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)

Human lactoferrin (hLF) is a member of the transferrin family and is found in most body fluids of human. Recent study showed that hLF played some roles in the regulation of cell growth. However, the biological function of hLF in the central nervous system and neuronal cells is still unclear. The MTT was used to assay cell viability, ELISA tests were used to assay caspase activities, and TUNEL staining was used to test the cytotoxicity of hLF to the cells. Our result showed that 700 microg/ml hLF significantly reduced the cell viability and increased the caspase 3 and 8 activities in PC12 neuronal cells. TUNEL staining further showed that 700 microg/ml hLF was cytotoxic to the PC12 through apoptosis-mediated pathway. In addition, 700 microg/ml hLF significantly decreased the protein expressions of phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) and Bcl-2 in PC12 cells, whereas 50 microg/ml hLF significantly increased the phosphorylation of ERK1/2 which could be specifically inhibited by PD98059. Furthermore, 50 microg/ml hLF could not only up-regulate the Bcl-2 expression but also protect PC12 cells from FasL-induced apoptosis. In conclusion, hLF plays a crucial role in the regulation of apoptosis and anti-apoptosis in PC12 neuronal cells via ERK1/2 phosphorylation pathway.
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PMID:Human lactoferrin exerts bi-directional actions on PC12 cell survival via ERK1/2 pathway. 1618 36

Many isothiocyanates (ITCs) such as sulforaphane (SFN), phenethyl isothiocyanate (PEITC) and allyl isothiocyanate (AITC) are highly effectively in chemoprevention or reduction of the risk of cancer and possess antitumor activities in vitro and in vivo. The activator protein 1 (AP-1) and MAPK signaling pathways are believed to play an important role in cancer chemoprevention and chemotherapy due to their involvement in tumor cell growth, proliferation, apoptosis and survival. In the present study, we determined the effects of SFN, PEITC and AITC on AP-1 activation, and investigated the roles of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways in the regulation of AP-1 activation and cell death elicited by these ITCs in human prostate cancer PC-3 cells. SFN, PEITC and AITC each induced AP-1 activity potently and caused a significant elevation in the phosphorylation of ERK1/2, JNK1/2, Elk-1 and c-Jun. Transfection with ERK2 and upstream kinase DNEE-MEK1 activated AP-1 activity, and transfection with dominant-negative mutant ERK2 (dnERK2) potently decreased AP-1 activation induced by SFN, PEITC and AITC. Transfection with JNK1 and upstream kinase MKK7 activated AP-1 activity, and transfection with dominant-negative mutant JNK1-APF significantly attenuated AP-1 activation induced by SFN, PEITC and AITC. Pretreatment with MEK1-ERK inhibitor U0126 and JNK inhibitor SP600125 substantially attenuated the decrease in cell viability induced by SFN, PEITC and AITC. Transfection with dnERK2 and JNK1-APF significantly reversed the decrease of Bcl-2 expression elicited by these ITCs. Furthermore, transfection with dnERK2 and JNK1-APF blocked the apoptosis induced by these ITCs in PC-3 cells. Taken together, our results indicate that the activation of the ERK and JNK signaling pathways is important for transcriptional activity of AP-1 and is involved in the regulation of cell death elicited by ITCs in PC-3 cells.
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PMID:ERK and JNK signaling pathways are involved in the regulation of activator protein 1 and cell death elicited by three isothiocyanates in human prostate cancer PC-3 cells. 1627 72

The 52-aminoacid peptide adrenomedullin (AM) is expressed in the normal and malignant prostate. We have previously shown that prostate cancer cells produce and secrete AM, which acts as an autocrine growth inhibitory factor. We have evaluated in the present study the role of AM in prostate cancer cell apoptosis, induced either by serum deprivation or treatment with the chemotherapeutic agent etoposide (which acts as an inhibitor of topoisomerase II). For this purpose we over-expressed AM in PC-3, DU 145 and LNCaP cells, which were transfected with an expression vector carrying AM. We also treated the parental cell lines with synthetic AM in normal culture conditions and in conditions of induced-apoptosis. After serum removal, AM prevented apoptosis in DU 145 and PC-3 cells, but not in LNCaP cells. When treated with etoposide, AM prevented apoptosis in PC-3 and LNCaP cells, but not in DU 145 cells. Cell cycle analysis demonstrated a significant decrease in the percentage of AM-overexpressing PC-3 cells in the subG0/G1 phase after treatment with etoposide, as compared to the percentage of mock-transfected PC-3 treated cells. Western blot showed that protein levels of phosphorylated ERK1/2 increased in parental PC-3 cells after treatment with etoposide. In PC-3 cells overexpressing AM, phosphorylated ERK1/2 basal levels were lower than basal levels of parental PC-3 cells, and treatment with etoposide did not result in such an increase. Etoposide produced a significant increase in cleaved PARP in parental PC-3 cells. However, PC-3 clones overexpressing AM that were treated with etoposide only showed a mild increase in fragmented PARP. The ratio Bcl-2/Bax was reduced in parental or mock-transfected PC-3 cells after treatment with etoposide. On the contrary, this ratio was not reduced in PC-3 clones with AM overexpression that were treated with etoposide. All these data demonstrate that AM plays a protective role against induced apoptosis in prostate cancer cells. These results may have important implications in prostate cancer resistance to chemotherapeutic agents.
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PMID:Adrenomedullin prevents apoptosis in prostate cancer cells. 1629 90

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) serves as an extracellular signal that triggers apoptosis in tumor cells. To characterize the molecular events involved in TRAIL-induced apoptotic signaling, we investigated the role of extracellular signal-regulated kinase 1/2 (ERK1/2) in HeLa cell death. Here we show that TRAIL-activated ERK1/2 through a tyrosine kinase-dependent pathway, subsequently elevated anti-apoptotic Bcl-2 protein levels. ERK1/2 inhibition with PD98059 promoted apoptotic cell death through the downregulation of ERK1/2 activity and Bcl-2 protein levels. Moreover, tyrosine kinase inhibition with Genistein in TRAIL-induced apoptosis effectively attenuated ERK1/2 activity and enhanced apoptotic cell death. Taken together, our results indicate that ERK1/2 activation via tyrosine kinase pathway plays a protective role as the cellular defense mechanism through the upregulation of Bcl-2 protein levels in TRAIL-induced apoptosis.
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PMID:The activation of ERK1/2 via a tyrosine kinase pathway attenuates trail-induced apoptosis in HeLa cells. 1630 93

Sodium butyrate (NaBu) has an inhibitory effect on histone deacetylases (HDACs). The mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAP, kinase are known to be modulated during NaBu-induced apoptosis. In the present study, we showed that low concentrations of NaBu could induce apoptosis synergistically with the inhibition of p38 MAP kinase as proven by using specific p38 MAP kinase inhibitor and dominant negative p38 transfection in a ras-transformed rat liver epithelial cell line (WB-ras). There were no changes in HDAC1, suggesting that NaBu might be able to kill transformed cells bypassing the HDAC inhibitory effect. We further demonstrated that inhibition of p38 MAP kinase potentiated apoptotic cascades, including cleavage of poly(ADP-ribose) polymerase, caspase-3, and decrease in Bcl-2/Bax ratio even at a lower concentration of NaBu. Thus, p38 MAP kinase played inhibitory roles in NaBu-induced apoptosis, and simultaneous modulation of MAP kinases in NaBu treatment could increase the efficiency of the chemotherapeutic effect of NaBu.
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PMID:Augmentation of sodium butyrate-induced apoptosis by p38 MAP kinase inhibition in rat liver epithelial cells. 1635 38

We previously showed that C-phycocyanin (PC), an antioxidant biliprotein pigment of Spirulina platensis (a blue-green alga), effectively inhibited doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. Here we investigated the cardioprotective effect of PC against ischemia-reperfusion (I/R)-induced myocardial injury in an isolated perfused Langendorff heart model. Rat hearts were subjected to 30 min of global ischemia at 37 degrees C followed by 45 min of reperfusion. Hearts were perfused with PC (10 microM) or Spirulina preparation (SP, 50 mg/l) for 15 min before the onset of ischemia and throughout reperfusion. After 45 min of reperfusion, untreated (control) hearts showed a significant decrease in recovery of coronary flow (44%), left ventricular developed pressure (21%), and rate-pressure product (24%), an increase in release of lactate dehydrogenase and creatine kinase in coronary effluent, significant myocardial infarction (44% of risk area), and TdT-mediated dUTP nick end label-positive apoptotic cells compared with the preischemic state. PC or SP significantly enhanced recovery of heart function and decreased infarct size, attenuated lactate dehydrogenase and creatine kinase release, and suppressed I/R-induced free radical generation. PC reversed I/R-induced activation of p38 MAPK, Bax, and caspase-3, suppression of Bcl-2, and increase in TdT-mediated dUTP nick end label-positive apoptotic cells. However, I/R also induced activation of ERK1/2, which was enhanced by PC treatment. Overall, these results for the first time showed that PC attenuated I/R-induced cardiac dysfunction through its antioxidant and antiapoptotic actions and modulation of p38 MAPK and ERK1/2.
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PMID:C-phycocyanin protects against ischemia-reperfusion injury of heart through involvement of p38 MAPK and ERK signaling. 1637 83

Extracts of Artemisia asiatica Nakai (Asteraceae) possess anti-inflammatory and antioxidative activities. Eupatilin (5,7-dihydroxy-3',4', 6-trimethoxyflavone), one of the pharmacologically active ingredients derived from A. asiatica was shown to induce apoptosis in human promyelocytic leukemia (HL-60) cells. In the present study, we examined the ability of eupatilin to induce apoptosis in human gastric cancer (AGS) cells. Eupatilin induced the apoptosis of AGS cells as revealed by a decrease in the ratio of pro-apoptotic Bax and anti-apoptotic Bcl-2, as well as the cleavage of caspase-3 and poly(ADP-ribose)polymerase (PARP). The pro-apoptotic effects of eupatilin were further verified by its perturbation of the mitochondrial transmembrane potential (DeltaPsim). In addition, eupatilin treatment led to an elevated expression of p53 and p21. Eupatilin inhibited the activation of ERK1/2 and Akt, which are important components of cell-survival pathways.
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PMID:Eupatilin, a pharmacologically active flavone derived from Artemisia plants, induces apoptosis in human gastric cancer (AGS) cells. 1639 20

Inflammatory cell recruitment, activation, and apoptosis are highly regulated processes involving several checkpoints controlling the resolution of inflammation. We investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathway (ie, ERK1/2) and apoptosis-regulating Bcl-2 family members (ie, Bcl-x(L) and Bax) in the resolution of a rat carrageenan-induced pleurisy model. The specific ERK1/2 inhibitor PD98059 enhanced the resolution of inflammation, whereas the MEK1/2 inhibitor U0126 had no effect and the flavonoid apigenin, a nonspecific inhibitor of ERK1/2 and COX-2, augmented inflammation. Specifically, PD98059 significantly decreased the total number of macrophages and neutrophils in the pleural cavity, mainly by increasing the rate of neutrophil apoptosis, as measured by Annexin V labeling and morphological analysis. Conversely, a specific inhibitor of proapoptotic Bax (V5) increased inflammation, indicating that by preventing apoptosis in vivo, resolution of inflammation is delayed. This was associated with a decrease in neutrophil apoptosis and an increase in macrophage and neutrophil numbers perpetuating the inflammatory response. In conclusion, this study shows that ERK1/2, Bax, and Bcl-x(L) play important functional roles in the resolution phase of the acute inflammatory response in vivo by influencing apoptosis. Importantly, these data may provide novel therapeutic targets for the treatment of inflammatory diseases.
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PMID:The involvement of the apoptosis-modulating proteins ERK 1/2, Bcl-xL and Bax in the resolution of acute inflammation in vivo. 1665 40

Oxidative stress has a complex effect on cancer development. To further study this process, we induced colon tumors with azoxymethane (AOM) in mice deficient for uncoupling protein-2 (UCP2). UCP2 has recently emerged as a negative regulator of mitochondrial oxidant production. When overexpressed, UCP2 protects cells from oxidative stress, while its absence may cause abundance of reactive oxygen species, release of pro-inflammatory cytokines and persistent activation of nuclear factor kappaB (NF-kappaB), a pleiotropic transcription factor with an increasingly recognized role in cancer. Here we show that Ucp2-/- mice develop more aberrant crypt foci and colon tumors than Ucp2+/+ littermates when examined 24 weeks after the completion of treatment with AOM (10 mg/kg i.p. weekly for a total of 6 weeks, n = 8-12). This effect is primarily seen in the proximal colon of Ucp2-/- mice (P < 0.05), in association with changes indicative of increased oxidative stress (increased staining for malondialdehyde and inducible nitric oxide synthase), enhanced NF-kappaB activation (increased levels of phosphorylated IkappaB and increased nuclear presence of p65) and a disrupted balance between intestinal epithelial cell proliferation (greater 5-bromo-2'-deoxy-uridine incorporation rates and increased phosphorylation of ERK1/2 and AKT) and apoptosis (decreased number of terminal deoxynucleotidyltransferase-mediated nick-end-labeling (TUNEL)-positive cells and increased expression of Bcl-2). In conclusion, our findings provide the first in vivo evidence for a link between UCP2 and tumorigenesis and indicate the need for additional studies to assess the role of mitochondrial uncoupling in cancer development.
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PMID:Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress. 1640 37

Varicella-zoster virus (VZV) is ultimately dependent upon its host cell for replication. To ensure its reproduction, VZV reorganizes various cellular functions by taking advantage of pre-existing signalling pathways. Recently, it was demonstrated that the activation of stress-related mitogen-activated protein kinase pathways following infection led to increased phosphorylation of cellular transcription factors involved in VZV gene expression. Here, it was shown that members of the extracellular signal-regulated kinase (ERK) pathway are also influenced following VZV infection: c-Raf remained inactive in infected MeWo cells, whereas MEK1/2 and ERK1/2 were phosphorylated transiently, reaching their highest level of phosphorylation at between 10 and 12 h post-infection. Inhibition of this pathway resulted in a severe reduction in viral progeny and in an increased apoptotic response, indicating that the functionality of this cascade is essential for successful high-rate replication. In addition, the activities of Bad, a cytoplasmic target of ERK via ribosomal S6 kinase, and the nuclear-localized target c-Myc were analysed. Bad is a member of the Bcl-2 family and has a key function in regulating apoptosis. Pro-apoptotic functions of Bad are repressed by phosphorylation. A 10-fold increase in Bad phosphorylation at Ser-112 was detected following infection, which was suppressed after inhibition of ERK. The transcription factor c-Myc is involved in the regulation of cell growth and apoptosis. By performing immunoblots and quantitative RT-PCR, suppression of c-Myc expression was demonstrated at both the transcriptional and translational levels in VZV-infected cells. These results suggest that VZV optimizes the conditions for its replication in different ways: upregulation of proviral-acting systems and suppression of potentially antiviral-acting systems.
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PMID:Varicella-zoster virus influences the activities of components and targets of the ERK signalling pathway. 1652 22


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