Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Caspase-3 (32 kDa) is one of the primary protease executioners of apoptosis and is activated by intra-chain proteolytic cleavage, which generates a large subunit (17 kDa) and a small subunit (12 kDa). Typically, after apoptotic stimuli, the level of cleaved caspase-3 increases while that of caspase-3 decreases. It has been shown that caspase-3 mRNA levels increase in cortex following traumatic brain injury or focal ischemia. In the present study, we demonstrate that both caspase-3 mRNA and protein increase in apoptotic PC12 cells following exposure to manganese which strongly induces caspase-3 cleavage. Up-regulation of caspase-3 protein was evident in manganese-treated PC12 cells and was moderate in cisplatin-, rotenone- and A23187-treated cells but was not observed in serum deprivation-, anisomycin-, camptothecin-, cycloheximide- or staurosporine-treated cells in which all treatments induced extensive DNA fragmentation. Manganese-induced up-regulation of caspase-3 mRNA was partially attenuated by the pretreatment with the MEK inhibitor U0126, but not with the c-Jun N-terminal kinase (JNK) inhibitor SP600125. In contrast, the increase in caspase-3 protein was suppressed by both U0126 and SP600125. These results suggest that p44/42 MAPK contributes to the up-regulation of caspase-3 mRNA and the JNK pathway regulates caspase-3 protein levels posttranslationally in manganese-induced apoptosis in PC12 cells.
 ...
PMID:p44/42 MAP kinase and c-Jun N-terminal kinase contribute to the up-regulation of caspase-3 in manganese-induced apoptosis in PC12 cells. 1678 41

The purpose of this study was to investigate whether latanoprost, a prostaglandin F2alpha analogue, has a direct anti-apoptotic effect both in retinal neuro-glial cells in culture and in diabetic retina. R28 cells, immortalized retinal neuroglial progenitor cells, were induced apoptosis by 24h serum deprivation. Serum withdrawal made up to 15% of R28 cells pyknotic and activated caspase-3 immunoreactive, and latanoprost acid suppressed apoptosis with dose dependency at an optimum concentration of 1.0 microM (P<0.001). UO126, a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) 1 and 2 inhibitor reversed this effect. Streptozotocin induced one- or three-month diabetic rats received balanced-salt-solution (BSS) in the left eye and latanoprost eye drops in the right for 5 days. Retinal wholemount was subjected to terminal dUTP nick end labeling (TUNEL) staining, whereas eyeballs were enucleated for cleaved caspase-3 immunofluorescence. Retinal homogenates were probed for phospho- or total p44/p42 MAPK and Akt. One- and three-month diabetic retina had 30.2+/-15.3 and 23.6+/-9.0 TUNEL positive cells per 0.5 cm(2), respectively, whereas control retina had few TUNEL positive cells. Latanoprost instillation significantly reduced these cells (10.0+/-3.1 and 11.3+/-3.1 cells per 0.5 cm(2) for 1M and 3M, respectively, P<0.01), whereas BSS did not. Latanoprost also significantly reduced cleaved caspase-3 immunoreactive cells in ganglion cell and inner nuclear layers (P<0.05). Latanoprost increased phosphorylated to total protein ratio of p44/p42 MAPK (P<0.05), but not of Akt. Taken together, the present findings suggest that latanoprost rescues retinal neurons and/or glial cells from apoptosis, which is probably mediated by p44/p42 MAPK through caspase-3 inhibition.
 ...
PMID:Latanoprost rescues retinal neuro-glial cells from apoptosis by inhibiting caspase-3, which is mediated by p44/p42 mitogen-activated protein kinase. 1683 45

Dracorhodin perchlorate, an anthocyanin red pigment, induces human premyelocytic leukemia HL-60 cell death through apoptotic pathway. Caspase -1, -3, -8, -9, and -10 inhibitors partially reversed the cell death induced by dracorhodin perchlorate. Caspase-3 and -8 were activated followed to the degradation of caspase-3 substrates, inhibitor of caspase-activated DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP). Dracorhodin perchlorate up-regulated the expression ratio of mitochondrial proteins, Bax/Bcl-XL. The cell death was accompanied with phosphorylation of ERK, JNK and p38 MAPK and partially reduced by MEK inhibitor (PD98059), JNK MAPK inhibitor (SP600125) and p38 MAPK inhibitor (SB 203580). Taken together, dracorhodin perchlorate-induced apoptosis in HL-60 cells via up-regulation of Bax, activation of caspases and ERK/p38/JNK MAPKs.
 ...
PMID:Dracorhodin perchlorate induces apoptosis in HL-60 cells. 1686 44

Uncarinic acid E, an active component isolated from Gelsemium elegans BENTH, has been reported to exhibit antitumor effects, but little is known about its molecular mechanisms of action. In this study, the growth-inhibitory activity of uncarinic acid E for HepG2 cells is in time- and dose-dependent manner. HepG2 cells treated with uncarinic acid E exhibited several typical characteristics of apoptosis through photomicroscopical observation, DNA agarose gel electrophoresis. The inhibitory effect of uncarinic acid E on HepG2 cells was partially reversed by the inhibitors of pan-caspase, caspase-3 and caspase-6. The protein expression ratio of Bcl-xL/Bax and Bcl-2/Bax was down-regulated and uncarinic acid E-induced apoptosis involves the initial phase mediated by the balance among Bcl-xL, Bcl-2 and Bax proteins, resulting in cytochrome c release from the mitochondria. Uncarinic acid E significantly increased the expression of p53 proteins indicates that p53 plays a pivotal role in the initiation phase of uncarinic acid E-induced HepG2 cell apoptosis. The phoshatidylinositol 3-kinase (PI3-K) family inhibitor wortmanin and the MEK inhibitor (PD98059) rescued the viability loss induced by uncarinic acid E through the expression of p53. Taken together, uncarinic acid E induces apoptosis in HepG2 cells via accumulation of p53, alters the Bax/Bcl-2 ratio, and activates caspases, resulting in cytochrome c release from the mitochondria.
 ...
PMID:The course of uncarinic acid E-induced apoptosis of HepG2 cells from damage to DNA and p53 activation to mitochondrial release of cytochrome c. 1688 Jun 19

Reactive oxygen species, including hydrogen peroxide (H(2)O(2)), are generated during ischemia-reperfusion and are critically involved in acute renal failure. The present studies examined the role of the extracellular signal-regulated kinase (ERK) pathway in H(2)O(2)-induced renal proximal tubular cells (RPTC) apoptosis. Exposure of RPTC to 1 mM H(2)O(2) resulted in apoptosis and activation of ERK1/2 and Akt. Pretreatment with the specific MEK inhibitors, U0126 and PD98059, or adenoviral infection with a construct that encodes a negative mutant of MEK1, protected cells against H(2)O(2)-induced apoptosis. In contrast, expression of constitutively active MEK1 enhanced H(2)O(2)-induced apoptosis. H(2)O(2) induced activation of caspase-3 and phosphorylation of histone H2B at serine 14, a posttranslational modification required for nuclear condensation, which also were blocked by ERK1/2 inhibition. Furthermore, blockade of ERK1/2 resulted in an increase in Akt phosphorylation and blockade of Akt potentiated apoptosis and diminished the protective effect conferred by ERK inhibition in H(2)O(2)-treated cells. Although Z-DEVD-FMK, a caspase-3 inhibitor, was able to inhibit histone H2B phosphorylation and apoptosis, it did not affect ERK1/2 phosphorylation. We suggest that ERK elicits apoptosis in epithelial cells by activating caspase-3 and inhibiting Akt pathways and elicits nuclear condensation through caspase-3 and histone H2B phosophorylation during oxidant injury.
 ...
PMID:ERK promotes hydrogen peroxide-induced apoptosis through caspase-3 activation and inhibition of Akt in renal epithelial cells. 1688 55


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