Disease relevance of Cst3

• Polymorphisms in the cystatin C gene have recently been associated with the risk of developing Age-related Macular Degeneration (AMD) [1].
• Gene deletion of cystatin C aggravates brain damage following focal ischemia but mitigates the neuronal injury after global ischemia in the mouse [2].
• Pharmacological inhibition of cathepsins has been shown to reduce neuronal damage after brain ischemia, suggesting that cystatin C is an endogenous neuroprotectant [2].
• Cystatin C is a strong endogenous inhibitor of lysosomal cysteine proteases, such as cathepsin B, L, H and S, that are involved in various biological processes such as degradation of cellular proteins and regulation of enzymes, as well as in pathological processes [2].
• Cyclophosphamide treatment in LS lymphosarcoma did not influence the concentration of cystatin C in tumor cells [3].

Psychiatry related information on Cst3

• Cystatin C has also amyloidogenic properties and is co-localized with beta-amyloid in degenerated neurons in Alzheimer's disease, suggesting a role in neuronal degeneration [2].

High impact information on Cst3

• Thus, the ratio of cystatin C to cathepsin S in developing DCs helps to determine the fate of newly synthesized MHC class II molecules [4].
• We have synthesized peptide derivatives mimicking the proposed proteinase-binding centre of cystatin C and find that they irreversibly inhibit cysteine proteinases [5].
• Cystatin C is a human cysteine proteinase inhibitor present in extracellular fluids [5].
• 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 [6].
• Constitutive secretion of cystatin C (gamma-trace) by monocytes and macrophages and its downregulation after stimulation [6].

Chemical compound and disease context of Cst3

• A cystatin C variant with L68Q substitution and a truncation of 10 NH2-terminal residues is the major constituent of the amyloid deposited in the cerebral vasculature of patients with the Icelandic form of hereditary cerebral hemorrhage with amyloidosis (HCHWA-I) [7].
• In contrast to wild-type cystatin C, recombinant human cystatin C with Gly substitutions for residues Arg(8), Leu(9), Val(10), and Trp(106), and with low or nonexistent affinity for cysteine proteinases, did not display any inhibitory effect on bone resorption [8].
• Z-RLVG-CHN(2), in which the reactive carboxyterminal diazomethane was substituted by nonreactive groups [-OH, -NH(2), or -N(CH(3))(2)], resulted in peptidyl derivatives, which, in contrast to Z-RLVG-CHN(2) and cystatin C, inhibited neither cysteine proteinases nor bone resorption [8].
• Ukrain treatment of LS lymphosarcoma was also followed by increased levels of cystatin C in tumor tissue (4-fold); cyclophosphane plus Ukrain had a similar positive effect [9].
• Peritoneal macrophages from mice with experimental HA-1 hepatoma compared to those from intact mice secreted more cystatin C with maximum polysaccharide-stimulated secretion after 30 min of incubation [10].

Biological context of Cst3

• Cst3 was mapped in the mouse to a position on distal chromosome 2 [11].
• The structure of the mouse CstC-encoding gene (Cst3) was examined by sequencing a 6.1-kb genomic DNA containing the entire gene, as well as 0.9 kb of 5' flanking and 1.7 kb of its 3' flanking region [11].
• 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 [1].
• These results suggested that cathepsins B and L are necessary for normal embryo development and uterine decidualization, and that decidua contributes to their control by a coordinated expression of cystatin C within the implantation site [12].
• The expression and function of cystatin C and cathepsin B and cathepsin L during mouse embryo implantation and placentation [12].

Anatomical context of Cst3

• Unexpectedly, mice transplanted with cystatin C-deficient bone marrow cells had increased elastin and collagen content in lesions [13].
• Microarray analysis of RPE/choroid mRNA revealed the expression of cathepsins B and L, as well as cystatin C under all experimental conditions [1].
• Isolation of cystatin C via functional cloning of astrocyte differentiation factors [14].
• After 12 weeks on an atherogenic diet, cystatin C deficiency yielded significantly increased tunica media elastic lamina fragmentation, decreased medial size, and increased smooth muscle cell and collagen content in aortic lesions of ApoE-/- mice [15].
• Cystatin C is distributed in all human tissues and fluids with a particular abundance in the cerebrospinal fluid [2].

Associations of Cst3 with chemical compounds

• Cystatin C, an inhibitor of the elastin-degrading cysteine proteases of the cathepsin family, is believed to be one of the key protease inhibitors in this process [13].
• CRES, however, inhibited the serine protease prohormone convertase 2 (PC2), a protease involved in prohormone processing in the neuroendocrine system, whereas cystatin C showed no inhibition [16].
• Progesterone and interferon-tau regulate cystatin C in the endometrium [17].
• In contrast, the inhibitory effects of Z-RLVG-CHN(2) and cystatin C, as well as that of calcitonin, on (3)H release was seen already after 2 h [8].
• Cyclophosphane treatment (50 mg/kg, single injection) increased cystatin C by up to 8-fold more in tumor issue [9].

Regulatory relationships of Cst3

• Lack of the cysteine protease inhibitor cystatin C promotes atherosclerosis in apolipoprotein E-deficient mice [18].
• Thymosin beta4 was found to be down-regulated whereas cystatin C and alphaCA were up-regulated in Hand1-null embryoid bodies [19].
• It has been proposed that the cysteine protease inhibitor cystatin C (CyC) plays a pivotal role in the control of this process by regulating the activity of cathepsin S, a protease involved in removal of the MHC II chaperone Ii, and hence in the formation of MHC II-peptide complexes [20].
• Differential screening of a cDNA library derived from mRNA of TGF beta-treated serum-free mouse embryo (astrocyte precursor) cells isolated a strongly TGF beta-regulated mRNA that codes for cystatin C, a cysteine protease inhibitor [21].
• Increased cystatin C in astrocytes of transgenic mice expressing the K670N-M671L mutation of the amyloid precursor protein and deposition in brain amyloid plaques [22].

Other interactions of Cst3

• Cystatin C deficiency increases elastic lamina degradation and aortic dilatation in apolipoprotein E-null mice [15].
• These observations suggest that leukocyte-specific expression of cystatin C is actively involved in matrix remodelling associated with plaque regression [13].
• Presenilin 2 mutations alter cystatin C trafficking in mouse primary neurons [23].
• Cystatin C was found on the top surfaces of both cell lines, whereas stefin A was found only on the top surface of the embryonic liver cells [24].
• Stefin A and cystatin C, but not stefin B, were present on the cell surface [24].

Analytical, diagnostic and therapeutic context of Cst3

• The mouse Cst3 mRNA was detected in all of thirteen tissues examined by Northern blot analysis [11].
• Apolipoprotein E-deficient mice (apoE-/-) were given a Western-type diet 15 weeks prior transplantation with bone marrow from mice lacking cystatin C (cysC-/-) or cystatin C positive (cysC+/+) mice, in both cases apoE+/+ to create conditions favouring plaque regression [13].
• After 25 weeks of atherogenic diet, mice lacking apoE and cystatin C (cysC(-/-) apoE(-/-)) had larger subvalvular plaques compared with cysC(+/+) apoE(-/-) mice (766,000+/-20,000 microm2 per section versus 662,000+/-19,000 microm2 per section; P=0.001), suggesting an atheroprotective role of cystatin C [18].
• Northern and western blotting showed that cystatin C, the main inhibitor of cathepsins, was a major product of the decidualizing stroma [12].
• To explore possible neuropathological consequences of this genetic association, we examined expression of cystatin C in brains from 22 AD and 11 control patients by immunohistochemistry [25].

References