Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p21-activated protein kinase (PAK)-2 is a member of the PAK family of serine/threonine kinases. PAKs are activated by the p21 G-proteins Rac and Cdc42 in response to a variety of extracellular signals and act in pathways controlling cell growth, shape, motility, survival, and death. PAK-2 is unique among the PAK family members because it is also activated through proteolytic cleavage by caspase-3 or similar proteases to generate the constitutively active PAK-2p34 fragment. Activation of full-length PAK-2 by Rac or Cdc42 stimulates cell survival and protects cells from cell death, whereas caspase-activated PAK-2p34 induces a cell death response. Caspase-activated PAK-2p34 is rapidly degraded by the 26 S proteasome, but full-length PAK-2 is not. Stabilization of PAK-2p34 by preventing its polyubiquitination and degradation results in a dramatic stimulation of cell death. Although many proteins have been shown to interact with and regulate full-length PAK-2, little is known about the regulation of caspase-activated PAK-2p34. Here, we identify PS-GAP as a regulator of caspase-activated PAK-2p34. PS-GAP is a GTPase-activating protein for Cdc42 and RhoA that was originally identified by its interaction with the tyrosine kinase PYK-2. PS-GAP interacts specifically with caspase-activated PAK-2p34, but not active or inactive full-length PAK-2, through a region between the GAP and SH3 domains. The interaction with PS-GAP inhibits the protein kinase activity of PAK-2p34 and changes the localization of PAK-2p34 from the nucleus to the perinuclear region. Furthermore, PS-GAP decreases the stimulation of cell death induced by stabilization of PAK-2p34.
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PMID:Identification and characterization of PS-GAP as a novel regulator of caspase-activated PAK-2. 1547 51

In stable adults or patients with kidney disease, the daily turnover of cellular proteins is very large, amounting to the quantity of protein in 1 to 1.5 kg of muscle. Consequently, even a small but persistent increase in protein degradation or decrease in protein synthesis leads to a substantial loss of muscle mass. In chronic kidney disease, the pathway that degrades muscle protein is the ubiquitin-proteasome system. We tested whether either of two complications of chronic kidney disease, metabolic acidosis or insulin resistance accelerates the loss of muscle protein. Metabolic acidosis activates the ubiquitin-proteasome system and this can explain an large number of clinical conditions in which metabolic acidosis also causes loss of muscle protein. Insulin deficiency as a model of insulin resistance also activates the ubiquitin-proteasome system. Both complications also activate caspase-3 and we found that this protease performs a critical initial step in breaking down the complex structure of muscle to provide actin, myosin and fragments of these proteins as substrates for the ubiquitin-proteasome system. Defects in insulin signalling processes can activate both caspase-3 and the ubiquitin-proteasome system to degrade muscle protein. Understanding mechanisms that activate protein breakdown will lead to therapies that successfully prevent the loss of muscle mass in patients with kidney disease.
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PMID:Cellular mechanisms causing loss of muscle mass in kidney disease. 1549 Apr 16

The role of the ubiquitin-proteasome pathway during roscovitine induced apoptosis was evaluated in the non-small cell lung carcinoma cell line MR65. To this end specific inhibitors of proteasome activity, MG132 and lactacystin were used. Addition of MG132 or lactacystin, 1 h prior to the addition of the CDK-inhibitor roscovitine to the cell cultures inhibited apoptosis significantly, as measured by PS exposure, cytokeratin 18 cleavage and caspase-3 activation. Furthermore, we show that inhibition of proteasome activation prior to induction of apoptosis by roscovitine prevents loss of mitochondrial inner transmembrane potential (DeltaPsim). In addition we found that MG132 and lactacystin prevent release of cytochrome c from the mitochondrion. In contrast to the above findings we see no effect of proteasome inhibition in Fas-mediated apoptosis. Taken together our data suggest a specific role for proteasomes very early in roscovitine-induced apoptosis, upstream from the caspase cascade and mitochondrion.
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PMID:Proteasomes act in the pre-mitochondrial signal transduction route towards roscovitine-induced apoptosis. 1549 36

The irreversible inhibitor of chymotrypsin-like serine proteases, N-tosyl-L-phenylalanine chloromethylketone (TPCK), was shown to prevent internucleosomal DNA cleavage caused by inducers of apoptosis. The pro-apoptotic properties of TPCK have been studied less thoroughly. The aim of the present study was to investigate the pro- and anti-apoptotic activities of TPCK on HL-60 cells and compare them with the actions of the mitochondrial electron transport inhibitor antimycin A (AMA). The results showed that TPCK alone caused activation of cell cycle checkpoints, mitochondrial cytochrome c release, caspase-3 activation, and chromatin condensation. Caspase-8 was not required for cytochrome c release but was crucial to caspase-3 activation. TPCK synergistically enhanced AMA-induced cytochrome c release and caspase-3 activation while completely blocking AMA-induced internucleosomal DNA fragmentation for at least 8 hours. Rather than blocking AMA-induced DNA fragmentation, the general serine protease inhibitor 4-(2-aminoethyl)-benzenesulphonyl fluoride (AEBSF) actually enhanced it. The pro-apoptotic effect of TPCK may be due to activation of cell cycle checkpoints via inhibition of the proteasome. The apoptotic pathways activated by TPCK and AMA probably converge at the level of the mitochondria. The mode by which TPCK prevents internucleosomal DNA fragmentation is probably not through serine protease inhibition.
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PMID:Pro- and anti-apoptotic effects of an inhibitor of chymotrypsin-like serine proteases. 1553 54

Beyond their nutritional effect, short-chain fatty acids, especially butyrate, modulate cell differentiation, proliferation, motility, and in particular, they induce cell cycle arrest and apoptosis. A bovine kidney epithelial cell line (Madin-Darby bovine kidney; MDBK) was used to investigate the cell cycle regulatory and apoptotic effects of butyrate. Butyrate not only induced apoptosis but also induced cell cycle arrest at the G1/S boundary and M/G2 in MDBK cells (P < 0.01). The cell responses were concentration-dependent (r(2) = 0.9482, P <0.001). In examining possible mechanisms for the apoptosis and cell cycle arrest induced by butyrate, the results showed that butyrate treatment activates caspase-3 activities and induces accumulation of acetylated histone. At least two proteins, cdc6 and cdk1, become targeted for destruction on butyrate treatment. These two proteins are downregulated (P < 0.01 and P < 0.05, respectively) by proteolytic pathways. Moreover, the proteasome inhibitor MG-132 (carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) reverses the cell cycle arrest induced by butyrate, indicating a multiprotein crosstalk wherein the ubiquitination/ proteasome pathway interacted with the caspase-signaling pathway. Because the proteasome inhibitor MG-132 blocked activation of caspase-3, these results functionally locate the proteasome pathway upstream of the caspase pathway. All these results indicate that butyrate functions as both a nutrient and signaling molecule regulating cell growth and proliferation.
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PMID:Butyrate-induced apoptosis and cell cycle arrest in bovine kidney epithelial cells: involvement of caspase and proteasome pathways. 1558 47

Pancreatic cancer remains a highly chemoresistant malignancy. Gemcitabine, the most effective first-line agent available, acts by disrupting cellular replication. Caspases belong to a family of proteases that function as key components of the apoptotic death machinery. We investigated the mechanisms by which gemcitabine blocks proliferation and whether it can induce apoptosis in pancreatic cancer cells. Quiescent pancreatic cancer cells (BxPC-3) were stimulated to proliferate (10% fetal calf serum) with or without gemcitabine, PS-341 (26S proteasome inhibitor), or both. Proliferation was measured by MTT assay and apoptosis by propidium iodine staining. To determine activation of the apoptotic regulatory cell proteins, caspase-3 and cleavage of poly(ADP-ribose)polymerase (PARP) into its 85-kDa fragment were assessed by Western blotting. Gemcitabine at even low doses (10 micromol/L) significantly inhibited cellular proliferation, whereas PS-341 (10 nmol/L) had no effect. With combined treatment, PS-341 potentiated the antiproliferative effects of gemcitabine (P=0.001). At 48 hours, the apoptotic fraction was greatly enhanced by the presence of PS-341 compared with gemcitabine alone. Caspase-3 accumulated as early as 30 minutes and was associated with cleavage of PARP to its apoptotic fragment. Gemcitabine, a nucleoside analogue, may in part exert its antiproliferative effects by directing pancreatic cancer cells to a default pathway of apoptosis. 26S proteasome inhibition potentiates this effect, suggesting its potential clinical value against chemoresistance in pancreatic cancer.
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PMID:Caspase-3 drives apoptosis in pancreatic cancer cells after treatment with gemcitabine. 1558 96

Malignant insulinoma is a critical cancer form with a poor prognosis. Because cure by surgery is infrequent, effective chemotherapy is in demand. Induction of cell death in tumor cells by proteasome inhibitors is emerging as a potential strategy in cancer therapy. Here we investigated whether inhibition of the proteasome has an antitumorigenic potential in insulinoma cells. Exposure of mouse betaTC3 insulinoma cells to the proteasome inhibitor N-Acetyl-Leu-Leu-Nle-CHO (ALLN) reduced cell viability, activated caspase-3, induced apoptosis, and suppressed insulin release. Treatment with ALLN also resulted in phosphorylation of c-jun N-terminal kinase (JNK) and an increase in in vitro phosphorylation of c-jun. In insulinoma cells with impaired JNK signaling, ALLN-induced apoptosis was significantly suppressed. Another proteasome inhibitor, lactacystin, also stimulated JNK activation, caused activation of caspase-3, suppressed cell viability, and induced apoptosis in betaTC3 and rat INS-1E cells. Both ALLN and lactacystin caused a marked decrease in the cellular amount of the JNK scaffold protein JNK-interacting protein 1/islet-brain-1. In primary pancreatic rat islet cells, proteasome inhibition reduced insulin secretion but had no impact on cell viability and even partially protected against the toxic effect of proinflammatory cytokines. Our findings demonstrate that proteasome inhibitors possess antitumorigenic and antiinsulinogenic effects on insulinoma cells.
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PMID:Antitumorigenic effect of proteasome inhibitors on insulinoma cells. 1561 49

Axonal regeneration can occur within hours of injury, the first step being the formation of a new growth cone. For sensory and retinal axons, regenerative ability in vivo correlates with the potential to form a new growth cone after axotomy in vitro. We show that this ability to regenerate a new growth cone depends on local protein synthesis and degradation within the axon. Axotomy in vitro leads to a fourfold to sixfold increase in 3H-leucine incorporation in both neurones and axons, starting within 10 min and peaking 1 h after axotomy. Application of protein synthesis inhibitors (cycloheximide and anisomycin) to cut axons, including axons whose cell bodies were removed, or proteasome inhibitors (lactacystin and N-acetyl-Nor-Leu-Leu-Al) all result in a reduction in the proportion of transected axons able to reform growth cones. Similar inhibition of growth cone formation was observed on addition of target of rapamycin (TOR), p38 MAPK (mitogen-activated protein kinase), and caspase-3 inhibitors. Comparing retinal and sensory axons of different developmental stages, levels of ribosomal protein P0 and phosphorylated translation initiation factor are high in sensory axons, lower in embryonic axons, and absent in adult retinal axons. Conditioning lesions, which increase the regenerative ability of sensory axons, lead to increases in intra-axonal protein synthetic and degradative machinery both in vitro and in vivo. Collectively, these findings suggest that local protein synthesis and degradation, controlled by various TOR-, p38 MAPK-, and caspase-dependent pathways, underlie growth cone initiation after axotomy.
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PMID:Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. 1564 76

Loss of protein and lean body mass occurs commonly in patients with chronic kidney disease (CKD). CKD or conditions associated with CKD will stimulate muscle loss, but the cellular mechanisms by which these conditions cause muscle atrophy are largely undefined. In animal models of uremia and other catabolic conditions or in peritoneal dialysis patients, there is evidence that the ubiquitin-proteasome proteolytic system is activated to degrade actomyosin and myofibrillar proteins in muscle. Before the ubiquitin system can degrade muscle proteins, however, an initial cleavage of actomyosin and myofibrils must occur. Caspase-3 performs this initial cleavage of actomyosin and leaves a footprint of its activity, accumulation of a 14-kDa actin fragment in muscle. A critical step in stimulating the ubiquitin-proteasome system in muscle was recently discovered, the activation of a specific E3 ubiquitin-conjugating enzyme, atrogin-1. Both caspase-3 and the ubiquitin system, including atrogin-1, are activated when insulin signaling is impaired, and specifically when phosphatidylinositol 3 kinase activity is suppressed. Strategies that prevent a decrease in phosphatidylinositol 3 kinase activity or inhibit caspase-3 activity could lead to treatments that prevent muscle wasting in CKD patients.
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PMID:Strategies for suppressing muscle atrophy in chronic kidney disease: mechanisms activating distinct proteolytic systems. 1564 2

Mutations in familial Parkinson's disease (PD) have been associated with the failure of protein degradation through the ubiquitin-proteasome system (UPS). Impairment of proteasome function has also been suggested to play a role in the pathogenesis of sporadic PD. We examined the proteasome activity in PC12 cells treated with 6-hydroxydopamine (6-OHDA), the dopamine synthetic derivate used in models of PD. We found that 6-OHDA treatment increased protein oxidation, as indicated by carbonyl group accumulation, and increased caspase-3 activity. In addition, there was an increase in trypsin-, chymotrypsin-, and postacidic-like proteasome activities in cells treated with 10-100 microM 6-OHDA, whereas higher doses caused a marked decline. 6-OHDA exposure also increased mRNA expression of the 19S regulatory subunit in a dose-dependent manner, whereas the expression of 20S- and 11S-subunit mRNAs did not change. Administration of the antioxidant N-acetylcysteine to 6-OHDA-treated cells prevented the alteration in proteasome functions. Moreover, reduction in cell viability owing to administration of proteasome inhibitor MG132 or lactacystin was partially prevented by the endogenous antioxidant-reduced glutathione. In conclusion, our data indicate that mild oxidative stress elevates proteasome activity in response to increase in protein damage. Severe oxidative insult might cause UPS failure, which leads to protein aggregation and cell death. Moreover, in the case of UPS inhibition or failure, the blockade of physiological reactive oxygen species production during normal aerobic metabolism is enough to ameliorate cell viability. Control of protein clearance by potent, brain-penetrating antioxidants might act to slow down the progression of PD.
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PMID:Oxidative stress, induced by 6-hydroxydopamine, reduces proteasome activities in PC12 cells: implications for the pathogenesis of Parkinson's disease. 1565 61


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