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)

Studies from our laboratory have demonstrated that the major green tea polyphenol, (-)-epigallocatechin 3-gallate (EGCG), exerts potent neuroprotective actions in the mice model of Parkinson's disease. These studies were extended to neuronal cell culture employing the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA). Pretreatment with EGCG (0.1-10 microm) attenuated human neuroblastoma (NB) SH-SY5Y cell death, induced by a 24-h exposure to 6-OHDA (50 microm). Potential cell signaling candidates involved in this neuroprotective effect were further examined. EGCG restored the reduced protein kinase C (PKC) and extracellular signal-regulated kinases (ERK1/2) activities caused by 6-OHDA toxicity. However, the neuroprotective effect of EGCG on cell survival was abolished by pretreatment with PKC inhibitor GF 109203X (1 microm). Because EGCG increased phosphorylated PKC, we suggest that PKC isoenzymes are involved in the neuroprotective action of EGCG against 6-OHDA. In addition, gene expression analysis revealed that EGCG prevented both the 6-OHDA-induced expression of several mRNAs, such as Bax, Bad, and Mdm2, and the decrease in Bcl-2, Bcl-w, and Bcl-x(L). These results suggest that the neuroprotective mechanism of EGCG against oxidative stress-induced cell death includes stimulation of PKC and modulation of cell survival/cell cycle genes.
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PMID:Involvement of protein kinase C activation and cell survival/ cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action. 1205 35

Studies in non-cardiomyocytic cells have shown that phosphorylation of the Bcl-2 family protein Bad on Ser-112, Ser-136 and Ser-155 decreases its pro-apoptotic activity. Both phenylephrine (100 microM) and the cell membrane-permeating cAMP analog, 8-(4-chlorophenylthio)-cAMP (100 microM), protected against 2-deoxy-D-glucose-induced apoptosis in neonatal rat cardiac myocytes as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). In cardiac myocytes, phenylephrine primarily stimulates the alpha-adrenoceptor, but, at high concentrations (100 microM), it also increases the activity of the cAMP-dependent protein kinase, protein kinase A (PKA) through the beta-adrenoceptor. Phenylephrine (100 microM) promoted rapid phosphorylation of Bad(Ser-112) and Bad(Ser-155), though we were unable to detect phosphorylation of Bad(Ser-136). Phosphorylation of Bad(Ser-112) was antagonized by either prazosin or propranolol, indicating that this phosphorylation required stimulation of both alpha(1)- and beta-adrenoceptors. Phosphorylation of Bad(Ser-155) was antagonized only by propranolol and was thus mediated through the beta-adrenoceptor. Inhibitor studies and partial purification of candidate kinases by fast protein liquid chromatography showed that the p90 ribosomal S6 kinases, p90RSK2/3 [which are activated by the extracellular signal-regulated kinases 1 and 2 (ERK1/2)] directly phosphorylated Bad(Ser-112), whereas the PKA catalytic subunit directly phosphorylated Bad(Ser-155). However, efficient phosphorylation of Bad(Ser-112) also required PKA activity. These data suggest that, although p90RSK2/3 phosphorylate Bad(Ser-112) directly, phosphorylation of this site is enhanced by phosphorylation of Bad(Ser-155). These phosphorylations potentially diminish the pro-apoptotic activity of Bad and contribute to the cytoprotective effects of phenylephrine and 8-(4-chlorophenylthio)-cAMP.
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PMID:Phenylephrine promotes phosphorylation of Bad in cardiac myocytes through the extracellular signal-regulated kinases 1/2 and protein kinase A. 1209 10

Loss of estrogen-responsiveness and impaired E-cadherin expression/function has been linked to increased metastatic potential of breast cancer cells. In this study, we report that proliferation of breast cancer cells can resume following removal of a toxic stimulus causing severe impairment of cell adhesion and estrogen responsiveness. This type of response was induced by okadaic acid (OA) in MCF-7 cells, and was accompanied by an almost complete block of DNA synthesis, loss of cell-cell contact and cell detachment from culture dishes, loss of estrogen receptor (ER), progesterone receptor (PR) and E-cadherin, whereas only a weak, if any, inhibition of protein synthesis could be observed. These responses were detected in MCF-7 cells after a 1-day treatment with 50 nM OA, and could be reversed if OA-treated cells were recovered in a culture medium devoid of the toxin, so that rescued cells resumed growth 8-12 days after replating. By pulse-chase experiments, we found that protein synthesis was not significantly affected in rescued cells, whose DNA synthesis, instead, was almost completely blocked during the first days of MCF-7 cell rescue from OA treatment. We also analyzed E-cadherin, mitogen activated protein kinase isoforms ERK1 and ERK2, Bcl-2 and BAX proteins during the rescue of MCF-7 cells from OA-induced cell death, and found that their expression followed temporally defined patterns. Cellular levels of E-cadherin returned to control levels within the first days of the rescue, followed by ER, ERK1, and ERK2, and finally by Bcl-2 and BAX proteins. Under our experimental conditions, restoration of cell adhesion did not require a functional ER system, but recovery of a normal ER pool accompanied resumption of estrogen-dependent proliferation of OA-treated MCF-7 cells.
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PMID:Recovery of cellular E-cadherin precedes replenishment of estrogen receptor and estrogen-dependent proliferation of breast cancer cells rescued from a death stimulus. 1211 23

Previously we showed that cardiac fibroblasts are cellular targets of estrogen and that there are significant differences in proliferative response of male and female cardiac fibroblasts under hypoxia, a condition of myocardial ischemia. Here, we tested the hypothesis that signaling pathways that control cell cycle progression and apoptosis in cardiac fibroblasts may be activated in a gender-specific manner. Cardiac fibroblasts from adult, age-matched male and female rat heart were exposed to hypoxia (2% O2) and normoxia. Western analysis of cell lysate was used to compare the level of basal and hypoxia-induced expression of signal transduction proteins, known to control cell cycle progression and cell death. Hypoxia led to significant activation of MAP (mitogen-activated protein) kinase and Jun kinase pathways, as shown by phosphorylated extracellular signal-regulated kinase (ERK1/2) and Jun kinase isotypes in male cells but this effect was modest in female cells. Male cells expressed higher levels of basal expression for transcription factors c-jun and NF-kB as well as the inhibitor of NF-kB (lk-B). Although hypoxia did not induce changes in the level of c-Jun in either cell type, it moderately increased the level of NF-kB in male cells but led to its decrease in female cells. Basal and hypoxia-induced expression of cyclin D1, c-fos, and PCNA seemed to be comparable in both male and female cells. However, hypoxia-induced activation of cyclin B1, which occurred in both cells, was stronger in female cells. Basal expression of apoptosis-associated transcription factor, p53, was comparable in both cells. However, under hypoxia, there was an increase in the p53 level only in female cells. Although female cells showed higher basal expression for survival-associated protein, Bcl-2, the level of this protein remained unchanged under hypoxia in both cells. Together, these data demonstrate differences in basal and hypoxia-induced expression of proteins with an established role in cell cycle progression and apoptosis in male and female cardiac fibroblasts. These differences may further point to gender-related differences in signal transduction pathways that control the proliferative response of those cells under hypoxia.
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PMID:Gender-related differences in basal and hypoxia-induced activation of signal transduction pathways controlling cell cycle progression and apoptosis, in cardiac fibroblasts. 1237 61

Human neuroblastoma cells, SH-SY5Y, contain relatively low levels of thioredoxin (Trx); thus, they serve favorably as a model for studying oxidative stress-induced apoptosis (Andoh, T., Chock, P. B., and Chiueh, C. C. (2001) J. Biol. Chem. 277, 9655-9660). When these neurotrophic cells were subjected to nonlethal 2-h serum deprivation, their neuronal nitric oxide synthase and Trx were up-regulated, and the cells became more tolerant of oxidative stress, indicating that NO may protect cells from serum deprivation-induced apoptosis. Here, the mechanism by which NO exerts its protective effects was investigated. Our results reveal that in SH-SY5Y cells, NO inhibits apoptosis through its ability to activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1 and Trx, which subsequently induces the expression of Bcl-2. Furthermore, active PKG promotes the elevation of c-Jun, phosphorylated MAPK/ERK1/2, and c-Myc, consistent with the notion that PKG enhances the expression of Trx through its c-Myc-, AP-1-, and PEA3-binding motifs. Elevation of Trx and Trx peroxidase-1 and Mn(II)-superoxide dismutase would reduce H(2)O(2) and O(2)(), respectively. Thus, the cytoprotective effect of NO in SH-SY5Y cells appears to proceed via the PKG-mediated pathway, and S-nitrosylation of caspases plays a minimal role.
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PMID:Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. 1241 92

Activation of G-protein coupled muscarinic acetylcholine receptors and MAPKs/ERK-1/2 has been found to inhibit neural cell apoptosis and promote neural cell survival. Bcl-2 protein family also plays an important role in regulating neural cell apoptosis and survival. However, signaling pathways coupling muscarinic receptors to Bcl-2 family remains to be elucidated. In the present study, it was found that carbachol not only activated MEK/ERK-1/2 signaling pathways, but also increased the expression levels of Bcl-2 and phospho-Bad proteins in human neuroblastoma SH-SY5Y cells. These effects were blocked by a muscarinic receptor antagonist (atropine) and a MEK inhibitor(PD98059) and were significantly attenuated by a Src family kinases inhibitor(PP1) and a PKC inhibitor (bisindolymaleimide-I), but were not influenced by a G(i/o)-uncoupling reagent (pertussin toxin) and a PI-3 kinase inhibitor (wortmannin). Furthermore, carbachol also stimulated Bcl-2 promoter-driven luciferase gene expression in transfected SH-SY5Y cells. Co-transfection of Ras or Raf dominant negative mutants with the pBcl-2-Luc plasmid abolished carbachol s effects. These data suggested that muscarinic acetylcholine receptors regulated the expression of Bcl-2 protein family by Ras-ERK-1/2 signaling pathway involving the pertussin toxin-insensitive G-proteins, PKC and Src.
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PMID:[G-protein-coupled muscarinic acetylcholine receptor activation up-regulates Bcl-2 and phospho-bad via Ras-ERK-1/2 signaling pathway]. 1251 26

While substantial and compelling evidence exists for sex-related differences in gross and microscopic brain structure, our understanding of the cellular mechanisms that give rise to these sexual dimorphisms is in its infancy. To investigate possible underlying mechanisms for sex-related differences in neuronal development, we examined neuronal survival and transductional signaling in male and female rat primary cortical neuronal cultures. We found that following 14 days in culture, the total number of surviving neurons was significantly higher in female cultures derived from either cortical plate (cp) or ventricular zone (vz), the regions where differentiating (cp) and proliferating (vz) cells are located. In addition, sex-related differences in the levels of phospho-ERK1 and Akt were also observed. Female cortical cultures had significantly higher levels of ERK1 in both cp and vz and higher levels of Akt in cp. No sex-related differences in Bcl-2 were observed. These data suggest that dimorphisms in cell survival may underlie enhanced neuronal survival (or decreased apoptosis) in female brain. Further, the appearance of sex-related differences at cellular and signaling levels in cortical neuronal cultures demonstrates that the effects of gender are not limited to parts of the brain mediating reproduction.
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PMID:Sex-related differences in neuronal cell survival and signaling in rats. 1252 89

The surface of the pathogenic yeast Candida albicans is coated with phospholipomannan (PLM), a phylogenetically unique glycolipid composed of beta-1,2-oligomannosides and phytoceramide. This study compared the specific contribution of PLM to the modulation of signaling pathways linked to the survival of C. albicans in macrophages in contrast to Saccharomyces cerevisiae. C. albicans endocytosis by J774 and disregulation of the ERK1/2 signal transduction pathway was associated downstream with a reduction in Bad Ser-112 phosphorylation and disappearance of free Bcl-2. This suggested an apoptotic effect, which was confirmed by staining of phosphatidylserine in the macrophage outer membrane. The addition of PLM to macrophages incubated with S. cerevisiae mimicked each of the disregulation steps observed with C. albicans and promoted the survival of S. cerevisiae. Externalization of membranous phosphatidylserine, loss of mitochondrial integrity, and DNA fragmentation induced by PLM showed that this molecule promoted yeast survival by inducing host cell death. These findings suggest strongly that PLM is a virulence attribute of C. albicans and that elucidation of the relationship between structure and apoptotic activity is an innovative field of research.
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PMID:Candida albicans phospholipomannan promotes survival of phagocytosed yeasts through modulation of bad phosphorylation and macrophage apoptosis. 1255 50

BAG-1 was originally identified as a binding partner of anti-apoptotic factor Bcl-2 [Takayama et al., Cell 80 (1995) 279-284]. Exogenous expression of BAG-1 was reported to confer cells resistance to several stresses [Chen et al., Oncogene 21 (2002) 7050]. We have obtained human cervical cancer HeLa cells with down-regulated BAG-1 levels by using a highly specific and efficient RNA interference approach. Surprisingly, cells with down-regulated BAG-1 exhibited significantly lower sensitivity against several anti-cancer drugs than parental cells expressing normal levels of the protein. Furthermore, growth rate of the cells was reduced when BAG-1 was down-regulated. Activity of ERK pathway appeared to be decreased in BAG-1 down-regulated cells, as shown by the reduced phosphorylation of ERK1/2 proteins. Taken together resistance against anti-cancer drugs acquired by BAG-1 down-regulated cells may well be accounted for by the retardation of cell cycle progression, implicating the importance of BAG-1 in cell growth regulation.
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PMID:Down-regulation of Bcl-2-interacting protein BAG-1 confers resistance to anti-cancer drugs. 1256 51

CC139 fibroblasts are one of several model systems in which the Raf --> MEK --> ERK1/2 pathway can inhibit apoptosis independently of the PI3K pathway; however, the precise mechanism for this protective effect is not known. Serum withdrawal from CC139 fibroblasts resulted in the rapid onset of apoptosis, which was prevented by actinomycin D or cycloheximide. Serum withdrawal promoted the rapid, de novo accumulation of Bim(EL), a proapoptotic 'BH3-only' member of the Bcl-2 protein family. Bim(EL) expression was an early event, occurring several hours prior to caspase activation. In contrast to studies in neurons, activation of the JNK --> c-Jun pathway was neither necessary nor sufficient to induce Bim(EL) expression. Selective inhibition of either the ERK pathway (with U0126) or the PI3K pathway (with LY294002) caused an increase in the expression of Bim(EL). Furthermore, selective activation of the ERK1/2 pathway by deltaRaf-1:ER* substantially reduced Bim(EL) expression, abolished conformational changes in Bax and blocked the appearance of apoptotic cells. The ability of deltaRaf-1:ER* to repress Bim(EL) expression required the ERK pathway but was independent of the PI3K --> PDK --> PKB pathway. Thus, serum withdrawal-induced expression of Bim(EL) occurs independently of the JNK --> c-Jun pathway and can be repressed by the ERK pathway independently of the PI3K pathway. This may contribute to Raf- and Ras-induced cell survival at low serum concentrations.
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PMID:Activation of ERK1/2 by deltaRaf-1:ER* represses Bim expression independently of the JNK or PI3K pathways. 1261 53


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