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)

The MET tyrosine kinase is the hepatocyte growth factor/scatter factor (HGF/SF) receptor, which elicits multiple biological responses in epithelial cells, including cell survival. We previously demonstrated that in stress conditions, the MET receptor is cleaved by caspases within its juxtamembrane region, generating a pro-apoptotic intracellular fragment of 40 kDa. The caspase cleavage site at aspartic acid D1000 is adjacent to tyrosine Y1001, which when phosphorylated upon MET activation, is involved in CBL recruitment, allowing receptor ubiquitination and down regulation. Scanning mutagenesis of the MET juxtamembrane region led us to demonstrate that V999 and D1000 are essential for the caspase cleavage, while D1000 and Y1001 are essential for CBL recruitment. By examining whether overlapping of these sites leads to a functional interference, an inverse relationship was found between generation of p40 MET and phosphorylation of MET, with a direct involvement of phosphorylated Y1001 in protecting MET against its caspase cleavage. A molecular modeling analysis of caspase 3 interaction with the juxtamembrane region of MET confirmed that phosphorylation of this tyrosine is not compatible with its recognition by active caspase 3. These data demonstrate a direct protection mechanism of an activated phosphorylated MET receptor, against its caspase-dependent cleavage.
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PMID:Phosphorylation of the MET receptor on juxtamembrane tyrosine residue 1001 inhibits its caspase-dependent cleavage. 1945 Jun 81

Attachment of stone crystals to tubular epithelium may initiate kidney stone formation. We previously reported that apical nucleolin related protein (NRP) expression during mitosis enhance attachment of Ca oxalate monohydrate crystals (COM). Some forms of injury may also increase affinity for crystals. We examined changes in subcellular localization of NRP during the course of cisplatin-induced apoptosis in cultured inner medullary collecting duct cells. Caspase-3 activation and chromatin condensation followed by nuclear fragmentation occurred after 20 h exposure to cisplatin, indicating the development of apoptosis. Cells were fixed without permeabilization and stained for surface NRP. Cells with condensed chromatin showed little or no cytoplasmic or apical NRP. Those at an early stage of nuclear fragmentation had cytoplasmic but not apical NRP and cells with advanced nuclear fragmentation were positively stained for apical NRP. Membrane proteins isolated by apical biotinylation and precipitated with avidin were analyzed by Western blot. Apical NRP was markedly increased after cisplatin compared to control, while expression of the apical marker, GP-135, and other putative attachment protein were unchanged. Hyaluronic acid was decreased. Cultures with apoptotic cells demonstrated increased adherence of COM that was inhibited by the polyanion (poly)aspartic acid. We conclude that pre-existing apoptotic injury may promote calcium oxalate crystals attachment to renal tubular epithelium via apical NRP expression.
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PMID:Induction of apoptosis with cisplatin enhances calcium oxalate crystal adherence to inner medullary collecting duct cells. 2007 9

Lunasin is a naturally occurring peptide with arginine-glycine-aspartic acid motif associated to its reported biological activity. We aimed to determine the potential of lunasin from soybean to stimulate apoptosis in HT-29 colon cancer cells. Lunasin caused cytotoxicity to HT-29 cells and induced G2/M cell cycle arrest with simultaneous increased in p21 expression. Lunasin-induced apoptosis as evidenced by a twofold increase in the percentage of cells undergoing apoptosis, decreased Bcl-2:Bax ratio from 8.5 to 0.4, increased caspase-3 activity by 77% and increased expression of pro-apoptotic nuclear clusterin by five fold when compared to untreated cells. In conclusion, lunasin stimulated apoptosis in HT-29 cells by activating apoptotic mitochondrial pathways and inducing expression of the pro-apoptotic nuclear clusterin.
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PMID:Lunasin promotes apoptosis in human colon cancer cells by mitochondrial pathway activation and induction of nuclear clusterin expression. 2020 42

The ability to form functional polymeric patterning structures has important implications for the studies of cell biology, tissue engineering, and medical diagnostics. We have developed a novel enzyme-assisted photolithography (EAPL) method for spatial functionalization of hydrogels via a high throughput fashion. A bisacrylated peptide crosslinker, containing a protease cleavable amino acid sequence and caged by a photolabile moiety, is used during hydrogel polymerization. A facile two-step process is employed, including UV exposure to decage the peptide crosslinker at a desired area and protease development to specifically digest gels at UV treated regions only. Importantly, proteolysis of the peptide bonds generates free nucleophilic amine groups at the patterned area that can be further functionalized. Using this strategy and caspase-3 as the enzyme developer, we demonstrate the simultaneous generation of topographical and functional patterns into poly(ethylene glycol) (PEG) hydrogels. We show that 20 microm-wide line arrays functionalized with arginine-glycine-aspartic acid (RGD)-containing peptides can be used to generate cell patterns with individual cell resolution. We also fabricated arrays 20 mum diameter cavities decorated with B lymphocyte specific anti-CD19, which was used to achieve a 600-fold enrichment of B-cells from a 0.1% starting B-cell mixture. The simple fabrication process, straightforward chemistry and an all-aqueous based biocompatible and environmentally friendly approach render EAPL a versatile platform to construct biologically responsive 2D patterns or 3D scaffolds for lab-on-a-chip systems and tissue engineering.
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PMID:Enzyme-assisted photolithography for spatial functionalization of hydrogels. 2043 69

Herpes Simplex Virus Type 1 (HSV-1) is ubiquitous, neurotropic, and the most common pathogenic causes of sporadic acute encephalitis in humans. Herpes simplex encephalitis is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. HSV-1 infects limbic system structures in the central nervous system and has been suggested as an environmental risk factor for Alzheimer's disease. However, the possible mechanisms that link HSV-1 infection with the neurodegenerative process are still largely unknown. In a previous study we demonstrated that HSV-1 triggers hyperphosphorylation of tau epitopes serine202/threonine205 and serine396/serine404 in neuronal cultures, resembling what occurs in neurodegenerative diseases. Therefore, the aim of the present study was to evaluate at the cellular level if another event associated with neurodegeneration, such as caspase-3 induced cleavage of tau, could also be triggered by HSV-1 infection in primary neuronal and astrocyte cultures. As expected, induction of caspase-3 activation and cleavage of tau protein at its specific site (aspartic acid 421) was observed by Western blot and immunofluorescence analyses in mice neuronal primary cultures infected with HSV-1. In agreement with our previous study on tau hyperphosphorylation, tau cleavage was also observed during the first 4 hours of infection, before neuronal death takes place. This tau processing has been previously demonstrated to increase the kinetics of tau aggregation in vitro and has also been observed in neurodegenerative pathologies. In conclusion, our findings support the idea that HSV-1 could contribute to induce neurodegenerative processes in age-associated pathologies such as Alzheimer's disease.
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PMID:Tau cleavage at D421 by caspase-3 is induced in neurons and astrocytes infected with herpes simplex virus type 1. 2109 75

Caspases-3, a member of the cysteine-aspartic acid protease (caspase) family, plays critical roles in the execution of apoptotic pathway. In this study, a caspase-3 homologue was cloned and characterized from large yellow croaker (Pseudosciaena crocea). The full-length cDNA of large yellow croaker caspase-3 (Lyccasp3) is 2222bp with an open reading frame of 858 bp encoding a polypeptide of 285 amino acids (aa). Lyccasp3 exhibited a conserved caspase-3 architecture including a prodomain, a large subunit and a small subunit. Moreover, several residues known to be critical in the caspase-3 catalytic centre and binding pocket, as well as the active-site pentapeptide motif Q(172)ACRG(176) were present in the deduced Lyccasp3. Recombinant Lyccasp3 (rLyccasp3) produced in Escherichia coli exhibited obvious hydrolyzing activity against synthetic peptide substrate Ac-DEVD-pNA. The Lyccasp3 was constitutively expressed in all the tissues examined, although the expression levels varied from tissue to tissue. Real-time PCR analysis revealed that Lyccasp3 transcript in spleen and kidney was quickly increased after stimulation with either poly (I:C) or inactivated trivalent bacterial vaccine. Enzyme activities of Lyccasp3 were also up-regulated in these two tissues post-stimulation when analyzed by hydrolyzing activity assay. Since the activity of large yellow croaker caspase-9 (Lyccasp9) in the spleen and kidney also increased when the fish was stimulated with the poly(I:C) or bacterial vaccine [1], we therefore proposed that the intrinsic apoptotic pathway, which is initiated by caspase-9 and executed by caspase-3, was activated during the immune response induced by poly(I:C) or bacterial vaccine in large yellow croaker.
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PMID:Molecular cloning and characterization of caspase-3 in large yellow croaker (Pseudosciaena crocea). 2128 91

Programmed cell death or apoptosis can be induced by a variety of mechanisms including genotoxic stress (1-3). The initiation of apoptosis involves the activation of a proteolytic cascade reminiscent of the blood-clotting pathway or activation of pancreatic proteases (4). It has been suggested that a single DNA strand break or persistent DNA adduct is sufficient to induce apoptosis (5). The protease cascade allows for the amplification of the initial signal and results in the degradation of cellular proteins and chromosomal DNA, which are packaged into apoptotic bodies and subsequently removed and recycled by phagocytic cells. The proteases involved in apoptosis employ active site cysteine residues, which catalyze the hydrolysis of the peptide bond following specific aspartic acid residues (6). This class of proteases has been termed caspases for cysteinyl, aspartate-specific proteases. A current view of the caspase cascade is presented in Fig. 1. Genotoxic stress results in the generation of an as yet undefined signal that results in the release of cytochrome C from the intermembrane space of mitochondria into the cytoplasm. It is in the cytoplasm that cytochrome C can form a complex with apocaspase 9, apoptotic protease activating factor-1 (Apaf-1) and deoxyadenosine 5'triphosphate (dATP). This complex is competent for the autoproteolytic activation of caspase-9 (7). Active caspase-9 then cleaves apocaspase-3 to generate an active caspase-3, which is responsible for cleaving specific target proteins, one of which is the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). The antiapoptotic factor Bcl-xL can sequester cytochrome C and inhibit the formation of the caspase-9-Apaf-1 complex effectively blocking apoptosis (8). The proapoptotic factor Bcl-xS promotes apoptosis by binding to Bcl-xL and thus blocking the inhibitory effect of this protein (8). Fig. 1. Programmed cell death pathway in response to genotoxic stress.
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PMID:DNA-Dependent Protein Kinase in Apoptosis. 2134 Aug 32

Noninvasive detection and in vivo imaging of apoptosis plays a critical role in the development of therapeutics in many different fields including cancer. We have developed an apoptosis biosensor by fusing green fluorescent protein (GFP) to the N-terminus of the naturally secreted Gaussia luciferase separated by a caspase-3 cleavage peptide consisting of aspartic acid (D), glutamic acid (E), valine (V), and aspartic acid (D) or DEVD. We showed that this fusion is retained in the cytoplasm of cells in an inactive form. Upon apoptosis, the DEVD peptide is cleaved in response to caspase-3 activation, freeing ssGluc, which can now enter the secretory pathway where it is folded properly and is released from the cells and can be detected in the conditioned medium in culture or in blood of live animals ex vivo over time. Because Gluc is secreted from cells via conventional pathway through the endoplasmic reticulum (ER), Golgi and vesicles, we showed that the presence of Gluc in these compartments in response to apoptosis can be visualized in vivo using bioluminescence imaging. This reporter provides a valuable tool for imaging and real-time monitoring of apoptosis and is compatible with high-throughput functional screening application in cultured cells and animal models.
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PMID:Multimodal in vivo imaging and blood monitoring of intrinsic and extrinsic apoptosis. 2134 14

Chinese hamster ovary (CHO) cells, its lung fibroblasts (V79), and human lymphocytes are routinely used in in vitro cytogenetic assays, which include micronuclei (MN), sister chromatid exchange (SCE), and chromosome aberration (CA) assays. Mitomycin C (MMC), a DNA cross-link alkylating agent, is both an anticancer medicine and a carcinogen. To study the differential representative values of cell types in MMC-treated cytogenetic assays and its upstream factor, cysteine aspartic acid-specific protease (caspase)-3. Among the chosen cell types, lymphocytes expressed the highest sensitivity in all three MMC-induced assays, whereas CHO and V79 showed varied sensitivity in different assays. In MN assay, the sensitivity of CHO is higher than or equal to V79; in SCE assay, the sensitivity of CHO is the same as V79; and in CA assay, the sensitivity of CHO is higher than V79. In-depth analysis of CA revealed that in chromatid breaks and dicentrics formation, lymphocyte was the most sensitive of all and CHO was more sensitive than V79; and in acentrics and interchanges formation, lymphocyte was much more sensitive than the others. Furthermore, we found caspase-3 activity plays an important role in MMC-induced cytogenetic assays, with MMC-induced caspase-3 activity resulting in more sensitivity in lymphocytes than in CHO and V79. Based on these findings, lymphocyte will make a suitable predictive or representative control reference in cytogenetic assays and caspase-3 activity with its high specificity, positive predictive value, and sensitivity.
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PMID:Evaluation of differential representative values between Chinese hamster cells and human lymphocytes in mitomycin C-induced cytogenetic assays and caspase-3 activity. 2176 8

Postsynaptic density protein 95 (PSD95) contains three PSD95/Drosophilia disk large/ZO-1[PDZ] homology domains and links neuronal nitric oxide synthase (nNOS) with the N-methyl-D: -aspartic acid receptor. Previous studies showed that the assembly of PSD95/nNOS signaling played an important role in rat ischemic brain injury. In this study, we aimed to elucidate the changes of PSD95 expression and location in retina after optic nerve crush. The optic nerve injury model of rats was created by crushing optic nerve at 2 mm retrobulbarly. Real-time PCR and Western blot analysis were used to analyze mRNA and protein expression of PSD95. The spatial distribution of PSD95 were evaluated by immunohistochemistry. Immunofluorescence was performed to observe the co-localization of PSD95. The PSD95 expression diminished at 1 day and elevated and peaked on the 7th day of post-injury. The mRNA and protein levels of PSD95 underwent the similar change. The association of PSD95 and rhodopsin was detected by immunofluorescence double staining. The injury-induced expression of PSD95 was physically co-existed with active caspase-3 (apoptotic marker) and nNOS. The spatiotemporal changes of PSD95 expression suggests that this protein likely to play a role in the degenerative process of never cells induced by optic nerve injury in the retina.
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PMID:Spatiotemporal expression of postsynaptic density 95 in rat retina after optic nerve injury. 2192 88


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