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

Serine/threonine phosphatase regulation of phosphorylation-mediated intracellular signaling controls a number of important processes in mammalian cells. In this study, we show that constitutively active protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase, is essential for T leukemia cell survival. Jurkat and CCRF-CEM T leukemia cells treated with the PP2A-selective inhibitor okadaic acid (OA) showed a dose- and time-dependent induction of apoptosis, as indicated by loss of mitochondrial transmembrane potential (delta psi(m)), cleavage-induced activation of caspase-3, -8, and -9, and DNA fragmentation. In addition, caspase-8 or caspase-9 inhibition with z-IETD-fmk or z-LEHD-fmk, respectively, largely prevented OA-induced apoptosis. Although OA treatment did not affect constitutive Bcl-2 expression, overexpression of Bcl-2 prevented both OA-induced DNA fragmentation and dissipation of delta psi(m). Furthermore, inhibition of caspase-3, -8, or -9 partially protected against OA-induced loss of delta psi(m). In addition, caspase-9 and caspase-3 inhibition largely prevented procaspase-3 and procaspase-8 cleavage, respectively, while caspase-8 inhibition partially interfered with procaspase-9 cleavage in OA-treated T leukemia cells. Thus, PP2A inhibition triggered the intrinsic pathway of apoptosis, which was enhanced by a mitochondrial feedback amplification loop. PP2A has also been implicated in the regulation of p38 mitogen-activated protein kinase (MAPK). Co-immunoprecipitation analysis revealed a physical association between the catalytic subunit of PP2A and p38 MAPK in T leukemia cells. Moreover, OA treatment caused p38 MAPK to be phosphorylated in a dose- and time-dependent fashion, indicating that PP2A prevented p38 MAPK activation. Although p38 MAPK activation usually promotes apoptosis, pharmacologic inhibition of p38 MAPK exacerbated OA-induced DNA fragmentation and loss of delta psi(m) in T leukemia cells, suggesting that, in this instance, the p38 MAPK signaling pathway promoted cell survival. Collectively, these findings indicate that PP2A and p38 MAPK have coordinate effects on signaling pathways that regulate the survival of T leukemia cells.
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PMID:Apoptosis induced by protein phosphatase 2A (PP2A) inhibition in T leukemia cells is negatively regulated by PP2A-associated p38 mitogen-activated protein kinase. 1684 42

In earlier studies from this laboratory, Xanthomonas campestris pv. glycines was found to exhibit a nutrition stress-related postexponential rapid cell death (RCD). The RCD was exhibited in protein-rich media but not in starch or other minimal media. This RCD in X. campestris pv. glycines was found to display features similar to those of the programmed cell death (PCD) of eukaryotes. Results of the present study showed that the observed RCD in this organism is both positively and negatively regulated by small molecules. The amino acids glycine and l-alanine as well as the D isomers of valine, methionine, and threonine were found to induce the synthesis of an active caspase-3-like protein that was associated with the onset of RCD. Addition of pyruvate and citrate to the culture medium induced both the synthesis of active caspase-3-like protein and RCD. Higher levels of intracellular accumulation of pyruvate and citrate were also observed under conditions favoring RCD. On the other hand, dextrin and maltose, the hydrolytic products of starch, inhibited the synthesis of the caspase-3-like protein. Addition of glucose and cyclic AMP (cAMP) to the RCD-favoring medium prevented RCD. Glucose, cAMP, caffeine (a known inhibitor of a phosphodiesterase that breaks down cAMP), and forskolin (from the herb Coleus forskholii, known to activate the enzyme adenylate cyclase that forms cAMP) inhibited the caspase enzyme activity in vivo and consequently the RCD process. The addition of glucose and other inhibitors of RCD enhanced intracellular cAMP accumulation. This is the first report demonstrating the involvement of small molecules in the regulation of nutrition stress-related stationary-phase rapid cell death in X. campestris pv. glycines, which is programmed.
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PMID:Molecules involved in the modulation of rapid cell death in Xanthomonas. 1685 30

One of the mechanisms that regulate cell death is the reversible phosphorylation of proteins. ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr(125) dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1alpha (PP1alpha) associates with phosphorylated caspase-9. IL-2 deprivation induces PP1alpha dephosphorylation, which leads to its activation and, as a consequence, dephosphorylation and activation of caspase-9 and subsequent dissociation of both molecules. In cell-free systems supplemented with ATP caspase-9 activation is induced by addition of cytochrome c and we show that in this process PP1alpha is indispensable for triggering caspase-9 as well as caspase-3 cleavage and activation. Moreover, PP1alpha associates with caspase-9 in vitro and in vivo, suggesting that it is the phosphatase responsible for caspase-9 dephosphorylation and activation. Finally, we describe two novel phosphatase-binding sites different from the previously described PP1alpha consensus motifs, and we demonstrate that these novel sites mediate the interaction of PP1alpha with caspase-9.
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PMID:Identification of PP1alpha as a caspase-9 regulator in IL-2 deprivation-induced apoptosis. 1688 6

Visceral leishmaniasis (VL) produced in BALB/c mice through intracardial administration of Leishmania donovani amastigotes was accompanied by hepatosplenomegaly with high organ parasite load and lymphadenopathy when followed up to 4-months or so. To elucidate the mechanism of immunosuppression associated with VL, we report here progressive impairment of the proliferative response of lymph node cells (lymphocytes) from infected animals (I-LNC) to in vitro stimulation with the combination of phorbol 12-myristate 13-acetate (PMA) and ionomycin (Io) that could be related to the downregulation of PKC and MAP kinase (ERK 1/2) activation process. Further, pretreatment of I-LNC with the protein phosphatase inhibitor okadaic acid (OA), but not with calyculin A or sodium orthovanadate, significantly restored their proliferative response as well as PMA-induced activation of PKC. A population of LNC (primarily T-lymphocytes) from chronically infected animals was shown to undergo apoptosis, the number of which increased considerably following PMA+ Io stimulation. The apoptotic pathway, which was followed through binding of cells to Annexin V, activation of caspase-3 and fragmentation of DNA, involved destabilization of mitochondria, probably as a result of downregulation of PKC and Bcl-2. Interestingly, prior incubation of I-LNC with OA reversed the state of cell cycle arrest (anergy) and apoptosis through progression of cells from G0/G1 to S and G2/M phases with transcriptional activation of IL-2 and IL-2R genes. Our results suggest that the cellular (immune) dysfunction in VL could be attributed to dephosphorylation of key molecules in the T-lymphocyte signaling pathway by Ser/Thr phosphatase leading to their inactivation.
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PMID:Lymph node cells from BALB/c mice with chronic visceral leishmaniasis exhibiting cellular anergy and apoptosis: involvement of Ser/Thr phosphatase. 1701 55

Acute treatment with kainate 30 mg/kg (KA) produced behavioral alterations and reactive gliosis. However, it did not produce major death of mouse hippocampal neurons, indicating that concentrations were not cytotoxic. KA caused rapid and temporal Erk phosphorylation (at 6h) and Akt dephosphorylation (1-3 days). Concomitantly, the activation of GSK3beta was increased 1-3 days after KA. After 7 days, a reduction in GSK3beta activation was observed. Caspase-3 activity increased, but to a lesser extent than calpain activation (measured by fluorimetry and calpain-cleaved alpha-spectrin). As calpain is involved in cdk5 activation, and cdk5 is related to GSK3beta, the cdk5/p25 pathway was examined. Results showed that the p25/p35 ratio in KA-injected mice for 3 days was 73.6% higher than control levels. However, no changes in cdk5 expression were detected. Both Western blot and immunohistochemistry against p-Tau(Thr(231)) indicated an increase at this phosphorylated site of tau protein. Indeed an increase in p-Tau(Ser(199)) and p-Tau(Ser(396)) was observed by Western blot. Our results demonstrate that tau hyperphosphorylation, induced by KA, is due to an increase in GSK3beta/cdk5 activity in combination with an inactivation of Akt. This indicates that the calpain/cdk5 pathway for tau phosphorylation has a potential role in delayed apoptotic death evoked by excitotoxicity. Moreover, the subsequent activation of caspase and calpain proteases leads to dephosphorylation of tau, thus increasing microtubular destructuration. Taken together, our results provide new insights in the activation of several kinase-pathways implicated in cytoskeletal alterations that are a common feature of neurodegenerative diseases.
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PMID:Kainate induces AKT, ERK and cdk5/GSK3beta pathway deregulation, phosphorylates tau protein in mouse hippocampus. 1711 46

The mechanisms by which infections induce diaphragm dysfunction remain poorly understood. The purpose of this study was to determine which caspase pathways (i.e., the extrinsic, death receptor-linked caspase-8 pathway, and/or the intrinsic, mitochondrial-related caspase-9 pathway) are responsible for endotoxin-induced diaphragm contractile dysfunction. We determined 1) whether endotoxin administration (12 mg/kg IP) to mice induces caspase-8 or -9 activation in the diaphragm; 2) whether administration of a caspase-8 inhibitor (N-acetyl-Ile-Glu-Thr-Asp-CHO, 3 mg/kg iv) or a caspase-9 inhibitor (N-acetyl-Leu-Glu-His-Asp-CHO, 3 mg/kg iv) blocks endotoxin-induced diaphragmatic weakness and caspase-3 activation; 3) whether TNF receptor 1-deficient mice have reduced caspase activation and diaphragm dysfunction following endotoxin; and 4) whether cytokines (TNF-alpha or cytomix, a mixture of TNF-alpha, interleukin-1beta, interferon-gamma, and endotoxin) evoke caspase activation in C(2)C(12) myotubes. Endotoxin markedly reduced diaphragm force generation (P < 0.001) and induced increases in caspase-3 and caspase-8 activity (P < 0.03), but failed to increase caspase-9. Inhibitors of caspase-8, but not of caspase-9, prevented endotoxin-induced reductions in diaphragm force and caspase-3 activation (P < 0.01). Mice deficient in TNF receptor 1 also had reduced caspase-8 activation (P < 0.001) and less contractile dysfunction (P < 0.01) after endotoxin. Furthermore, incubation of C(2)C(12) cells with either TNF-alpha or cytomix elicited significant caspase-8 activation. The caspase-8 pathway is strongly activated in the diaphragm following endotoxin and is responsible for caspase-3 activation and diaphragm weakness.
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PMID:The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction. 1721 30

Geminin has been proposed to coordinate cell cycle and differentiation events through balanced interactions with the cell cycle regulator Cdt1 and with homeobox transcription factors and chromatin remodeling activities implicated in cell fate decisions. Here we show that Geminin is cleaved in primary cells and cancer cell lines induced to undergo apoptosis by a variety of stimuli. Geminin targeting is mediated by caspase-3 both in vivo and in vitro. Two sites at the carboxyl terminus of Geminin (named C1 and C2) are cleaved by the caspase, producing truncated forms of Geminin. We provide evidence that Geminin cleavage is regulated by phosphorylation. Casein kinase II alters Geminin cleavage at site C1 in vitro, whereas mutating phosphorylation competent Ser/Thr residues proximal to site C1 affects Geminin cleavage in vivo. We show that truncated Geminin produced by cleavage at C1 can promote apoptosis. In contrast, Geminin cleaved at site C2 has lost the ability to interact with Brahma (Brm), a catalytic subunit of the SWI/SNF chromatin remodeling complex, while binding efficiently to Cdt1, indicating that targeting of Geminin during apoptosis differentially affects interactions with its binding partners.
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PMID:Geminin cleavage during apoptosis by caspase-3 alters its binding ability to the SWI/SNF subunit Brahma. 1726 82

PTPA, which possesses a peptidyl prolyl isomerase activity, was initially isolated as a protein that stimulates the weak phosphotyrosyl phosphatase activity of the Ser/Thr phosphatase PP2A. Here we show that transient overexpression of PTPA leads to cell death in a time-dependent manner in mammalian cells. PTPA-overproducing cells manifest hallmarks of apoptosis including chromatin condensation, membrane blebbing, positive staining with annexin V, dephosphorylation of Bad, and caspase-3 cleavage. Incubation of cells with the PP2A inhibitor okadaic acid does not prevent either dephosphorylation of Bad or PTPA-induced apoptosis, indicating that PTPA is unlikely to mediate its proapoptotic effect via PP2A. Moreover, we find no evidence for the involvement of either p53 or MAP kinases. Our data reveal a potential novel role for PTPA in the apoptotic process.
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PMID:Overexpression of the cis/trans isomerase PTPA triggers caspase 3-dependent apoptosis. 1733 20

Prostate carcinoma is one of the most common malignant tumors and has become a more common cancer in men. Previous studies demonstrated that evodiamine (EVO) exhibited anti-tumor activities on several cancers, but its effects on androgen-independent prostate cancer are unclear. In the present study, the action mechanisms of EVO on the growth of androgen-independent prostate cancer cells (DU145 and PC3 cells) were explored. EVO dramatically inhibited the growth and elevated cytotoxicity of DU145 and PC3 cells. The flow cytometric analysis of EVO-treated cells indicated a block of G2/M phase and an elevated level of DNA fragmentation. The G2/M arrest was accompanied by elevated Cdc2 kinase activity, an increase in expression of cyclin B1 and phosphorylated Cdc2 (Thr 161), and a decrease in expression of phosphorylated Cdc2 (Tyr 15), Myt-1, and interphase Cdc25C. TUNEL examination showed that EVO-induced apoptosis was observed at 72 h. EVO elevated the activities of caspase 3, 8, and 9 in DU145 cells, while in PC3 cells only the activities of caspase 3 and 9 were elevated. EVO also triggered the processing of caspase 3 and 9 in both DU145 and PC3 cells. We demonstrate that roscovitine treatment result in the reversion of G2/M arrest in response to EVO in both DU145 and PC3. However, inhibitory effect of roscovitine on EVO-induced apoptosis could only be observed in DU145 rather than PC3. In DU145, G2/M arrest might be a signal for initiation of EVO-triggered apoptosis. Whereas EVO-triggered PC3 apoptosis might be independent of G2/M arrest. These results suggested that EVO inhibited the growth of prostate cancer cell lines, DU145 and PC3, through an accumulation at G2/M phase and an induction of apoptosis.
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PMID:Anti-proliferative effects of evodiamine on human prostate cancer cell lines DU145 and PC3. 1734 Jun 28

Apoptosis signal-regulating kinase-1 (ASK-1) is an important molecule for the pro-apoptotic signaling. ASK-1 also contributes to the cellular survival for many types of cells. Thus, ASK-1 has a broad range of biological activities depending on the cell type. The present study assessed the role(s) of ASK-1 in colorectal cancer cells (HT-29) by using adenovirus vectors expressing wild-type (WT)-ASK-1 or dominant-negative (DN) mutant of ASK-1 and recombinant adenovirus containing the bacterial beta-galactosidase gene (Ad-LacZ), a negative control for Ad-DN-ASK-1. Selective phosphorylation of ASK-1 at Thr 845, a kinase domain site, but not Ser 83 nor 967 sites was induced by serum stimulation in a time-dependent manner. Transfection with Ad-DN-ASK-1 inhibited the serum-induced phosphorylation of p38 mitogen-activated protein kinase, a downstream molecule of ASK-1. Transfection with Ad-DN-ASK-1 diminished the serum-induced cell proliferation in a dose-dependent manner, whereas WT-ASK-1 increased it. Apoptosis assessed by Hoechst staining was induced in the Ad-DN-ASK-1 treated cells. In vivo transfection of Ad-DN-ASK-1 into tumor xenografts of HT-29 cells in nude mice significantly decreased the tumor volume on day 29. Cleaved caspase-3 was found in the tumors of DN-ASK-1 treated mice. We obtained the first evidence that DN-ASK-1 transfection exerted significant antitumor effects on colon cancer mediated by apoptosis.
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PMID:Growth inhibition of colon cancer cells by transfection of dominant-negative apoptosis signal-regulating kinase-1. 1734 15


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