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PubMed1987

Constitutive secretion of cystatin C (gamma-trace) by monocytes and macrophages and its downregulation after stimulation.

Cystatin C (gamma-trace) was found to be a constitutively secreted protein of isolated human monocytes and mouse peritoneal macrophages, as well as the histiocytic lymphoma cell lines U937, P388D.1, and J774. This proteinase inhibitor is not uniquely secreted by monocytes/macrophages, but was also identified in the conditioned media from several primary cells, including brain cells, and diverse established cell lines. In vitro treatment of resident mouse peritoneal macrophages with either LPS or IFN-gamma caused a downregulation in cystatin C secretion. Elaboration of this protein was also diminished by macrophages that had been stimulated by thioglycollate in vivo, and treatment of these cells with LPS led to further decline. It is suggested that, under some inflammatory conditions, downregulation of cystatin C may contribute to tissue pathology.

Animals↗
PubMed2003

In vitro anti-cancer activities in Caco-2 and HCT-116 cells of recombinant cystatin C prepared by a Pichia expression system.

Caco-2 and HCT-116 cells were used to access growth-inhibition and anti-invasion activity of recombinant cystatin C expressed in Pichia pastoris X33, G12W/H86V. The mutant G12W/H86V prepared by a pilot plant production system showed more than 10% growth inhibition of Caco-2 cells at 0.56-56 nM concentrations. Growth-inhibited cells had lower cathepsin L activity than the control cells that were not treated with the inhibitor. Conversely, the cathepsin B activity was not changed by treatment with G12W/H86V. The in vitro anti-invasion test using HCT-116 cells showed that G12W/H86V suppressed the cell invasion by 15%, while its wild-type cystatin, aspartic protease inhibitor pepstatin A, and matrix metalloproteinase (MMP) inhibitor MMP-2/MMP-9 inhibitor III did not suppress cell invasion. These results indicate that the recombinant cystatin C with higher protease inhibitory activity effectively retards the growth and invasiveness of human colon carcinoma cells.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Neuropathological changes in a mouse model of progressive myoclonus epilepsy: cystatin B deficiency and Unverricht-Lundborg disease.

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is a recessively inherited neurodegenerative disease caused by loss-of-function mutations in the gene encoding cystatin B, a cysteine protease inhibitor. Mice with disruptions in this gene display myoclonic seizures, progressive ataxia, and cerebellar pathology closely paralleling EPMI in humans. To provide further insight into our understanding of EPM1, we report pathological findings in brains from cystatin B-deficient mice. In addition to confirming the loss of cerebellar granular cell neurons by apoptosis, we identified additional neuronal apoptosis in young mutant mice (3-4 months old) within the hippocampal formation and entorhinal cortex. In older mutant mice (16-18 months old), there was also gliosis most marked in the presubiculum and parasubiculum of the hippocampal formation, as well as the entorhinal cortex, neocortex, and striatum. Furthermore, widespread white matter gliosis was also noted, which may be a secondary phenomenon. Within the cerebral cortex, cellular atrophy was a prominent finding in the superficial neurons of the prosubiculum. Finally, we show that mutant mice in either a "seizure-prone" or "seizure-resistant" genetic background display similar neuropathological changes. These findings indicate that neuronal atrophy is an important consequence of cystatin-B deficiency independent of seizure events, suggesting a physiological role for this protein in the maintenance of normal neuronal structure.

Animals↗
PubMed1997

Cloning of human keratolinin cDNA: keratolinin is identical with a cysteine proteinase inhibitor, cystatin A, and is regulated by Ca2+, TPA, and cAMP.

Keratolinin has been described as one of the precursor proteins of cornified cell envelope of keratinocytes. Using rabbit polyclonal anti-human keratolinin antibody, we isolated a cDNA clone of human keratolinin gene from a human Agt11 cDNA expression library that was constructed by random priming from poly(A)+RNA extracted from cultured normal human keratinocytes. Screening by rabbit anti-human keratolinin antibody detected one positive clone (HKL-1). The recombinant 12.5-kDa protein constructed from the clone reacted specifically with the anti-human keratolinin antibody. DNA sequence analysis revealed that HKL-1 clone was 448 bp long, and its putative amino acid sequence was identical with that of a human cysteine proteinase inhibitor, cystatin A. Western blot analysis showed that the commercially available recombinant cystatin A also reacted specifically with the anti-human keratolinin antibody. Northern blot analysis indicated that HKL-1 clone hybridizes with mRNA of about 0.5 kb, consistent with the size of the HKL-1 clone. The keratolinin mRNA was highly expressed in cultured human keratinocytes in high Ca2+ (1 mM); in low Ca2+ (0.05 mM), the keratolinin mRNA expression was significantly lower. Using SV40-transformed human keratinocytes (SVHK cells), we further analyzed the regulation of keratolinin mRNA. In low Ca2+ (0.05 mM), keratolinin mRNA in SVHK cells was marginally detectable. Upon shift to 1 mM calcium, keratolinin mRNA was markedly increased. The upregulation of keratolinin mRNA was also observed by the treatment of SVHK cells with 10 ng TPA per ml or 100 microM forskolin under low calcium conditions (0.05 mM). Our results indicate that keratolinin is identical with cystatin A, a cysteine proteinase inhibitor, and its expression is positively regulated by Ca2+, TPA, and forskolin.

Amino Acid Sequence↗
PubMed1989

The saga of cystatin C gene mutation causing amyloid angiopathy and brain hemorrhage--clinical genetics in Iceland.

Firstly, we review investigations of hereditary cystatin C amyloid angiopathy, which is caused by a mutation in the cystatin C gene. Symptoms of brain haemorrhages, which lead to death in young adults, are the hallmark of this disorder. The mutation can now be detected by the RFLP method using Alu I restriction enzyme and cystatin C cDNA probe. Secondly, we give an overview of other clinical genetic studies in Iceland with emphasis on activities initiated or sponsored by the Genetical Committee of the University of Iceland. The list of references covers most publications on genetic studies of Icelanders.

Amyloidosis↗
PubMed1997

Interactions between ovine cathepsin L, cystatin C and alpha 2-macroglobulin. Potential role in the genital tract.

The specific inhibitor of cysteine proteinases, cystatin C, was purified from ram rete testis fluid and the conditioned medium of Sertoli cells. This molecule associated with sheep liver cathepsin L at one of the fastest rates ever described for a proteinase/inhibitor interaction (1.75 +/- 0.20 x 10(8) M-1.s-1). But the association rate constant for the interaction of cathepsin L with alpha 2-macroglobulin, a non-specific inhibitor of proteinases, was also extremely high (8.8 +/- 0.75 x 10(6) M-1.s-1). Cathepsin L complexed with alpha 2-macroglobulin was protected from inhibition by type 2 and type 3 cystatins. The data indicate that cystatin C is the most potent inhibitor of cathepsin L in mammalian male genital tract fluids, whereas alpha 2-macroglobulin may act as a terminal acceptor of this enzyme. These inhibitors could therefore inhibit the activated form of procathepsin L which may appear during the complex process of spermatozoa production and maturation in the testis and epididymis.

Amino Acid Sequence↗
PubMed1987

Hereditary cystatin C (gamma-trace) amyloid angiopathy of the CNS causing cerebral hemorrhage.

Hereditary CNS amyloid angiopathy occurring in Icelanders is the first human disorder known to be caused by deposition of cystatin C amyloid fibrils in the walls of the brain arteries leading to single or or multiple strokes with fatal outcome. One or more affected members have been verified by histological examination in 8 families containing 127 affected. These originated from the same geographic area. Abnormally low value of cystatin C found in the cerebrospinal fluid of those affected can be used to support or make diagnosis of this disease, also in asymptomatic relatives. By amino acid sequence analysis the amyloid fibrils in the patients are found to be a variant of cystatin C (gamma-trace), a major cysteine proteinase inhibitor. The variant protein has an amino acid substitution (glutamine for leucine) at position 58 in the amyloid molecule. It is postulated that a point mutation has occurred leading to production of amyloidogenic protein causing the disorder.

Amyloid↗
PubMed1996

Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is an autosomal recessive inherited form of epilepsy, previously linked to human chromosome 21q22.3. The gene encoding cystatin B was shown to be localized to this region, and levels of messenger RNA encoded by this gene were found to be decreased in cells from affected individuals. Two mutations, a 3' splice site mutation and a stop codon mutation, were identified in the gene encoding cystatin B in EPM1 patients but were not present in unaffected individuals. These results provide evidence that mutations in the gene encoding cystatin B are responsible for the primary defect in patients with EPM1.

Amino Acid Sequence↗
PubMed1985

Distribution of cystatin C (gamma-trace), an inhibitor of lysosomal cysteine proteinases, in the anterior lobe of simian and human pituitary glands.

Cystatin C, a protein inhibitor of lysosomal cysteine proteinases, was demonstrated by immunohistochemical techniques to be present in most luteinizing hormone- (LH-)containing cells in simian and human adenohypophyses. Immunoreactivity of cystatin C was also found in simian adrenocorticotrophic hormone- (ACTH-)containing cells localized to an area corresponding to the pars intermedia but not in the ACTH-containing cells of the anterior pituitary lobe of monkey. No immunoreactivity of cystatin C was detected in the growth hormone- (GH-) and prolactin-containing cells of monkey and man.

Adrenocorticotropic Hormone↗
PubMed1990

Immunohistochemical characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to beta protein and cystatin C.

Using immunohistochemical staining methods with antibodies to amyloid beta protein and human cystatin C, we examined cerebrovascular amyloid protein in the brains from 46 cases with cerebral amyloid angiopathy (seven with Alzheimer's disease, one with Down's syndrome, 18 with intracranial hemorrhage, 10 with cerebral infarction, and 10 elderly patients without any neurologic disorder). All cerebrovascular amyloid deposits in these 46 cases were consistently immunoreactive to anti-beta protein antibody. However, in nine cases some vascular walls with strong beta protein immunoreactivity also reacted less intensely with the anti-cystatin C antiserum. Of these nine cases, seven showed relatively heavy cerebrovascular amyloid deposition, and all seven had suffered a fatal subcortical hemorrhage presumably caused by cerebral amyloid angiopathy. Previous limited studies have suggested that the amyloid protein seen in elderly individuals with cerebral amyloid angiopathy is composed of beta protein. However, subcortical hemorrhage rarely occurs in such individuals. Our study shows that aged patients with different brain disorders commonly suffer from beta protein-type cerebral amyloid angiopathy, and we also suggest that the severity of beta protein-type cerebrovascular amyloid deposition is a fundamental factor in cerebral amyloid angiopathy-induced brain hemorrhage in the elderly. The nature of the cystatin C-immunoreactive substance in some of these vascular lesions is uncertain, but it might conceivably play an additional important role in the pathogenesis of brain hemorrhage in these cases.

Adult↗
PubMed1995

Cystatin C mutation in an elderly man with sporadic amyloid angiopathy and intracerebral hemorrhage.

BACKGROUND: Cerebral amyloid angiopathy (CAA) with intracerebral hemorrhage (ICH) occurs both sporadically and as a result of mutations in either cystatin C or the amyloid precursor protein. ICH due to cystatin C mutations typically occurs in young people of Icelandic origin. CASE DESCRIPTION: We report a case of sporadic CAA with ICH in an elderly Croatian man with a mutation in cystatin C identical to that found in Icelandic hereditary cerebral hemorrhage with amyloidosis. CONCLUSIONS: This is the first case report of sporadic CAA associated with the same mutation causing hereditary cerebral hemorrhage with amyloidosis of the Icelandic type. Sporadic CAA may thus be associated with genetic mutations in some patients. The frequency of these mutations is yet to be determined.

Cerebral Amyloid Angiopathy↗
PubMed1992

Demonstration of sequence variations in the promoter region of the human cystatin C gene.

Four point mutations in the promoter region of the human cystatin C gene have been detected by direct sequencing of polymerase chain reaction (PCR) amplified DNA. The four base changes are all localized within a short segment of 85 base pairs. Three cystatin C gene alleles could be defined with respect to these promoter mutations; one with the sequence previously published, one carrying three of the mutations and one with all four base substitutions. Two of the observed mutations are involved in a novel Sst II polymorphism and another generates a new Dde I restriction site. A PCR-based assay for analysis of these Sst II and Dde I sites was designed and used to demonstrate Mendelian inheritance of the polymorphisms as well as to determine the frequencies of the cystatin C gene alleles in the population.

Base Sequence↗
PubMed1999

Interaction of cystatin C variants with papain and human cathepsins B, H and L.

Recombinant human cystatin C and two of its mutants were expressed in Escherichia coli. The recombinant inhibitor was found to be identical to authentic cystatin C as judged by isoelectric focusing (pI 9.2) and kinetics of inhibition of papain and human cathepsins B, H and L. N-terminal truncation of 8 residues resulted in a decrease of isoelectric point (pI 7.8), but the inhibitory properties were similar to those of recombinant cystatin C, suggesting that Leu9 is a critical residue for the inhibition. The mutation of Trp106 to Ser, however, resulted in a decreased affinity of the inhibitor for the enzymes tested, with the largest effect on cathepsin B inhibition (approximately 100-fold increase in Ki).

Cathepsin B↗
PubMed2005

No association between the cystatin C gene polymorphism and Alzheimer's disease: a case-control study in an Italian population.

Cystatin C is an amyloidogenic protein found together with beta-amyloid in cerebral arteriolar walls of both patients with Alzheimer's Disease (AD) and conghopilic amyloid angiopathy. Several findings implicate cystatin C in the pathogenesis of vascular diseases. Recent genetic association studies proposed cystatin C gene (CST3) as a susceptibility factor for AD, although other reports did not replicate this finding. We conducted a case-control study including 192 probable AD cases and 192 age- and sex-matched controls to test the association between CST3 and AD. Possible interaction between CST3 and age at onset of AD or apolipoprotein E (APOE) was also examined. No significant differences in CST3 genotype or allele frequencies between cases and controls was observed, while the risk of AD increased in subjects carrying the APOE epsilon4 allele (OR 3.5, 95% CI [2.1-5.9]). There was no interaction between CST3 with age or APOE. Our findings do not support a role of CST3 gene in Italian sporadic AD.

Aged↗
PubMed1999

Distribution, activity and concentration of cathepsin B and cystatin C in the wall of aortic aneurysm.

Intensity of immunohistochemical reaction to cathepsin B is stronger and to cystatin C weaker in the wall of aortic aneurysm than in normal aorta. Localization of cathepsin B and cystatin C in the aneurysm wall is different from that in the control aorta, but activity and concentration of cystatin C in the aneurysmal wall is lower than in normal aorta. The parietal thrombus of aneurysm also shows high activity of cathepsin B. The obtained results point to participation of cathepsin B in degradation of aneurysmal structural proteins and in enlargement of the aneurysmal size.

Adult↗
PubMedDate not supplied

Expression of cathepsin B and cystatin C in the human adenohypophysis and in pituitary adenomas.

The localization of cathepsin B, a potential promoter of prolactin (PRL) release via extra renal renin-angiotensin system in the adenohypophysis, and its inhibitor cystatin C in the human adenohypophysis and in pituitary adenomas were examined using single and dual immunohistochemical staining. In the adenohypophysis, cathepsin B was expressed in about 50% of the ACTH-producing cells, and in 5% or less of the GH- and PRL-producing cells. In contrast, cystatin C was expressed in about 70% of the GH- and PRL-producing cells, but in only 5% or less of the ACTH-producing cells. PRL-producing adenomas strongly expressed cathepsin B, but only weakly expressed cystatin C, a pattern of staining contrary to the expression in normal PRL-producing cells. The above results suggest that cathepsin B may play a role in promoting PRL release especially in PRL-producing adenomas.

Adenoma↗
PubMed2001

[Cystatin C as a marker of glomerular filtration rate].

The assessment of the glomerular filtration rate (GFR) is the most commonly used test of renal function. Cystatin C, a cysteine protease inhibitor, which can be measured by light scattering immunoassay, possesses many of the attributes required of the ideal GFR marker. This paper reviews so far obtained results dealing with cystatin C measurement, reference intervals and its diagnostic significance in nephropathy. Although serum cystatin C can generally be recommended as a marker of GFR, especially to detect mild GFR reductions, further clinical studies should be performed to confirm the validate in renal transplants and cancer patients.

Biomarkers↗
PubMed2003

[Immunoenzyme technique for analysis of cystatin C in serum of patients with hemoblastosis].

Cystatin C is a low-molecular endogenous inhibitor of cysteic proteinases. Sets for immune-enzyme assay of cystatin C in human blood serum (KRKK, Slovenia) were made used of in the case study. The concentration of cystatin C (CCC) in blood serum was found to be higher in cases of certain hemoblastoses (Non-Hodgkin's disease, lymphogranulomatosis and multiple myeloma), with the highest concentration of the inhibitor being observed in patients with resistance to the conducted polychemotherapy and a poor prognostication. The treatment of Non-Hodgkin's disease and of lymphogranulomatosis brought about a normalized CCC in blood serum. It was suggested that CCC in blood serum reflects a nature of tumor growth and, obviously, it can be a criterion in assessing the therapy efficiency. The concentration of alpha 1-proteinases inhibitor remained unchanged before and after treatment.

Acute Disease↗