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Role of cathepsins in blastocyst hatching in the golden hamster.
Sireesha GV, Mason RW, Hassanein M, Tonack S, Navarrete Santos A, Fischer B, Seshagiri PB
(2008) Mol Hum Reprod 14: 337-46
MeSH Terms: Animals, Blastocyst, Cathepsins, Cells, Cultured, Cricetinae, Cysteine Proteinase Inhibitors, Embryo Culture Techniques, Embryo, Mammalian, Embryonic Development, Female, Gene Expression Regulation, Developmental, Male, Mesocricetus, Pregnancy, Zona Pellucida
Show Abstract · Added May 29, 2014
The mammalian embryo is encased in a glycoproteinaceous coat, the zona pellucida (ZP) during preimplantation development. Prior to implantation, the blastocyst must undergo 'hatching' or ZP escape. In hamsters, there is a thinning of the ZP followed by a focal lysis and a complete dissolution of the ZP during blastocyst hatching. Earlier studies from our laboratory have indicated a role for cysteine proteases in the hatching phenomenon. In this study, we tested the effect of specific inhibitors of the three classes of cysteine protease on blastocyst hatching. Cystatin, an endogenous cathepsin inhibitor, blocked blastocyst hatching. Similarly, Fmoc-Tyr-Ala-diazomethane, a synthetic cathepsin inhibitor, blocked hatching. Both showed dose-dependent and temporal inhibition of hatching. However, Z-Val-Ala-Asp-fluoromethylketone, a synthetic caspase inhibitor, and calpastatin, an endogenous calpain inhibitor, had no effect on hatching. The cathepsins were localized to blastocyst cells. Exogenous addition of cathepsins L, P or B to cultured 8-cell embryos caused a complete ZP dissolution. The expression of mRNA and protein of cathepsins L and P was observed in peri-hatching blastocysts. Cathepsins L and P were detected in trophectodermal projections and in the ZP of peri-hatching blastocysts. These data provide the first evidence that blastocyst-derived cathepsins are functionally involved as zonalytic factors in the hatching of blastocysts in the golden hamster.
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15 MeSH Terms
Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration.
Mathur BN, Neely MD, Dyllick-Brenzinger M, Tandon A, Deutch AY
(2007) Brain Res 1168: 83-9
MeSH Terms: Animals, Animals, Newborn, Corpus Striatum, Cysteine Proteinase Inhibitors, Dopamine, Male, Motor Activity, Nerve Degeneration, Oligopeptides, Organ Culture Techniques, Rats, Rats, Sprague-Dawley, Substantia Nigra
Show Abstract · Added May 27, 2014
Proteasomal dysfunction has been suggested to contribute to the degeneration of nigrostriatal dopamine neurons in Parkinson's disease. A recent study reported that systemic treatment of rats with the proteasome inhibitor Z-lle-Glu(OtBu)-Ala-Leu-al (PSI) causes a slowly progressive degeneration of nigrostriatal dopamine neurons, the presence of inclusion bodies in dopamine neurons, and motor impairment. We examined in vitro and in vivo the effects of PSI on nigrostriatal dopamine neurons. Mass spectrometric analysis was employed to verify the authenticity of the PSI compound. PSI was non-specifically toxic to neurons in ventral mesencephalic organotypic slice cultures, indicating that impairment of proteasome function in vitro is toxic. Moreover, systemic administration of PSI transiently decreased brain proteasome activity. Systemic treatment of rats with PSI did not, however, result in any biochemical or anatomical evidence of lesions of nigrostriatal dopamine neurons, nor were any changes in locomotor activity observed. These data suggest that systemic administration of proteasome inhibitors to normal adult rats does not reliably cause an animal model of parkinsonism.
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13 MeSH Terms
Pressure-induced regulation of IL-6 in retinal glial cells: involvement of the ubiquitin/proteasome pathway and NFkappaB.
Sappington RM, Calkins DJ
(2006) Invest Ophthalmol Vis Sci 47: 3860-9
MeSH Terms: Animals, Animals, Newborn, Astrocytes, Cell Separation, Cells, Cultured, Cysteine Proteinase Inhibitors, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Indirect, Hydrostatic Pressure, Interleukin-6, Leupeptins, Microglia, NF-kappa B, RNA, Messenger, Rats, Rats, Sprague-Dawley, Retina, Reverse Transcriptase Polymerase Chain Reaction, Tetradecanoylphorbol Acetate, Ubiquitin-Protein Ligase Complexes
Show Abstract · Added May 27, 2014
PURPOSE - To investigate how hydrostatic pressure influences regulation of interleukin (IL)-6 by retinal glia and whether this regulation is associated with the ubiquitin/proteasome pathway (UPP) and activation of the transcription factor nuclear factor (NF)kappaB.
METHODS - Astrocytes and microglia isolated from rat retina were maintained in vitro, and the IL-6 concentration in the media at ambient and elevated pressure were compared, with and without the proteasome inhibitor MG132 (10 microM). Immunocytochemistry was used to correlate translocation of NFkappaB with pressure.
RESULTS - Exposure to elevated pressure for 24 hours maximally altered the concentration of media IL-6 of glia cultures, where IL-6 concentrations decreased in astrocyte cultures and increased in microglia cultures. These pressure-induced changes in IL-6 were largely insensitive to MG132 in astrocytes, but were largely MG132-sensitive in microglia. Like IL-6 regulation, pressure-induced activation of NFkappaB also differed between the two glial cell types, where nuclear localization of NFkappaB was transient in astrocytes, but sustained in microglia. Elevated pressure also increased MG132-sensitive expression of IL-6 mRNA by microglia.
CONCLUSIONS - Though pressure-induced regulation of IL-6 by astrocytes is preceded by NFkappaB translocation, it is not altered by MG132 and therefore is not likely to be regulated by NFkappaB or the UPP. In contrast, pressure-induced regulation of IL-6 protein and mRNA by microglia is preceded by NFkappaB translocation and is sensitive to MG132. Together with precedence in the literature, these data suggest that pressure-induced activation of the UPP leads to transcription of IL-6 driven by NFkappaB.
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20 MeSH Terms
Reovirus variants selected for resistance to ammonium chloride have mutations in viral outer-capsid protein sigma3.
Clark KM, Wetzel JD, Gu Y, Ebert DH, McAbee SA, Stoneman EK, Baer GS, Zhu Y, Wilson GJ, Prasad BV, Dermody TS
(2006) J Virol 80: 671-81
MeSH Terms: Adaptation, Physiological, Ammonium Chloride, Animals, Capsid Proteins, Cathepsin L, Cathepsins, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Drug Resistance, Viral, L Cells, Mice, Models, Molecular, Molecular Sequence Data, Mutation, Reoviridae, Serial Passage, Viral Proteins, Viral Regulatory and Accessory Proteins, Virus Assembly
Show Abstract · Added December 10, 2013
Mammalian reoviruses are internalized into cells by receptor-mediated endocytosis. Within the endocytic compartment, the viral outer capsid undergoes acid-dependent proteolysis resulting in removal of the sigma3 protein and proteolytic cleavage of the mu1/mu1C protein. Ammonium chloride (AC) is a weak base that blocks disassembly of reovirus virions by inhibiting acidification of intracellular vacuoles. To identify domains in reovirus proteins that influence pH-sensitive steps in viral disassembly, we adapted strain type 3 Dearing (T3D) to growth in murine L929 cells treated with AC. In comparison to wild-type (wt) T3D, AC-adapted (ACA-D) variant viruses exhibited increased yields in AC-treated cells. AC resistance of reassortant viruses generated from a cross of wt type 1 Lang and ACA-D variant ACA-D1 segregated with the sigma3-encoding S4 gene. The deduced sigma3 amino acid sequences of six independently derived ACA-D variants contain one or two mutations each, affecting a total of six residues. Four of these mutations, I180T, A246G, I347S, and Y354H, cluster in the virion-distal lobe of sigma3. Linkage of these mutations to AC resistance was confirmed in experiments using reovirus disassembly intermediates recoated with wt or mutant sigma3 proteins. In comparison to wt virions, ACA-D viruses displayed enhanced susceptibility to proteolysis by endocytic protease cathepsin L. Image reconstructions of cryoelectron micrographs of three ACA-D viruses that each contain a single mutation in the virion-distal lobe of sigma3 demonstrated native capsid protein organization and minimal alterations in sigma3 structure. These results suggest that mutations in sigma3 that confer resistance to inhibitors of vacuolar acidification identify a specific domain that regulates proteolytic disassembly.
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19 MeSH Terms
Involvement of the ubiquitin pathway in decreasing Ku70 levels in response to drug-induced apoptosis.
Gama V, Yoshida T, Gomez JA, Basile DP, Mayo LD, Haas AL, Matsuyama S
(2006) Exp Cell Res 312: 488-99
MeSH Terms: Acetylcysteine, Amino Acid Chloromethyl Ketones, Antigens, Nuclear, Apoptosis, Caspase Inhibitors, Cell Line, Cysteine Proteinase Inhibitors, DNA-Binding Proteins, Doxorubicin, Gene Expression, HeLa Cells, Humans, Ku Autoantigen, Leupeptins, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Signal Transduction, Staurosporine, Ubiquitin, Ubiquitin-Protein Ligase Complexes
Show Abstract · Added October 26, 2015
Ku70 plays an important role in DNA damage repair and prevention of cell death. Previously, we reported that apoptosis caused a decrease in cellular Ku70 levels. In this study, we analyzed the mechanism of how Ku70 levels decrease during drug-induced apoptosis. In HeLa cells, staurosporin (STS) caused a decrease in Ku70 levels without significantly affecting Ku70 mRNA levels. We found that Ku70 protein was highly ubiquitinated in various cell types, such as HeLa, HEK293T, Dami (a megakaryocytic cell line), endothelial, and rat kidney cells. An increase in ubiquitinated Ku70 protein was observed in apoptotic cells, and proteasome inhibitors attenuated the decrease in Ku70 levels in apoptotic cells. These results suggest that the ubiquitin-proteasome proteolytic pathway plays a role in decreasing Ku70 levels in apoptotic cells. Ku70 forms a heterodimer with Ku80, which is required for the DNA repair activity of Ku proteins. We also found that Ku80 levels decreased in apoptotic cells and that Ku80 is a target of ubiquitin. Ubiquitinated Ku70 was not found in the Ku70-Ku80 heterodimer, suggesting that modification by ubiquitin inhibits Ku heterodimer formation. We propose that the ubiquitin-dependent modification of Ku70 plays an important role in the control of cellular levels of Ku70.
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20 MeSH Terms
Hypoxia alters cathepsin B / inhibitor profiles in oral carcinoma cell lines.
Wickramasinghe NS, Banerjee K, Nagaraj NS, Vigneswaran N, Zacharias W
(2005) Anticancer Res 25: 2841-9
MeSH Terms: Aged, Carcinoma, Squamous Cell, Cathepsin B, Cell Growth Processes, Cell Hypoxia, Cell Line, Tumor, Cystatin B, Cystatin C, Cystatins, Cysteine Proteinase Inhibitors, Humans, Hypopharyngeal Neoplasms, Male, Middle Aged, Mouth Neoplasms
Show Abstract · Added June 14, 2013
BACKGROUND - The tumor microenvironment is believed to contribute to the malignant properties of tumor cells in heterogeneous tumor tissues. We investigated the impact of hypoxia (1% oxygen) on the expression of cathepsin B and its natural inhibitors cystatin B and C.
MATERIALS AND METHODS - Patient-matched oral carcinoma cell lines from primary tumor and lymph node metastasis were used to study the effects of hypoxia on proliferation, protein expression, and proteolytic and inhibitor activities.
RESULTS - Hypoxic growth led to elevated cathepsin B expression and activity, and this effect was greater in metastatic than in primary tumor cells. Also, hypoxia led to down-regulation of the inhibitors cystatin C and B, resulting in increased residual activity of cathepsin B.
CONCLUSION - These data suggest that the invasive and/or metastatic potential of cells may be enhanced under hypoxia by increasing cathepsin-mediated proteolysis. The results provide strong evidence for the involvement of cathepsin B and its cystatin inhibitors in hypoxia-enhanced tumor progression.
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15 MeSH Terms
Nuclear survivin as a biomarker for non-small-cell lung cancer.
Lu B, Gonzalez A, Massion PP, Shyr Y, Shaktour B, Carbone DP, Hallahan DE
(2004) Br J Cancer 91: 537-40
MeSH Terms: Aged, Apoptosis, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Cell Nucleus, Cysteine Proteinase Inhibitors, Cytoplasm, Female, Humans, Immunohistochemistry, Inhibitor of Apoptosis Proteins, Lung Neoplasms, Male, Microtubule-Associated Proteins, Middle Aged, Neoplasm Proteins, Prognosis, Retrospective Studies, Survival Analysis, Survivin
Show Abstract · Added March 5, 2014
Survivin inhibits apoptosis and promotes mitosis. We determined whether nuclear or cytoplasmic localisation of survivin predicts survival of 48 patients with resected non-small-cell lung cancer (NSCLC). Patients with nuclear staining of survivin had significantly worse survival (relative risk: 3.9, P=0.02). Therefore, survivin may be a biomarker for NSCLC.
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Extracellular signal-regulated kinase 7, a regulator of hormone-dependent estrogen receptor destruction.
Henrich LM, Smith JA, Kitt D, Errington TM, Nguyen B, Traish AM, Lannigan DA
(2003) Mol Cell Biol 23: 5979-88
MeSH Terms: Animals, Binding Sites, Breast, Breast Neoplasms, Cells, Cultured, Cricetinae, Cysteine Proteinase Inhibitors, Estrogen Receptor alpha, Extracellular Signal-Regulated MAP Kinases, Female, Hormones, Humans, Kidney, Leupeptins, Mitogen-Activated Protein Kinases, Mutation, Peptide Hydrolases, Phosphorylation, Proteasome Endopeptidase Complex, Receptors, Estrogen, Reference Values, Signal Transduction, Ubiquitin
Show Abstract · Added January 20, 2015
Estrogen receptor alpha (ER alpha) degradation is regulated by ubiquitination, but the signaling pathways that modulate ER alpha turnover are unknown. We found that extracellular signal-regulated kinase 7 (ERK7) preferentially enhances the destruction of ER alpha but not the related androgen receptor. Loss of ERK7 was correlated with breast cancer progression, and all ER alpha-positive breast tumors had decreased ERK7 expression compared to that found in normal breast tissue. In human breast cells, a dominant-negative ERK7 mutant decreased the rate of endogenous ER alpha degradation >4-fold in the presence of hormone and potentiated estrogen responsiveness. ERK7 targets the ER alpha ligand-binding domain for destruction by enhancing its ubiquitination. Thus, ERK7 is a novel regulator of estrogen responsiveness through its control of ER alpha turnover.
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23 MeSH Terms
A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin.
Zhou YP, Sreenan S, Pan CY, Currie KP, Bindokas VP, Horikawa Y, Lee JP, Ostrega D, Ahmed N, Baldwin AC, Cox NJ, Fox AP, Miller RJ, Bell GI, Polonsky KS
(2003) Metabolism 52: 528-34
MeSH Terms: Animals, Calcium, Calpain, Cell Separation, Cysteine Proteinase Inhibitors, Dipeptides, Energy Metabolism, Glucose, In Vitro Techniques, Insulin, Islets of Langerhans, Leucine, Mice, Mice, Inbred C57BL, Mitochondria, NADP, Oxidation-Reduction
Show Abstract · Added March 30, 2013
Genetic variation in the gene for a cytosolic cysteine protease, calpain-10, increases the susceptibility to type 2 diabetes apparently by altering levels of gene expression. In view of the importance of altered beta-cell function in the pathophysiology of type 2 diabetes, the present study was undertaken to define the effects on insulin secretion of exposing pancreatic islets to calpain inhibitors for 48 hours. Exposure of mouse islets to calpain inhibitors (ALLN, ALLM, E-64-d, MDL 18270, and PD147631) of different structure and mechanism of action for 48 hours reversibly suppresses glucose-induced insulin secretion by 40% to 80%. Exposure of islets to inhibitors of other proteases, ie, cathepsin B and proteasome, did not affect insulin secretion. The 48-hour incubation with calpain inhibitors also attenuates insulin secretory responses to the mitochondrial fuel alpha-ketoisocaproate (KIC). The same incubation also suppresses glucose metabolism and intracellular calcium ([Ca(2+)](i)) responses to glucose or KIC in islets. In summary, long-term inhibition of islet calpain activity attenuates insulin secretion possibly by limiting the rate of glucose metabolism. A reduction of calpain activity in islet could contribute to the development of beta-cell failure in type 2 diabetes thereby providing a link between genetic susceptibility to diabetes and the pathophysiologic manifestations of the disease.
Copyright 2003 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Expression of cysteine proteinase of Clonorchis sinensis and its use in serodiagnosis of clonorchiasis.
Na BK, Lee HJ, Cho SH, Lee HW, Cho JH, Kho WG, Lee JS, Lee JS, Song KJ, Park PH, Song CY, Kim TS
(2002) J Parasitol 88: 1000-6
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Blotting, Western, Clonorchiasis, Clonorchis sinensis, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, DNA, Helminth, Electrophoresis, Polyacrylamide Gel, Escherichia coli, Hot Temperature, Humans, Hydrogen-Ion Concentration, Molecular Sequence Data, Molecular Weight, RNA, Helminth, Random Amplified Polymorphic DNA Technique, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid
Show Abstract · Added March 14, 2014
A gene encoding cysteine proteinase from Clonorchis sinensis has been cloned and expressed in Escherichia coli. The cysteine proteinase cDNA fragment was amplified by reverse transcription-polymerase chain reaction using degenerate oligonucleotide primers derived from conserved active site of cysteine proteinases. The 5' and 3' regions of the gene were amplified using rapid amplification of cDNA ends. The cloned gene has an open reading frame of 696 bp and deduced amino acid sequence of 232. Sequence analysis and alignment showed significant homologies with the eukaryotic cysteine proteinases and conservation of the Cys, His, and Asp residues that form the catalytic triad. Analysis of the expressed protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the molecular weight of the protein was approximately 28.5 kDa. Proteolytic activity of the expressed protein was inhibited by cysteine proteinase inhibitors such as L-trans-epoxysuccinyl-leucylamide-(4-guanidino)-butane, iodoacetic acid, and leupeptin. The expressed protein showed biochemical properties similar to those of cysteine proteinases of other parasites. The expressed protein strongly reacted with the sera from patients with clonorchiasis but not with the sera from patients with paragonimiasis, fascioliasis, cysticercosis, and sparganosis, or with sera from normal human controls. These results suggest that the expressed protein may be valuable as a specific diagnostic material for the immunodiagnosis of clonorchiasis.
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20 MeSH Terms