Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factors are known to favor both proliferation and survival of hepatocytes. In the present study, we investigated if c-FLIP(L) (cellular FLICE-inhibitory protein, long isoform) could be involved in epidermal growth factor (EGF)-stimulated proliferation of rat hepatocytes since c-FLIP(L) regulates both cell proliferation and procaspase-8 maturation. Treatment with MEK inhibitors prevented induction of c-FLIP(L) by EGF along with total inhibition of DNA replication. However, EGF failed to inhibit processing of procaspase-8 in the presence of EGF suggesting that c-FLIP(L) does not play its canonical anti-apoptotic role in this model. Downregulation of c-FLIP expression using siRNA oligonucleotides strongly reduced DNA replication but did not result in enhanced apoptosis. Moreover, intermediate cleavage products of c-FLIP(L) and caspase-8 were found in EGF-treated hepatocytes in the absence of caspase-3 maturation and cell death. To determine whether the Fas/FADD/caspase-8/c-FLIP(L) complex was required for this activity, Fas, procaspase-8 and Fas-associated death domain protein (FADD) expression or function was inhibited using siRNA or constructs encoding dominant negative mutant proteins. Inhibition of any of these components of the Fas/FADD/caspase-8 pathway decreased DNA replication suggesting a function of these proteins in cell-cycle arrest. Similar results were obtained when the IETD-like caspase activity detectable in EGF-treated hepatocytes was inhibited by the pan-caspase inhibitor, z-ASP. Finally, we demonstrated co-immunoprecipitation between EGFR and Fas within 15 min following EGF stimulation. In conclusion, our results indicate that the Fas/FADD/c-FLIP(L)/caspase-8 pathway positively controls the G(1)/S transition in EGF-stimulated hepatocytes. Our data provide new insights into the mechanisms by which apoptotic proteins participate to mitogenic signals during the G(1) phase.
 ...
PMID:A role for caspase-8 and c-FLIPL in proliferation and cell-cycle progression of primary hepatocytes. 1603 71

Granulin-epithelin precursor (GEP/progranulin) is an autocrine growth factor for ovarian cancer. We examined the production and function of GEP and report that: (1) GEP production is regulated by endothelin (ET-1), lysophosphatidic acid (LPA), and cAMP; (2) cAMP signals GEP production through exchange protein activated by cAMP (EPAC); (3) ET-1 and cAMP/EPAC induce GEP through ERK1/2; and (4) neutralization of GEP results in apoptosis. Exposure of HEY-A8 and OVCAR3 ovarian cancer cells to LPA and ET-1 yielded GEP production and secretion in a dose- and time-dependent fashion; neither stimulated significant concentrations of cAMP directly. Stimulation of cAMP production with pertussis and cholera toxin, or forskolin induced GEP in a PKA-independent fashion. EPAC, an intracellular cAMP receptor, is activated specifically by the cAMP analog, 8-CPT-2'-O-Me-cAMP (8-CPT); 8-CPT treatment stimulated GEP production and secretion. The MEK inhibitor, U0126, abrogated GEP production in response to ET-1 and 8-CPT, confirming involvement of MAPK. A partial inhibition of basal and stimulated GEP production was observed when cells were treated with a internal calcium chelator, BAPTA. Neutralizing anti-GEP antibody reversed basal as well as LPA, ET-1 and 8-CPT-induced ovarian cancer cell growth and induced apoptosis as demonstrated by caspase-3 and PARP cleavage, DNA fragmentation, and nuclear condensation. These results indicate that GEP is a growth and survival factor for ovarian cancer, induced by LPA and ET-1 and cAMP/EPAC through ERK1/2.
 ...
PMID:Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin-epithelin precursor (GEP), a prosurvival factor for ovarian cancer. 1604 62

Monocytes and macrophages play a key role in the initiation and persistence of inflammatory reactions. The possibility to interfere with the survival of these cells, once recruited and activated at sites of inflammation, is an attractive therapeutic option. Although resting monocytes are susceptible to pharmacologically induced apoptosis, no data are available about the possibility to modulate the survival of activated monocytes. The present work was planned to investigate if dexamethasone is able to promote apoptosis of human monocytes activated by immune complexes. When monocytes were cultured with immune complexes, a dose-dependent inhibition of apoptosis was observed. Dexamethasone stimulated apoptosis of resting and activated monocytes in a dose-dependent manner. Both the immune complex inhibitory activity and dexamethasone stimulatory properties depend on NF-kappaB/XIAP and Ras/MEK/ERK/CD95 pathways. In fact, the exposure of monocytes to immune complexes increased NF-kB activation and XIAP expression, which in turn were inhibited by dexamethasone. On the other hand, immune complex-stimulated monocytes displayed a reduced expression of CD95, which is prevented by dexamethasone, as well as by MEK inhibitor U0126. Furthermore, anti-CD95 ZB4 mAb prevented dexamethasone-induced apoptosis in immune complex stimulated monocytes. Similarly, ZB4 inhibited dexamethasone-mediated augmentation of caspase 3 activity. The present findings suggest that Fc triggering by insoluble immune complexes result in the activation of two intracellular pathways crucial for the survival of monocytes: 1. Ras/MEK/ERK pathway responsible for the down-regulation of CD95 expression; 2. NF-kappaB pathway governing the expression of XIAP. Both the pathways are susceptible to inhibition by monocyte treatment with pharmacologic concentrations of dexamethasone.
 ...
PMID:Dexamethasone -induced apoptosis of human monocytes exposed to immune complexes. Intervention of CD95- and XIAP-dependent pathways. 1616 24

Megakaryocytopoiesis is characterized by progressive polyploidization and acquisition of megakaryo-cytic markers. MAPK pathways play a key role during megakaryocytic differentiation of megakaryocyte precursors or leukemic cells. Apoptosis is the physiological fate of normal megakaryocyte after differentiation and maturation. The aim of this study was to investigate the signaling pathways involved in diosgenin-induced differentiation and the fate of diosgenin-differentiated HEL cells. The present report shows that diosgenin induced megakaryocytic differentiation of HEL cells through a combined activation of ERK and inhibition of the p38 MAPK pathways. Inhibition of ERK activation by a MEK inhibitor abrogated diosgenin-induced differentiation. Afterwards, differentiated cells showed a marked inhibition of expression of survival factors NF-kappaB, Akt and Bcl-xL and activation of caspase-3 together with PARP cleavage leading to apoptotic death of diosgenin-differentiated cells.
 ...
PMID:Role of MAPKs and NF-kappaB in diosgenin-induced megakaryocytic differentiation and subsequent apoptosis in HEL cells. 1632 97

Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN or CD147), a member of the immunoglobulin family and a glycoprotein enriched on the surface of tumor cells, promotes invasion, metastasis, and growth and survival of malignant cells and confers resistance to some chemotherapeutic drugs. However, the molecular mechanisms underlying the actions of EMMPRIN are not fully understood. In this study we sought to determine whether EMMPRIN contributes to the malignant phenotype of breast cancer by inhibiting anoikis, a form of apoptosis induced by loss or alteration of cell-cell or cell-matrix anchorage, and to explore the signaling pathways involved. We found that in the absence of attachment, human breast carcinoma cells expressing high levels of EMMPRIN formed less compact aggregates with larger surface area and less fibronectin matrix assembly, had higher viability, and were resistant to anoikis. Knockdown of EMMPRIN expression by RNA interference (small interfering RNA or short hairpin RNA) sensitized cancer cells to anoikis, as demonstrated by activation of caspase-3, increased DNA fragmentation, and decreased cellular viability. Furthermore, we observed that the accumulation of Bim, a proapoptotic BH3-only protein, was reduced in EMMPRIN-expressing cells and that silencing of EMMPRIN expression elevated Bim protein levels and enhanced cellular sensitivity to anoikis. Treatment of cells with a MEK inhibitor (U0126) or proteasome inhibitor (epoxomicin) also up-regulated Bim accumulation and rendered cells more sensitive to anoikis. These results indicated that expression of EMMPRIN protects cancer cells from anoikis and that this effect is mediated at least in part by a MAP kinase-dependent reduction of Bim. Because anoikis deficiency is a key feature of neoplastic transformation and invasive growth of epithelial cancer cells, our study on the role of EMMPRIN in anoikis resistance and the mechanism involved underscores the potential of EMMPRIN expression as a prognostic marker and novel target for cancer therapy.
 ...
PMID:Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to Anoikis through inhibition of Bim. 1644 28

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used drugs for the treatment of inflammatory disease and have a chemopreventive effect in a variety of tumors. Several studies have demonstrated unequivocally that certain NSAIDs cause antiproliferative effects independent of cyclooxygenase (COX) activity. In this study, we investigated the effect of chemically unrelated NSAIDs in the proliferation of glioma cell lines and the possible mechanisms involved in indomethacin-mediated inhibition of proliferation in glioma cells lines. The glioma cell lines were treated with NSAIDs and proliferation was measured by cell counting. Indomethacin, acetaminophen, sulindac sulfide and NS-398 (N-[2-cyclohexyloxy)-4-nitrophenyl]methane-sulfonamide) induced a time- and concentration-dependent inhibition of C6 rat glioma cell proliferation. The inhibition of COX by chemically unrelated NSAIDs leads to inhibition of rat and human glioma cell proliferation. The tetrazolium reduction assay (MTT) indicated a reduction in cell viability induced by indomethacin. None of the NSAIDs tested induced caspase-3/7 activation, assayed with a fluorigenic substrate. The indomethacin-induced inhibition of C6 cells proliferation was abrogated by the use of the c-Src inhibitor, PP2 and the MEK inhibitor, PD 098059, suggesting COX-independent mechanisms. Indomethacin decreased the percentage of cells in the S phase, with relative increases in the G0/G1 and/or the G2/M phase. NSAIDs may be clinically important for pharmacological intervention in gliomas.
 ...
PMID:Nonsteroidal anti-inflammatory drugs inhibit the growth of C6 and U138-MG glioma cell lines. 1648 11

Valproic acid is widely used for the treatment of epilepsy and mood disorders, but its mode of action is unclear. Treatment of neuronal cells with valproic acid promotes neurite sprouting, is neuroprotective and drives neurogenesis; however its effects on non-neuronal brain cells are less clear. We report that valproic acid induces apoptosis in the mouse microglial cell line, BV-2, at concentrations within the therapeutic range. When BV-2 cells were incubated for 24 h with 500-1000 microM valproic acid we observed a reduction in cell number, the appearance of apoptotic morphology and increased caspase 3 cleavage. Exposure of a macrophage cell line (RAW 264.7) to similar concentrations of valproic acid also led to reduced cell number but no caspase 3 cleavage, suggesting these cells responded to valproic acid with reduced proliferation rather than apoptosis. This was confirmed using bromodeoxyuridine incorporation studies. Similar concentrations of valproic acid added to Neuro-2a, SK-N-SH and C6 cell lines as well as human NTera-2 astrocytes did not evoke cell death. The caspase 3 inhibitor DEVD-CHO inhibited valproic acid-induced apoptosis in BV-2 cells whereas the MEK inhibitor U0126 potentiated valproic acid-mediated apoptosis. These results demonstrate that valproic acid selectively induces apoptosis in BV-2 cells by way of a caspase 3-mediated action. As activated microglia secrete neurotoxins in neurodegenerative diseases such as Alzheimer's, Parkinson's, and HIV dementia, valproic acid may alleviate these diseases by selectively killing microglia.
 ...
PMID:Valproic acid induces caspase 3-mediated apoptosis in microglial cells. 1660 May 18

The present study investigated if copper (Cu) exposure of trout hepatocytes, which stimulates formation of reactive oxygen species (ROS) and increases intracellular free Ca(2+) (Ca(2+)i), leads to an activation of extracellular signal-regulated kinase (ERK), the mechanisms underlying this activation, and the role of ERK signaling in cell death. Cu stimulated a time- and dose-dependent increase of phosphorylated extracellular signal-regulated kinase (pERK), and preventing the associated Ca(2+) influx or radical formation diminished or inhibited ERK activation, respectively. Furthermore, Cu enhanced caspase 3/7 activity and necrosis, and both effects were inhibited by treatments diminishing radical production and by chelating extracellular Ca(2+). In addition, ERK activity, and to a lesser extent caspase activity, was reduced by inhibiting mitochondrial ATP production, suggesting ATP dependence of the process. Inhibition of the ERK activator MEK, as well as of p38, significantly reduced caspase activation and necrosis, whereas c-Jun N-terminal kinase (JNK) inhibition diminished only caspase activity. Likewise, inhibition of MEK and p38, but not of JNK, prevented Cu-induced ROS production. In summary, we found that stimulation of ERK by Cu exposure of trout hepatocytes is dependent on radical formation and ATP, whereas Ca(2+) only modulates ERK activity. At the same time, activated ERK, as well as p38, contributes to enhanced ROS formation, whereas JNK did not. All three mitogen-activated protein kinases appear to promote apoptotic cell death upon Cu exposure, and ERK and p38 also stimulate necrosis.
 ...
PMID:Copper-induced stimulation of extracellular signal-regulated kinase in trout hepatocytes: the role of reactive oxygen species, Ca2+, and cell energetics and the impact of extracellular signal-regulated kinase signaling on apoptosis and necrosis. 1667 22

Activation of cAMP response element binding protein (CREB) is implicated in neuronal survival. The mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activates a transcription factor CREB. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) protects neurons from ischemia via enhancing ERK dependent CREB phosphorylation. To investigate whether NAMDA induces endogenous survival pathways in apoptotic conditions and whether the neuroprotectant enhances a preexisting survival pathway, we determined the degree of ERK-CREB activation and resistance to apoptosis in staurosporine-treated SK-N-BE(2)C neurons. Compared to forskolin-treated apoptotic cultures, NAMDA-treated cultures induced a minimum activation on ERK (pERK) or CREB (pCREB). However, NAMDA enhanced the activation of ERK and CREB in the presence of forskolin (1.7-fold increase for pCREB, 2.1-fold increase for pERK2, p<0.05 from forskolin). The effect was completely blocked by a specific MEK inhibitor U0126, suggesting the involvement of ERK dependent CREB signaling. Cleavage of caspase-3 and poly-(ADP-ribose)-polymerase was additively reduced in cultures treated with NAMDA and forskolin simultaneously, but not in the presence of U0126. The data showed that NAMDA enhances forskolin-induced ERK-CREB activation and potentiates forskolin-induced resistance to apoptosis. The study indicates that enhancing endogenous survival pathways by NAMDA combined with other neuroprotective measure(s) might be a useful strategy to reduce apoptosis.
 ...
PMID:Enhanced ERK dependent CREB activation reduces apoptosis in staurosporine-treated human neuroblastoma SK-N-BE(2)C cells. 1667 46

Our previous studies have shown that atRA treatment resulted in cell-cycle block and growth inhibition in mouse embryonic palatal mesenchymal (MEPM). In the current study, gestation day (GD) 13 MEPM cells were used to test the hypothesis that the growth inhibition by atRA is due to apoptosis. The effects of atRA on apoptosis were assessed by performing MTT assay, Cell Death Detection ELISA and flow cytometry, respectively. Data analysis confirmed that atRA treatment induced apoptosis-like cell death, as shown by decreased cell viability and increased fragmented DNA and sub-G1 fraction. atRA-induced apoptosis was associated with upregulation of bcl-2, translocation of bax protein to the mitochondria from the cytosol, activation of caspase-3 and cytochrome c release into cytosol. atRA-induced apoptosis was abrogated by z-DEVD-fmk, a caspase-3 specific inhibitor, and z-VAD-fmk, a general caspase inhibitor, suggesting that the atRA-induced cell death of MEPM cells occurs through the cytochrome c- and caspase-3-dependent pathways. In addition, atRA treatment caused a strong and sustained activation of c-Jun N-terminal kinase (JNK) and p38 kinase (p38), as well as an early but transient activation of extracellular signal-regulated kinase (ERK). Importantly, atRA-induced DNA fragmentation and capase-3 activation were prevented by pretreatment with the JNK inhibitor (SP600125) and the p38 MAPK inhibitor (SB202190), but not by pretreatment with MEK inhibitor (U0126). From these results, we suggest that mitogen-activated protein kinase-dependent pathways is involved in the atRA-induced apoptosis of MEPM cells.
 ...
PMID:atRA-induced apoptosis of mouse embryonic palate mesenchymal cells involves activation of MAPK pathway. 1671 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>