Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cystatin C is the major inhibitor of the cysteine cathepsins. Polymorphisms in the cystatin C gene have recently been associated with the risk of developing Age-related Macular Degeneration (AMD). Oxidative stress is also thought to play a key role in the pathogenesis of AMD. We surveyed the retinal pigment epithelium (RPE) and choroid of the C57BL/6J mouse for the expression of the cysteine cathepsins under normoxic and hyperoxic (75% O(2)) conditions. Microarray analysis of RPE/choroid mRNA revealed the expression of cathepsins B and L, as well as cystatin C under all experimental conditions. The microarray results were confirmed by real-time quantitative polymerase chain reaction (PCR). Localization of the mRNA species for cystatin C and cathepsin B, as well as, localization of protein species for cystatin C, cathepsins B and L were performed to evaluate the tissue distribution of these species. Our results indicate that cystatin C is largely synthesized in the RPE and secreted from the basal side. Cathepsin B is the major cysteine protease in the RPE and choroid. The expression of all mRNAs and proteins was elevated by exposure to oxidative stress.
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PMID:Regulation of cysteine cathepsin expression by oxidative stress in the retinal pigment epithelium/choroid of the mouse. 1668 24

Increases in expression and activity of matrix-degrading enzymes such as the cysteine proteinases cathepsins B and L, and abnormal levels of their inhibitors, the cystatins, are associated with tumor cell invasion and metastasis. Environmental conditions have been shown to be causative factors in the development of a metastatic/invasive phenotype. We hypothesized that cell-matrix interactions affect the expression and activity of cathepsins B and L and their inhibitors in the prostate cancer cell lines, PC3 and DU145. To test this possibility, PC3 and DU145 were plated on uncoated surfaces or on surfaces coated with the reconstituted basement membrane, Matrigel. The cells were analyzed for cathepsins B and L immunolocalization, protein expression and activity 48 h after plating. Our data demonstrated that cathepsins B and L displayed a distinct punctate distribution with little co-localization; individual cells displayed a predominant staining for one or the other enzyme. Cathepsin B had a perinuclear distribution in PC3 grown on uncoated surfaces but a more peripheral staining in PC3 plated on Matrigel. Localization of cathepsin L remained predominantly perinuclear regardless of the plating surface. In addition to the translocation of cathepsin B from a perinuclear distribution to the cell periphery, growth of PC3 on Matrigel shifted cathepsin B activity from the cell extract to the media. There were no significant changes in cathepsins B and L immunolocalization or activity in DU145 with regard to plating surfaces. Likewise, the activity of endogenous cysteine proteinase inhibitors (CPIs) and protein expression of cystatin C remained unchanged in both cell lines. In conclusion, the interaction of PC3 prostate cancer cells with extracellular matrix components affects the distribution of cathepsin B protein and activity.
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PMID:Matrigel influences morphology and cathepsin B distribution of prostate cancer PC3 cells. 1682 Sep 9

Alteration in the lysosomal system (LS) may represent a central mechanism in neurodegeneration. 6-Hydroxydopamine (6-OHDA) induces oxidative stress and cell death in catecholaminergic cells. The LS and caspases participate in apoptosis, although the mechanism(s) that is involved is not completely understood. Here, we show that Pheochromocytoma (PC12) cells exposed to 6-OHDA results in lysosomal dysregulation, caspase activation and cell death. Cells exposed to 6-OHDA increased expression and release of cystatin C (CC) and suppressed cathepsin B (CB). CB activity significantly declined 24h following exposure to 6-OHDA, however neutralization of CC restored CB activity. Cathepsin D (CD) and caspase-3 activity also increased following exposure to 6-OHDA. Inhibition of CD and caspase-3 with pepstatin A (PA) and DEVD-Cho, respectively, attenuated the 6-OHDA induced cell death at 48 and 72 h. However, the CB inhibitor CA-074 Me failed to protect cells. Additionally, poly-ADP-ribose polymerase (PARP) cleavage was evaluated after exposure to 6-OHDA and PA, CA-074 Me, and DEVD-Cho. Only DEVD-Cho significantly decreased PARP cleavage following exposure to 6-OHDA. Hence, caspase-3 mediated PARP cleavage following exposure to 6-OHDA appears independent of CB and CD alterations. These studies suggest alternate pathways and potential therapeutic targets of cell death associated with oxidative stress, CC, and lysosomal dysregulation.
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PMID:6-Hydroxydopamine induces cystatin C-mediated cysteine protease suppression and cathepsin D activation. 1724

Of seven human cystatins investigated, none inhibited the cysteine proteases staphopain A and B secreted by the human pathogen Staphylococcus aureus. Rather, the extracellular cystatins C, D and E/M were hydrolyzed by both staphopains. Based on MALDI-TOF time-course experiments, staphopain A cleavage of cystatin C and D should be physiologically relevant and occur upon S. aureus infection. Staphopain A hydrolyzed the Gly11 bond of cystatin C and the Ala10 bond of cystatin D with similar Km values of approximately 33 and 32 microM, respectively. Such N-terminal truncation of cystatin C caused >300-fold lower inhibition of papain, cathepsin B, L and K, whereas the cathepsin H activity was compromised by a factor of ca. 10. Similarly, truncation of cystatin D caused alleviated inhibition of all endogenous target enzymes investigated. The normal activity of the cystatins is thus down-regulated, indicating that the bacterial enzymes can cause disturbance of the host protease-inhibitor balance. To illustrate the in vivo consequences, a mixed cystatin C assay showed release of cathepsin B activity in the presence of staphopain A. Results presented for the specificity of staphopains when interacting with cystatins as natural protein substrates could aid in the development of therapeutic agents directed toward these proteolytic virulence factors.
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PMID:Down-regulation of human extracellular cysteine protease inhibitors by the secreted staphylococcal cysteine proteases, staphopain A and B. 1739 Oct 65

Regulated secretory vesicles produce, store, and secrete active peptide hormones and neurotransmitters that function in cell-cell communication. To gain knowledge of the protein systems involved in such secretory vesicle functions, we analyzed proteins in the soluble and membrane fractions of dense core secretory vesicles purified from neuroendocrine chromaffin cells. Soluble and membrane fractions of these vesicles were subjected to SDS-PAGE separation, and proteins from systematically sectioned gel lanes were identified by microcapillary LC-MS/MS (microLC-MS/MS) of tryptic peptides. The identified proteins revealed functional categories of prohormones, proteases, catecholamine neurotransmitter metabolism, protein folding, redox regulation, ATPases, calcium regulation, signaling components, exocytotic mechanisms, and related functions. Several novel secretory vesicle components involved in proteolysis were identified consisting of cathepsin B, cathepsin D, cystatin C, ubiquitin, and TIMP, as well carboxypeptidase E/H and proprotein convertases that are known to participate in prohormone processing. Significantly, the membrane fraction exclusively contained an extensive number of GTP nucleotide-binding proteins related to Rab, Rho, and Ras signaling molecules, together with SNARE-related proteins and annexins that are involved in trafficking and exocytosis of secretory vesicle components. Membranes also preferentially contained ATPases that regulate proton translocation. These results implicate membrane-specific functions for signaling and exocytosis that allow these secretory vesicles to produce, store, and secrete active peptide hormones and neurotransmitters released from adrenal medulla for the control of physiological functions in health and disease. In summary, this proteomic study illustrates secretory vesicle protein systems utilized for the production and secretion of regulatory factors that control neuroendocrine functions.
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PMID:Proteomics of neuroendocrine secretory vesicles reveal distinct functional systems for biosynthesis and exocytosis of peptide hormones and neurotransmitters. 1740 50

Alterations in lysosomal proteases have been implicated in many neurodegenerative diseases. The current study demonstrates a concentration-dependent decrease in PC12 cell viability and transient changes in cystatin C (CYSC), cathepsin B (CATB), cathepsin D (CATD) and caspase-3 following exposure to H2O2. Furthermore, activation of CATD occurred following exposure to H2O2 and cysteine protease suppression, while inhibition of CATD with pepstatin A significantly improved cell viability. Additionally, significant PARP cleavage, suggestive of caspase-3-like activity, was observed following H2O2 exposure, while inhibition of caspase-3 significantly increased cell viability compared to H2O2 administration alone. Collectively, our data suggest that H2O2 induced cell death is regulated at least in part by caspase-3 and CATD. Furthermore, cysteine protease suppression increases CATD expression and activity. These studies provide insight for alternate pathways and potential therapeutic targets of cell death associated with oxidative stress and lysosomal protease alterations.
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PMID:Hydrogen peroxide induces lysosomal protease alterations in PC12 cells. 1744 Aug 10

Cathepsins (CTSs) are peptidases that have biological roles in degrading extracellular matrix, catabolism of intracellular proteins, and processing of pro-hormones. Cystatin C (CST3) is a secreted inhibitor of lysosomal cysteine proteases cathepsin B (CTSB) and CTSL. Our working hypothesis is that cathepsins and cystatins play important roles in implantation and placentation in sheep. Expression of CTSB, CTSD, CTSH, CTSK, CTSL, CTSS, CTSZ, and CST3 mRNAs was detected in ovine uteroplacental tissues with distinct temporal and/or spatial expression patterns between Days 40 and 120 of pregnancy. Of particular note, CTSB, CTSD, and CTSZ mRNAs were predominantly detected in the chorion of the placenta and were more abundant in the placentomes than the intercaruncular endometria. CTSL and CST3 mRNAs were abundant in the endometrial epithelia and chorion, whereas CTSK, CTSS and CTSH mRNAs were most abundant in the stratum compactum stroma of the intercaruncular endometrium. Consistent with localisation of mRNAs, immunoreactive CTSL and CST3 proteins were mainly observed in the intercaruncular endometrial glands and intercotyledonary placenta during later pregnancy. These results support the working hypothesis that CTS and CST3 in uteroplacental tissues are involved in endometrial remodelling and placentation in sheep.
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PMID:Differential expression of cathepsins and cystatin C in ovine uteroplacental tissues. 1755 11

Altered protease activity is considered important for tumour invasion and metastasis, processes in which the cysteine proteases cathepsin B and L are involved. Their natural inhibitor cystatin C is a secreted protein, suggesting that it functions to control extracellular protease activity. Because cystatins added to cell cultures can inhibit polio, herpes simplex and coronavirus replication, which are intracellular processes, the internalization and intracellular regulation of cysteine proteases by cystatin C should be considered. The extension, mechanism and biological importance of this hypothetical process are unknown. We investigated whether internalization of cystatin C occurs in a set of human cell lines. Demonstrated by flow cytometry and confocal microscopy, A-431, MCF-7, MDA-MB-453, MDA-MB-468 and Capan-1 cells internalized fluorophore-conjugated cystatin C when exposed to physiological concentrations (1 microm). During cystatin C incubation, intracellular cystatin C increased after 5 min and accumulated for at least 6 h, reaching four to six times the baseline level. Western blotting showed that the internalized inhibitor was not degraded. It was functionally intact and extracts of cells exposed to cystatin C showed a higher capacity to inhibit papain and cathepsin B than control cells (decrease in enzyme activity of 34% and 37%, respectively). The uptake of labelled cystatin C was inhibited by unlabelled inhibitor, suggesting a specific pathway for the internalization. We conclude that the cysteine protease inhibitor cystatin C is internalized in significant quantities in various cancer cell lines. This is a potentially important physiological phenomenon not previously described for this group of inhibitors.
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PMID:Internalization of cystatin C in human cell lines. 1869 80

Numerous studies have linked cathepsins and their inhibitor cystatin C to tumor invasion and metastasis. We examined whether cathepsin B, cathepsin H, cathepsin X and cystatin C could be detected in sera from women with early stage or inflammatory breast cancer and whether they correlated with clinicopathological characteristics. Preoperative serum was obtained from 176 patients with early-stage breast cancer (tumor size <or= 5 cm, negative lymph nodes) and 31 patients with inflammatory breast cancer. Cathepsin and cystatin C levels were measured by ELISA. The patient and tumor characteristics under study were age at diagnosis, menopausal status, tumor size, tumor grade, and steroid hormone receptor status. Serum cathepsin B levels were significantly lower in patients with poorly differentiated tumors. High cystatin C levels were associated with tumor size, postmenopausal status and patient age. Interestingly, significantly lower levels of cathepsin X and H were found in patients with inflammatory breast cancer, a trend also observed for cathepsin B and cystatin C. In conclusion, our results show a limited association of cathepsins B, H, X and cystatin C with established prognostic parameters. These data are promising and encourage future analysis of the clinical outcome of our patients in order to examine the potential prognostic value of these biomarkers. Further, this study indicates a role for cathepsin X and H in inflammatory breast cancer.
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PMID:Cathepsin B, cathepsin H, cathepsin X and cystatin C in sera of patients with early-stage and inflammatory breast cancer. 1894 42

Impaired degradation of amyloid beta (Abeta) peptides could lead to Abeta accumulation, an early trigger of Alzheimer's disease (AD). How Abeta-degrading enzymes are regulated remains largely unknown. Cystatin C (CysC, CST3) is an endogenous inhibitor of cysteine proteases, including cathepsin B (CatB), a recently discovered Abeta-degrading enzyme. A CST3 polymorphism is associated with an increased risk of late-onset sporadic AD. Here, we identified CysC as the key inhibitor of CatB-induced Abeta degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble Abeta levels, the relative abundance of Abeta1-42, and plaque load. CysC removal also attenuated Abeta-associated cognitive deficits and behavioral abnormalities and restored synaptic plasticity in the hippocampus. Importantly, the beneficial effects of CysC reduction were abolished on a CatB null background, providing direct evidence that CysC regulates soluble Abeta and Abeta-associated neuronal deficits through inhibiting CatB-induced Abeta degradation.
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PMID:Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease. 1895 17


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