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)

MAP kinase pathways comprise a group of parallel protein phosphorylation cascades, which are involved in signaling triggered by a variety of stimuli. Previous findings suggested that the ERK and the JNK pathways have opposing roles in regulating proliferation and survival or apoptosis and that apoptosis can be promoted by inhibiting the ERK pathway or by activation of the JNK pathway. In order to test this hypothesis and explore whether it can be exploited as a strategy for killing human cancer cells, we used gene transfer experiments with a range of cancer cell lines. We expressed the catalytic fragment of human MEKK1 to activate JNK and the Ras-binding domain (RBD) of Raf-1 to inhibit the Ras-ERK pathway. In addition, we designed several RBD-MEKK1 fusion proteins aiming to simultaneously activate the JNK and block the ERK pathway. We found that the MEKK1 proteins as well as the RBD alone could reduce colony formation in all cell lines. The survival time of MEKK1-expressing cells depended on the cell line. In HeLa cells, survival could be prolonged by inhibition of caspases but not by coexpression of the anti-apoptotic protein Bcl-2. Due to a lower kinase activity the RBD-MEKK1 fusion proteins were less effective in apoptosis induction than the MEKK1 kinase domain alone. Using mutant forms of Ras and Raf-1 we could show that the reduced kinase activity of RBD-MEKK1 fusion proteins was caused by binding to the Ras protein. The expression of lethal doses of MEKK1 resulted in a strong activation of all three major MAP kinase families JNK, ERK, and p38. Blocking these pathways either by coexpressing a dominant negative form of MKK4 or with inhibitors of MEK or p38 failed to inhibit apoptosis. This suggests that MEKK1 induces apoptosis by causing a general deregulation of MAP kinase signaling rather than by the activation of a single pathway.
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PMID:The kinase domain of MEKK1 induces apoptosis by dysregulation of MAP kinase pathways. 1256 21

Leukotrienes play an important pathophysiological role in chronic inflammatory states and, as previously shown, cause increased levels of cyclooxygenase-2 (COX-2) in intestinal epithelial cells. The anti-apoptotic protein Bcl-2 is also elevated by LTD(4) stimulation, and in colon cancer, so we studied the mechanisms of COX-2 and Bcl-2 regulation. We found that LTD(4) induced a 3-fold elevation of COX-2 transcription in Int 407 cells and a 2-fold equivalent in colon cancer cells, Caco-2. This was mediated through a pertussis toxin (PTX) sensitive G-protein and the MAP kinase Erk-1/2 pathway, and this was also shown to be the route to up-regulation of Bcl-2 by LTD(4). In good agreement with this, we detected a strong activation of Erk-1/2 that was further increased by COX-2 inhibition, pointing towards the existence of negative feedback regulation. Furthermore, COX-2 activity is responsible for the effects on Bcl-2, but this is not conveyed through the production of PGE(2).
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PMID:Regulation of leukotriene-dependent induction of cyclooxygenase-2 and Bcl-2. 1260 50

Many uncertainties remain regarding the physiological function of the prion protein PrP and the consequences of its conversion into the pathological scrapie isoform in prion diseases. Here, we show for the first time that different signal transduction pathways are involved in neurite outgrowth and neuronal survival elicited by PrP in cell culture of primary neurons. These pathways include the nonreceptor Src-related family member p59(Fyn), PI3 kinase/Akt, cAMP-dependent protein kinase A, and MAP kinase. Regulation of Bcl-2 and Bax expression also correlates with the survival effect elicited by PrP. The combined results, along with our observation that PrP carries the recognition molecule-related HNK-1 carbohydrate, argue strongly for a role of the molecule in neural recognition by interacting with yet unknown heterophilic neuronal receptors, as shown by comparison of neurite outgrowth from neurons of PrP-deficient and wild-type mice.
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PMID:Prion protein as trans-interacting partner for neurons is involved in neurite outgrowth and neuronal survival. 1267 32

Interactions between the protein kinase C (PKC) and Chk1 inhibitor UCN-01 and the heat shock protein 90 (Hsp90) antagonist 17-AAG have been examined in human leukemia cells in relation to effects on signal transduction pathways and apoptosis. Simultaneous exposure (30 hours) of U937 monocytic leukemia cells to minimally toxic concentrations of 17-AAG (eg, 400 nM) and UCN-01 (eg, 75 nM) triggered a pronounced increase in mitochondrial injury (ie, loss of mitochondrial membrane potential [Deltapsim]; cytosolic release of cytochrome c), caspase activation, and apoptosis. Synergistic induction of apoptosis was also observed in other human leukemia cell types (eg, Jurkat, NB4). Coexposure of human leukemia cells to 17-AAG and the PKC inhibitor bisindolylmaleimide (GFX) did not result in enhanced lethality, arguing against the possibility that the PKC inhibitory actions of UCN-01 are responsible for synergistic interactions. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and marked down-regulation of Raf-1, MEK1/2, and mitogen-activated protein kinase (MAPK). Coadministration of 17-AAG and UCN-01 did not modify expression of Hsp90, Hsp27, phospho-JNK, or phospho-p38 MAPK, but was associated with further p34cdc2 dephosphorylation and diminished expression of Bcl-2, Mcl-1, and XIAP. In addition, inducible expression of both a constitutively active MEK1/2 or myristolated Akt construct, which overcame inhibition of ERK and Akt activation, respectively, significantly attenuated 17-AAG/UCN-01-mediated lethality. Together, these findings indicate that the Hsp90 antagonist 17-AAG potentiates UCN-01 cytotoxicity in a variety of human leukemia cell types and suggest that interference with both the Akt and Raf-1/MEK/MAP kinase cytoprotective signaling pathways contribute to this phenomenon.
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PMID:Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways. 1273 74

Cytokines such as interleukin 3 (IL-3), kit ligand (KL), and flt3 ligand (FL) promote survival of hematopoietic stem cells and myeloid progenitor cells. In many cell types, members of the Bcl-2 gene family are major regulators of survival, but the mediating mechanisms are not fully understood. Using two myeloid progenitor cell lines, FDCP-mix and FDC-P1, as well as primary mouse bone marrow progenitors, we demonstrate that KL-mediated survival is dependent on the activation of phosphatidylinositol-3 (PI-3) kinase. The inhibitor LY294002 was able to completely abolish survival mediated by KL, whereas IL-3 and FL were only partially affected. Although all three cytokines induced phosphorylation of protein kinase B (PKB), only KL required PI-3 kinase activity to elicit survival in hematopoietic progenitors. In contrast, pretreatment of cells with inhibitors to the MAP kinase pathway did not affect the survival. We next established if IL-3 and FL activated antiapoptotic Bcl-2 and the related genes Bcl-XL and Mcl-1. By RNA protection assay and Western blot analysis, we show that all three genes are induced by IL-3, whereas FL induces Bcl-2 and to some extent Bcl-XL. Importantly, KL could not sustain their expression. Moreover, use of inhibitors implied that IL-3 was mainly exerting its effect on Bcl-2 at the level of transcription. The addition of LY294002 did not affect the expression of Bcl-2 and Bcl-XL, and thus, we conclude that expression of antiapoptotic Bcl-2 family member genes is not dependent on PI-3 kinase activity. Our results indicate that cytokines exert distinct survival effects and that FL and IL-3 are capable of sustaining progenitor survival by up-regulating the expression of Bcl-2 and related genes.
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PMID:Phosphatidylinositol 3-kinase is essential for kit ligand-mediated survival, whereas interleukin-3 and flt3 ligand induce expression of antiapoptotic Bcl-2 family genes. 1296 Feb 81

Effects of the PI-3 kinase inhibitor LY294002 (LY) have been examined in relation to responses of human leukemia cells to histone deacetylase inhibitors (HDIs). Coexposure of U937 cells for 24 h to marginally toxic concentrations of LY294002 (e.g., 30 microM) and sodium butyrate (SB; 1 mM) resulted in a marked increase in mitochondrial damage (e.g., cytochrome c and Smac/DIABLO release, loss of DeltaPsi(m)), caspase activation, and apoptosis. Similar results were observed in Jurkat, HL-60, and K562 leukemic cells and with other HDIs (e.g., SAHA, MS-275). Exposure of cells to SB/LY was associated with Bcl-2 and Bid cleavage, XIAP and Mcl-1 downregulation, and diminished CD11b expression. While LY blocked SB-mediated Akt activation, enforced expression of a constitutively active (myristolated) Akt failed to attenuate SB/LY-mediated lethality. Unexpectedly, treatment of cells with SB+/-LY resulted in a marked reduction in phosphorylation (activation) of p44/42 mitogen-activated protein (MAP) kinase. Moreover, enforced expression of a constitutively active MEK1 construct partially but significantly attenuated SB/LY-induced apoptosis. Lastly, cotreatment with LY blocked SB-mediated induction of p21(CIP1/WAF1); moreover, enforced expression of p21(CIP1/WAF1) significantly reduced SB/LY-mediated apoptosis. Together, these findings indicate that LY promotes SB-mediated apoptosis through an AKT-independent process that involves MEK/MAP kinase inactivation and interference with p21(CIP1/WAF1) induction.
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PMID:Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition. 1367 62

The production of interleukin-6 (IL-6) has been discovered in a variety of human tumors. Here we report the expression of IL-6, IL-6 receptor alpha (IL-6Ralpha), and gp130 in human esophageal carcinoma tissues. We further demonstrate that IL-6 protects an esophageal carcinoma cell line CE48T/VGH from apoptosis induced by staurosporine. IL-6 stimulation induced a rapid phosphorylation of gp130 and STAT3, and a dominant-negative STAT3 completely abolished the antiapoptotic effect. IL-6 also activated ERK 1/2 in CE48T/VGH cells. Inhibition of the ERK activation by PD98059 and transfection of a dominant-negative ERK2 completely blocked the protection of IL-6 against apoptosis. Thus, both STAT and MAP kinase pathways are responsible for the IL-6-delivered survival signal in human esophageal carcinoma cells. In contrast, PI3-K inhibitors only partially attenuated the effect of IL-6, suggesting that PI3-K does not play a major role in the antiapoptotic signal of IL-6 in our system. To investigate whether IL-6 could induce the production of antiapoptotic molecules, proteins of the Bcl-2 family were measured. While Bcl-2, Bcl-x(L,), and Bax were not affected, Mcl-1 was induced by IL-6 in human esophageal carcinoma cells. Our results suggest that IL-6 may contribute to the progression of esophageal cancers in an autocrine or paracrine manner.
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PMID:Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. 1458 7

The prostate apoptosis response-4 (par-4) gene was isolated in a differential screen for immediate-early genes that are up-regulated during apoptosis of prostate cancer cells. Unlike most other immediate-early genes, par-4 is exclusively induced during apoptosis. The expression or induction of par-4 is not restricted to prostatic cells. The par-4 gene is widely expressed in diverse normal tissues and cell types and conserved during evolution. Par-4 protein contains a leucine zipper domain that is essential for sensitization of cells to apoptosis. Functional studies indicate that par-4 expression is necessary to induce apoptosis. Par-4 protein may induce apoptosis by a p53-independent pathway that involves cytoplasmic inactivation of atypical protein kinase C isoforms resulting in down-regulation of MAP kinase activity and an up-regulation of p38 kinase activity. However, Par-4 is detected in the cytoplasm and in the nucleus, suggesting both cytoplasmic and nuclear roles for the pro-apoptotic protein. Interestingly, Par-4 is predicted to contain a death domain homologous to that of Fas or TRADD, and may therefore trigger a death cascade analogous to that of the death domain proteins. Par-4-dependent apoptosis is abrogated by Bcl-2 and by caspase inhibitors. Identification of the components of the p53-independent apoptosis pathway induced by Par-4 may help to further elucidate the mechanism of Par-4 action. Moreover, in view of the pro-apoptotic function of Par-4, its role in diseases, such as cancer and neurogenerative disorders, whose pathophysiology involves apoptotic cell death needs further investigation.
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PMID:Apoptosis mediated by a novel leucine zipper protein Par-4. 1464 2

Selective and sustained activation of the Raf/MAP kinase pathway in MCF-10A Delta Raf-ER cells, a spontaneously immortalized human mammary epithelial cell line, was previously shown to protect these cells from suspension-induced cell death, a critical feature of the Ras-transformed phenotype. Although autocrine signalling through the EGF receptor is crucial for the protection induced by Raf in these cells, we report here the existence of an additional, more direct survival mechanism, linking Raf activation to the inhibition of a proapoptotic member of the Bcl-2 family, Bim. While detachment from the matrix results in transcriptional induction of two variants of this BH3-only protein, BimEL and BimL, activation of the Raf/ERK signalling both prevents Bim upregulation specifically and leads to phosphorylation and degradation of the BimEL isoform. This represents an important route to protect epithelial cells from the proapoptotic effect of Bim.
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PMID:Role of Bim in the survival pathway induced by Raf in epithelial cells. 1467 26

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


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