localized in proximal tubular cells. Rats with persistent proteinuria showed a significantly increased number of terminal dUTP nick-end labeling positive apoptotic cells compared with UNX-controls, both in glomeruli and tubulointerstitium. Double staining for apoptosis and AT2 receptor showed that most terminal dUTP nick-end labeling positive cells were found in tubules expressing AT2 receptor. Using an antibody that recognizes the active form caspase-3, we observed an increment in caspase-3 activation in rats receiving BSA with respect to those receiving saline. Rats with persistent proteinuria showed a diminution in the phosphorylation of Bcl-2 with respect to UNX-controls both at day 8 and day 28. By contrast, no changes were observed either in the Bax or in the Bcl-2 protein levels. The administration of BSA to UNX rats induced a diminution in the phosphorylation of ERK with respect to UNX-control at all times studied. The changes observed in ERK activities took place without alterations of ERK1/2 protein levels. In summary, our data suggest that persistent proteinuria causes apoptosis in tubular cells through the activation of AT2 receptor, which can, in turn, inhibit MAP kinase (ERK1/2) activation and Bcl-2 phosphorylation.
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PMID:Persistent proteinuria up-regulates angiotensin II type 2 receptor and induces apoptosis in proximal tubular cells. 1511 28

Engagement of antigen receptors on immature B cells induces apoptosis, while at the mature stage, it stimulates cell activation and proliferation. The difference in B cell receptor (BCR)-mediated signaling pathways regulating death or survival of B cells is not fully understood. We aimed to characterize the pathway leading to BCR-driven apoptosis. Transitional immature B cells were obtained from the spleen of sublethally irradiated and auto-reconstituted mice. We have detected a short-lived BCR-driven activation of mitogen-activated protein kinases (ERK1/2 and p38 MAPK) and Akt/PKB in transitional immature B cells that correlated with the lack of c-Fos expression, reduced phosphorylation of Akt substrates and a susceptibility for apoptosis. Simultaneous signaling through BCR and CD40 protected immature B cells from apoptosis, however, without inducing Bcl-2 expression. The BCR-induced apoptosis of immature B cells is a result of the collapse of mitochondrial membrane potential and the subsequent activation of caspase-3.
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PMID:Antigen receptor-mediated signaling pathways in transitional immature B cells. 1515 67


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