UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
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Among the group of bioactive sphingolipids, sphingosylphosphorylcholine (SPC) has been known to induce both antiproliferative and proliferative effects depending on cell type. In the present investigation we show that SPC (1-10 microM) reduced the proliferation of FRO cells (an anaplastic thyroid carcinoma cell line) in a concentration dependent manner. The effect was pertussis toxin insensitive, and independent of phospholipase C, protein kinase C, p38 kinase, or jun kinase. In addition to inhibiting the migration of FRO cells, application of SPC induced a rapid (<10 min) rounding of the cells, which was dependent on extracellular sodium. However, DAPI staining and caspase-3 analysis could not reveal any apoptotic effects of SPC. Furthermore, when cells treated with SPC for 24h were washed and replated, they continued to grow, albeit somewhat slower than control cells. Flow cytometry analysis revealed a significant increase in the population of cells in the G2-M phase, and a reduction in S phase. SPC reduced the phosphorylation of Akt with about 50% and evoked a substantial decrease in the amount of phosphorylated mitogen-activated protein (MAP) kinase. In cells treated with the PI3 kinase inhibitor wortmannin, both migration and proliferation were inhibited, as well as the amount of phosphorylated MAP kinase. Treatment of the cells with either SPC or wortmannin increased the levels of p21, but decreased that of cyclin B1 and Cdc2. Taken together, SPC is an effective suppressor of thyroid cancer cell proliferation and migration, and this effect is, in part, mediated by inhibition of both the PI3K-Akt and the MAP kinase signalling pathways.
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PMID:Antiproliferative effect of sphingosylphosphorylcholine in thyroid FRO cancer cells mediated by cell cycle arrest in the G2/M phase. 1760 21

Sanguinarine is a benzophenanthridine alkaloid that is derived from the root of Sanguinaria canadensis and other poppy fumaria species, and is known to have antimicrobial, antiinflammatory and antioxidant properties. This study investigated the possible mechanisms through which sanguinarine exerts its antiproliferative action in cultured C6 rat glioblastoma cells. The exposure of C6 cells to sanguinarine resulted in growth inhibition and the induction of apoptosis in a dose-dependent manner, as measured by the MTT assay, fluorescence microscopy, agarose gel electrophoresis and annexin-V-based assay. The sanguinarine treatment induced the proteolytic activation of caspases and ICAD/DFF45, which was associated with the modulation of the Bcl-2 family, concomitant degradation of poly(ADP ribose) polymerase and phospholipase C-gamma1 protein, and DNA fragmentation. z-DEVD-fmk, a caspase-3-specific inhibitor, blocked poly(ADP ribose) polymerase degradation, DNA fragmentation and increased the survival rate of sanguinarine-treated C6 cells. Moreover, the activity of extracellular signal-regulated kinase and Akt was downregulated in sanguinarine-treated cells, and PD98059, a specific extracellular signal-regulated kinase inhibitor, and phosphatidylinositol 3'-kinase/Akt inhibitors, LY294002 and wortmanin, sensitized the cells to sanguinarine-induced apoptosis, indicating that the downregulation of the extracellular signal-regulated kinase and Akt signaling pathway may play a key role in sanguinarine-induced apoptosis in C6 cells.
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PMID:Induction of apoptosis by sanguinarine in C6 rat glioblastoma cells is associated with the modulation of the Bcl-2 family and activation of caspases through downregulation of extracellular signal-regulated kinase and Akt. 1766 97

We investigated, in monocytic leukemia U937 cells, the effects of docosahexaenoic acid (DHA; 22:6 n-3) on calcium signaling and determined the implication of phospholipase C (PLC) and protein kinase C (PKC) in this pathway. DHA induced dose-dependent increases in [Ca2+]i, which were contributed by intracellular pool, via the production of inositol-1,4,5-triphosphate (IP3) and store-operated Ca2+ (SOC) influx, via opening of Ca2+ release-activated Ca2+ (CRAC) channels. Chemical inhibition of PLC, PKCgamma, and PKCdelta, but not of PKCbeta I/II, PKCalpha, or PKCbetaI, significantly diminished DHA-induced increases in [Ca2+]i. In vitro PKC assays revealed that DHA induced a approximately 2-fold increase in PKCgamma and -delta activities, which were temporally correlated with the DHA-induced increases in [Ca2+]i. In cell-free assays, DHA, but not other structural analogs of fatty acids, activated these PKC isoforms. Competition experiments revealed that DHA-induced activation of both the PKCs was dose-dependently inhibited by phosphatidylserine (PS). Furthermore, DHA induced apoptosis via reactive oxygen species (ROS) production, followed by caspase-3 activation. Chemical inhibition of PKCgamma/delta and of SOC/CRAC channels significantly attenuated both DHA-stimulated ROS production and caspase-3 activity. Our study suggests that DHA-induced activation of PLC/IP3 pathway and activation of PKCgamma/delta, via its action on PS binding site, may be involved in apoptosis in U937 cells.
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PMID:Docosahexaenoic acid induces increases in [Ca2+]i via inositol 1,4,5-triphosphate production and activates protein kinase C gamma and -delta via phosphatidylserine binding site: implication in apoptosis in U937 cells. 1787 67

Human immunodeficiency virus (HIV)-1 Tat is a multifunctional protein involved in viral replication, inflammation and apoptosis. Tat activates phospholipase C-beta (PLC-beta), presumably via a pertussis toxin (PTX) sensitive G(i) protein, which is critical for neuronal apoptosis. In this study, we show that Tat-mediated intracellular Ca(2+) release in rat pheochromocytoma (PC-12) cells and rat primary cortical neuronal cultures was abrogated by pretreatment with either pertussis toxin and/or its B-oligomer subunit (PTX-B), devoid of ADP ribosyltransferase activity. PTX-B pretreatment also inhibited intracellular Ca(2+) release by bradykinin and 2,4,6-trimethyl-N-(m-3-trifluoromethylphenyl) benzenesulfonamide (m-3M3FBS), a director activator of phospholipase C. Activation of protein kinase C (PKC) by phorbol 12,13-dibutyrate (PdBu) mimicked the PTX-B-mediated inhibition of m-3M3FBS-stimulated intracellular Ca(2+) increase, while inhibition of PKC by bisindolylmaleimide I hydrochloride (BIM) reversed the inhibitory action of PTX-B. Functionally, PTX-B reduced Tat-induced Bax and caspase-3 proteins and reduced cell apoptosis. We conclude that PTX inhibition of Tat-mediated intracellular Ca(2+) release is independent of ADP ribosylation of the G(i) protein via the A protomer, but mediated by the B-oligomer. Furthermore, PTX-B suppresses HIV-1 Tat-mediated apoptosis by reducing its activation of PLC-beta through a PKC activation pathway.
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PMID:Pertussis toxin B-oligomer suppresses human immunodeficiency virus-1 Tat-induced neuronal apoptosis through feedback inhibition of phospholipase C-beta by protein kinase C. 1809 42

The endoplasmic reticulum (ER) plays a critical role in the maintenance of intracellular homeostasis and its dysfunction is thought to lead to neuronal death, which results in neurodegenerative disorders. Since phospholipase C (PLC) isozymes are involved in maintenance of the intracellular Ca2+ concentration by regulating Ca2+ release from the ER, their expression might be affected by ER stress. Of these isozymes, PLC-beta 1 and -gamma 1, in particular, are known to protect cells from oxidative stress and thus alteration of their expression profile under ER stress-loaded conditions is interesting. Using primary cultured rat cortical neurons, we here examined whether expression of PLC-beta 1 and -gamma 1 was altered in ER stress-loaded neurons induced by tunicamycin (Tm). In ER stress-loaded neurons treated with Tm in the range of 0.03-3 microg/ml for 20 h, the viability of the neurons was decreased dose-dependently, the decrease being significant with 0.3 or more microg/ml, and expression of the representative ER stress markers, GRP78/BiP, and cleaved caspase-3 and -12, was increased after 24 h postincubation, confirming the induction of ER stress in the neurons. In the ER stress-loaded neurons obtained on Tm treatment, the expression level of PLC-beta 1 decreased dose-dependently. On the other hand, there was no difference in the PLC-gamma 1 protein expression level between control and ER stress-loaded neurons. Overall, we demonstrated that ER stress decreases the expression of PLC-beta 1, but not -gamma 1, in neurons.
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PMID:Decreased expression of phospholipase C-beta 1 protein in endoplasmic reticulum stress-loaded neurons. 1837 69

Streptochlorin is a small molecule that produced by marine Streptomyces sp. that is known to have anti-angiogenic and anti-cancer properties. However, the mechanism by which streptochlorin functions is not well understood. In this study, we investigated the pro-apoptotic effect of streptochlorin in human leukemic U937 cells. Streptochlorin treatment resulted in concentration- and time-dependent growth inhibition by inducing apoptosis. The increase in apoptosis that was induced by streptochlorin was correlated with down-regulation of anti-apoptotic Bcl-2 expression, up-regulation of pro-apoptotic Bax and FasL, a decrease in the mitochondrial membrane potential (MMP), activation of caspases and degradation of poly-(ADP-ribose)polymerase and phospholipase C-gamma1 protein. In addition, the cytotoxic effects and apoptotic characteristics induced by streptochlorin were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role that caspase-3 played in the process. Furthermore, Bcl-2 overexpression significantly reversed the streptochlorin-induced growth inhibitory effects via inhibition of the MMP collapse and caspases activation and effectively attenuated the apoptotic response to streptochlorin. However, the elevated levels of FasL expression induced by streptochlorin were not reduced by Bcl-2 overexpression. Taken together, these findings demonstrate that the pro-apoptotic effect of streptochlorin is mediated through activation of caspases and mitochondria in U937 cells.
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PMID:Induction of apoptosis by streptochlorin isolated from Streptomyces sp. in human leukemic U937 cells. 1863 25

20-Hydroxyecdysone (20E) triggers programmed cell death (PCD) and regulates de novo gene expression in the anterior silk glands (ASGs) of the silkworm Bombyx mori. PCD is mediated via a nongenomic pathway that includes Ca2+ as a second messenger and the activation of protein kinase C/caspase-3-like protease; however, the steps leading to a concomitant buildup of intracellular Ca2+ are unknown. We employed pharmacological tools to identify the components of this pathway. ASGs were cultured in the presence of 1 microM 20E and one of the following inhibitors: a G-protein-coupled receptor (GPCR) inhibitor, a phospholipase C (PLC) inhibitor, an inositol 1,4,5-trisphosphate receptor (IP3R) antagonist, and an L- or T-type Ca2+ channel blocker. The T-type Ca2+ channel blocker inhibited 20E-induced nuclear and DNA fragmentation; in contrast, PCD was induced by 20E in Ca2+-free medium, indicating that the source of Ca2+ is an intracellular reservoir. The IP3R antagonist inhibited nuclear and DNA fragmentation, suggesting that the endoplasmic reticulum may be the Ca2+ source. Finally, the GPCR and PLC inhibitors effectively blocked nuclear and DNA fragmentation. Our results indicate that 20E increases the intracellular level of Ca2+ by activating IP3R, and that this effect may be brought about by the serial activation of GPCR, PLC, and IP3.
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PMID:Intracellular mobilization of Ca2+ by the insect steroid hormone 20-hydroxyecdysone during programmed cell death in silkworm anterior silk glands. 1904 19

The ghrelin receptor (GHS-R1a) displays a high level of constitutive signaling through a phospholipase C/protein kinase C-dependent pathway. Therefore, we have investigated the role of agonist-dependent and agonist-independent signaling of GHS-R1a in apoptosis using the seabream GHS-R1a stably expressed in human embryonic kidney 293 cells (HEK-sbGHS-R1a cells). Cadmium-induced activation of caspase-3 was significantly attenuated in HEK-sbGHS-R1a cells compared to wild-type HEK293 cells, while the apoptotic responses to the protein kinase C inhibitor staurosporine were similar. GHS-R1a ligands had no effect on caspase-3 activation or on cell proliferation. Concentrations of the inverse agonist [d-Arg(1),d-Phe(5),d-Trp(7,9),Leu(11)]-substance P sufficient to inhibit constitutive inositol phosphate generation did not enhance caspase-3 activity, suggesting a possible role of phosphatidylcholine-specific phospholipase C in the anti-apoptotic activity of GHS-R1a. In conclusion, our data suggests that the constitutive activity of sbGHS-R1a may be sufficient alone to attenuate apoptosis via a protein kinase C-dependent pathway.
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PMID:The constitutive activity of the ghrelin receptor attenuates apoptosis via a protein kinase C-dependent pathway. 1913 27

Clodronate, a halogenated bisphosphonate, can inhibit the growth of human thyroid carcinoma (TC) cells. Previously, we found that a clodronate-induced Ca(2+) transient was correlated with clodronate-induced growth inhibition in TC cells. However, the details of the signaling process underlying the antiproliferative effect of clodronate on TC cells are not clear. In this study, we investigated the antiproliferative mechanism of clodronate on papillary TC (PTC) cells and xenotransplanted animals using a combination of pharmacological drugs. Reverse transcription-polymerase chain reaction analysis confirmed the endogenous expression of P2Y receptor isoforms in PTC cells. The P2 antagonist suramin not only inhibited the antiproliferative effect of clodronate and ATP on TC cells but also blocked all the Ca(2+) transients induced by clodronate and ATP. The release of Ca(2+) from the endoplasmic reticulum and membrane depolarization of mitochondria was observed during the clodronate-induced Ca(2+) transients. The results of terminal deoxynucleotidyltransferase dUTP nick-end labeling assays and flow cytometry with annexin V and caspase-3 staining suggest that both ATP and clodronate induce apoptosis. Significant inhibition of tumor invasion and colony formation was also observed in clodronate-treated PTC cells. We further demonstrated that only the cAMP inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536), and not inhibitors of phospholipase C [1-[6-[[17beta-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122)] or store-operated Ca(2+) entry (2-aminoethyl diphenylborinate), can significantly reverse the effect of clodronate. Finally, in vivo animal and green fluorescent protein imaging studies further proved that the tumor inhibitory effect of clodronate on xenotransplanted CG3 cells can be reversed by treatment with suramin. In conclusion, we demonstrated that clodronate-induced PTC cell apoptosis and tumor inhibition are partially mediated by the P2Y receptor-cAMP cascade.
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PMID:Clodronate-induced cell apoptosis in human thyroid carcinoma is mediated via the P2 receptor signaling pathway. 1944 40

This study examines the role of IGF2/mannose 6-phosphate receptor (IGF2R) signaling in the signaling transduction regulation and cell apoptosis in H9c2 cardiomyoblast cells. However, it is difficult to recognize the distinct activation of IGF2 signaling without interfacing with IGFI receptor (IGF1R) after exposure to IGF2. Leu27IGF2, an analog of IGF2 that interacts selectively with the IGF2R, was used to specifically activate IGF2R signaling in this study. DNA fragmentation and TUNEL assay revealed that in contrast to IGF1 treatment preventing angiotensin II and AG1024-induced cell apoptosis, Leu27IGF2 appears to synergistically increase apoptosis in those cells. We further found cell apoptosis induction and an increase in the active form of caspase 3 in the treatment of cells with Leu27IGF2, but not IGF1. To detect the interaction between IGF2R and Galphaq using the immunoprecipitation assay, we found that IGF2R could directly interact with Galphaq and after treatment with Leu27IGF2 the binding ability of Galphaq to IGF2R had increased. This sequentially resulted in the phosphorylation of phospholipase C-beta, a key downstream modulator of Galphaq, on serine 537. Moreover, disruption of the Galphaq protein by small interferon RNA reduced the cell apoptosis induced by Leu27IGF2. Our findings demonstrate that IGF2R activation appears to induce cell apoptosis via Galphaq-deriving signaling cascades and its effect is completely different from IGF1R survival signaling.
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PMID:Leu27IGF2 plays an opposite role to IGF1 to induce H9c2 cardiomyoblast cell apoptosis via Galphaq signaling. 1955 92

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