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)

Mxi1 is thought to negatively regulate Myc function and may therefore be a potential tumor suppressor gene. Little effort has yet been made to find alterations involving this gene in human solid tumors. We screened 31 human gastric cancers, 7 esophageal cancers, 85 bone and soft tissue tumors of various types, including 4 neurofibrosarcomas. We also examined 29 human tumor cell lines consisting of 12 esophageal cancers, 7 glioma/glioblastomas and 10 others for Mxi1 mutations in exons 1, 2, 4 (HLH domain), 5 and 6. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and subsequent sequencing revealed three distinct polymorphisms in the intron-exon boundary upstream from exon 6. We discovered a missense mutation, GCA to GTA (Ala 54 Val), in exon 2 in a neurofibrosarcoma patient (case 1), two missense mutations, AAA to CAA (Lys 118 Gln) and GAA to GGA (Glu 154 Gly) in exon 5 of another neurofibrosarcoma patient (case 2), and 3 amino acid substitutions, GTG to GCG (Val 179 Ala), GTT to GCT (Val 181 Ala) and TTC to CTC (Phe 186 Leu), in a third neurofibrosarcoma patient (case 3). In case 3, loss of heterozygosity was also demonstrated by informative (TTC)3/(TTC)2 polymorphism. Our data demonstrate that mutations occur in the Mxi1 gene in neurofibrosarcoma. Missense mutations in the functional domain of Mxi1 in these cases may be involved in the pathogenesis of neurofibrosarcoma.
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PMID:Mxi1 mutations in human neurofibrosarcomas. 1047 Feb 86

Human cystatin C is a cysteine proteinase inhibitor belonging to the cystatin superfamily, which previously has been shown to inhibit bone resorption in bone organ culture. The aminoterminal segment, Arg(8)-Leu(9)-Val(10)-Gly(11) (RLVG), of the single polypeptide chain of cystatin C constitutes an essential part of its inhibitory center. In the present study, the effect of benzyloxycarbonyl-Arg(8)-Leu(9)-Val(10)-Gly(11)-diazomethane (Z-RLVG-CHN(2)) on bone resorption in vitro was compared with the effects of cystatin C and calcitonin. Bone resorption was assessed by the release of (45)Ca and (3)H from mouse calvarial bones prelabeled with [(45)Ca]CaCl(2) and [(3)H]-proline, respectively. Z-RLVG-CHN(2) concentration-dependently inhibited the release of (45)Ca and (3)H in bones stimulated by parathyroid hormone (PTH), with half-maximal inhibition obtained at 1 micromol/L. The inhibitory actions of Z-RLVG-CHN(2) and cystatin C were persistent, whereas action induced initially by calcitonin was lost with time. The inhibition caused by Z-RLVG-CHN(2) and cystatin C on PTH-stimulated (45)Ca release was observed after 6 h, whereas inhibition by calcitonin was seen already after 2 h. 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. 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. 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. These data strongly indicate that Z-RLVG-CHN(2) inhibits bone resorption in vitro by a mechanism that seems primarily to be due to an inhibition of bone matrix degradation via cysteine proteinases. The data also corroborate the hypothesis that cystatin C inhibits bone resorption by virtue of its cysteine proteinase inhibitory capacity.
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PMID:A peptidyl derivative structurally based on the inhibitory center of cystatin C inhibits bone resorption in vitro. 1077 84

Genetic variations in the locus encoding the transporter associated with antigen processing, subunit 1 (TAP1), were systematically studied using samples from Caucasians, Africans, Brazilians, and compared with data from chimpanzees. PCR-amplified genomic sequences corresponding to the 11 exons were analyzed by single-strand conformation polymorphism (SSCP) and sequencing. Six nonsynonymous and 2 synonymous single nucleotide polymorphisms (SNPs) were found to be common in one ethnic group or another, and they involved codons 254 (Gly-GGC/Gly-GGT) in exon 3, 333 (Ile-ATC/Val-GTC) in exon 4, 370 (Ala-GCT/Val-GTT) in exon 5, 458 (Val-GTG/Leu-TTG) in exon 6, 518 (Val-GTC/Ile-ATC) in exon 7, 637 (Asp-GAC/Gly-GGC), 648 (Arg-CGA/Gln-CAA) and 661 (Pro-CCG/Pro-CCA) in exon 10. At each SNP site the sequence listed first was predominant in all ethnic groups. Several SNPs segregated on the same chromosome regardless of populations and species. Together, the SNPs produced 5 major human TAP1 alleles, 4 of which matched the officially recognized alleles *0101, *02011, *0301, and *0401; the 5th allele differed from each of those by at least 4 SNPs. Overall, TAP1*0101 was the predominant allele in all ethnic groups, with frequencies ranging from 0.667 in Zambians to 0.808 in US Caucasians. The TAP1*0401 frequency showed the greatest difference between Africans (0.221-0.254) and Caucasians (0.033), with Brazilians (0.058) fitting in the middle. Consistent with earlier work based on Caucasians and gorillas, *0101 appeared to be the newest human TAP1 allele, suggesting a dramatic spread of *0101 into all human populations examined. Characterization of TAP1 polymorphisms allowed the design of a PCR-based genotyping scheme that targeted 7 SNP sites and required 2 separate genotyping techniques.
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PMID:TAPI polymorphisms in several human ethnic groups: characteristics, evolution, and genotyping strategies. 1125 43

Leukemia, a form of haematological malignancy, is a multi-stage disease and a wide range of diverse genes has been speculated to correlate with its initiation and development. Ras has been speculated to be an initiating gene for haematological malignancy, but more investigation will be needed to determine the genes associated with the progression of the disease. 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat leukemia provides a good tool for research into various stages of the disease. The entire coding regions of p53 and ras genes were examined for mutations in the present study. In this experiment, we used fluorescence-labeled polymerase chain reaction single-stranded conformation polymorphism analysis (PCR-SSCP) and direct sequencing to detect mutations of both genes on rat erythroleukemia. Fifteen out of 18 (83.3%) rat leukemias were found to have N-ras codon 61 mutation, consistent with previous results. The result of direct sequencing showed a single base substitution (CAA to CTA), resulting in an amino-acid change from Gln to Leu. No mutations were found in H-ras, K-ras or codon 12 of N-ras. The incidence of p53 gene mutation was 16.6% (3/18) in rat leukemia at late-stage. In the present study, mutation of the p53 gene was detected in three DMBA-induced leukemias as follows: a single-base substitution (CAT to CGT) at codon 177 (exon 5), resulting in an amino-acid change from Arg to Leu, a CGG to CTG/CGG changed at codon 211 (exon 6) resulting in an amino-acid change from His to Arg/His, and a GGG to TGG at codon 242 (exon 6) resulting in an amino-acid change from Gly to Trp, respectively. Thus, mutations of p53 gene do not seem to respond to the carcinogenesis of the DMBA-induced leukemia, in contrast to mutation of the N-ras oncogene, and may possibly be involved in the progress of multi-stage leukemogenesis.
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PMID:Incidence of p53 and ras gene mutations in DMBA-induced rat leukemias. 1238 83

Replacement of the three N-terminal residues preceding the conserved Gly of cystatin A by the corresponding 10-residue long segment of cystatin C increased the affinity of the inhibitor for the major lysosomal cysteine proteinase, cathepsin B, by approximately 15-fold. This tighter binding was predominantly due to a higher overall association rate constant. Characterization of the interaction with an inactive Cys29 to Ala variant of cathepsin B indicated that the higher rate constant was a result of an increased ability of the N-terminal region of the chimeric inhibitor to promote displacement of the cathepsin B occluding loop in the second binding step. The low dissociation rate constant for the binding of cystatin A to cathepsin B was retained by the chimeric inhibitor, which therefore had a higher affinity for this enzyme than any natural cystatin identified so far. In contrast, the N-terminal substitution negligibly affected the ability of cystatin A to inhibit papain. However, substitutions of Gly75 in the second binding loop of cystatin A by Trp or His, making the loop similar to those of cystatins C or B, respectively, increased the affinity for papain by approximately 10-fold. This enhanced affinity was due to both a higher association rate constant and a lower dissociation rate constant. Modeling of complexes between the two variants and papain indicated the possibility of favorable interactions being established between the substituting residues and the enzyme. The second-loop substitutions negligibly affected or moderately reduced the affinity for cathepsin B. Together, these results show that the inhibitory ability of cystatins can be substantially improved by protein engineering.
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PMID:Grafting of features of cystatins C or B into the N-terminal region or second binding loop of cystatin A (stefin A) substantially enhances inhibition of cysteine proteinases. 1450 83

The effects of cystatin C and other cysteine proteinase inhibitors on osteoclast formation and differentiation have been investigated. Cystatin C decreased osteoclast formation stimulated by parathyroid hormone (PTH), 1,25(OH)2-vitamin D3 or interleukin-6 (IL-6) (in the presence of its soluble receptor) as assessed by the number of tartrate-resistant acid phosphatase (TRAP+) multinucleated cells in mouse bone marrow cultures. The inhibitory effect was associated with decreased mRNA expression for the calcitonin receptor as well as decreased number of specific binding sites for 125I-calcitonin, and without any effect on the mRNA expression of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL). Similarly, the cysteine proteinase inhibitors leupeptin, E-64 and benzyloxycarbonyl-Phe-Ala-diazomethane (Z-FA-CHN2) decreased PTH-stimulated formation of TRAP+ multinucleated cells and binding of 125I-calcitonin. A peptidyl derivative synthesized to mimic part of the proteinase-binding site of cystatin C (benzyloxycarbonyl-Arg-Leu-Val-Gly-diazomethane, or Z-RLVG-CHN2) also decreased PTH-stimulated osteoclast formation. In a 9-day culture, addition of cystatin C during the last 5 days was sufficient to cause substantial inhibition of osteoclast formation. Cystatin C-induced decrease of osteoclast formation was associated with enhanced number of F4/80-positive macrophages and increased mRNA expression of the macrophage receptor c-fms in the bone marrow culture. Osteoclast formation in mouse bone marrow cultures as well as in mouse spleen cell cultures, stimulated by macrophage colony-stimulating factor (M-CSF) and RANKL was also decreased by different cysteine proteinase inhibitors. In addition, cystatin C inhibited M-CSF/RANKL induction of calcitonin receptor mRNA in spleen cell cultures. The inhibitory effect by cystatin C in spleen cells was associated with decreased mRNA expression of RANK and the transcription factor NFAT2. It is concluded that cysteine proteinase inhibitors decrease formation of osteoclasts by interfering at a late stage of pre-osteoclast differentiation.
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PMID:Osteoclastogenesis is decreased by cysteine proteinase inhibitors. 1500 89

Highly purified human brain cathepsin H (EC 3.4.22.16) was used to study its involvement in degradation of different brain peptides. Its action was determined to be selective. On Leu-enkephalin, dynorphin (1-6), dynorphin (1-13), alpha-neoendorphin, and Lys-bradykinin, it showed a preferential aminopeptidase activity by cleaving off hydrophobic or basic amino acids. It showed no aminopeptidase activity on bradykinin, which has Pro adjacent to its N-terminal amino acid, on neurotensin with blocked N-terminal amino acid, or on dermorphin with second amino acid D-alanine. After prolonged incubation, cathepsin H acted as an endopeptidase. Dermorphin and dynorphin (1-13) were cleaved at bonds with Phe in the P2 position, while dynorphin (1-6), alpha-neoendorphin, bradykinin and Lys-bradykinin were cleaved at bonds with Gly in the P2 position. Further on, it was shown that human brain cathepsin H activity could be controlled in vivo by cystatin C in its full-length form or its [delta1-10] variant, already known to be co-localized in astrocytes, since the Ki values for the inhibition are in the 10(-10) M range.
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PMID:Human brain cathepsin H as a neuropeptide and bradykinin metabolizing enzyme. 1512 51

Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor complexes in fluorogenic substrate assays. The data demonstrate that whereas human cystatins C and D are equipotent as inhibitors of bone resorption, cystatin D is 10-fold less potent as an inhibitor of osteoclastogenesis and 200-fold less potent as an inhibitor of cathepsin K activity. A recombinant human cystatin C variant with Gly substitutions for residues Arg8, Leu9, Val10, and Trp106 did not inhibit bone resorption, had 1,000-fold decreased inhibitory effect on cathepsin K activity compared to wildtype cystatin C, but was equipotent with wildtype cystatin C as an inhibitor of osteoclastogenesis. It is concluded that (i) different cysteine proteinases are likely to be involved in bone resorption and osteoclast formation, (ii) cathepsin K may not be an exclusive target enzyme in any of the two systems, and (iii) the enzyme(s) involved in osteoclastogenesis might not be a typical papain-like cysteine proteinase.
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PMID:Different cysteine proteinases involved in bone resorption and osteoclast formation. 1590 14

Acute renal failure (ARF) is a frequent problem in the intensive care unit and is associated with a high mortality. Early recognition could help clinical management, but current indices lack sufficient predictive value for ARF. Therefore, there might be a need for biomarkers in detecting renal tubular injury and/or dysfunction at an early stage before a decline in glomerular filtration rate is noted by an increased serum creatinine. A MEDLINE/PubMed search was performed, including all articles about biomarkers for ARF. All publication types, human and animal studies, or subsets were searched in English language. An extraction of relevant articles was made for the purpose of this narrative review. These biomarkers include tubular enzymes (alpha- and pi-glutathione S-transferase, N-acetyl-glucosaminidase, alkaline phosphatase, gamma-glutamyl transpeptidase, Ala-(Leu-Gly)-aminopeptidase, and fructose-1,6-biphosphatase), low-molecular weight urinary proteins (alpha1- and beta2-microglobulin, retinol-binding protein, adenosine deaminase-binding protein, and cystatin C), Na+/H+ exchanger, neutrophil gelatinase-associated lipocalin, cysteine-rich protein 61, kidney injury molecule 1, urinary interleukins/adhesion molecules, and markers of glomerular filtration such as proatrial natriuretic peptide (1-98) and cystatin C. These biomarkers, detected in urine or serum shortly after tubular injury, have been suggested to contribute to prediction of ARF and need for renal replacement therapy. However, excretion of these biomarkers may also increase after reversible and mild dysfunction and may not necessarily be associated with persistent or irreversible damage. Large prospective studies in human are needed to demonstrate an improved outcome of biomarker-driven management of the patient at risk for ARF.
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PMID:Biomarkers of acute renal injury and renal failure. 1691 49

Eight transfer RNA (tRNA) genes which were previously mapped to five regions of the Pisum sativum (pea) chloroplast DNA (ctDNA) have been sequenced. They have been identified as tRNA(Val)(GAC), tRNA(Asn)(GUU), tRNA(Arg)(ACG), tRNA(Leu)(CAA), tRNA(Tyr)(GUA), tRNA(Glu)(UUC), tRNA(His)(GUG), and tRNA(Arg)(UCU) by their anticodons and by their similarity to other previously identified tRNA genes from the chloroplast DNAs of higher plants or from E. gracilis. In addition,two other tRNA genes, tRNA(Gly) (UCC) and tRNA(Ile)(GAU), have been partially sequenced. The tRNA genes are compared to other known chloroplast tRNA genes from higher plants and are found to be 90-100% homologous. In addition there are similarities in the overall arrangement of the individual genes between different plants. The 5' flanking regions and the internal sequences of tRNA genes have been studied for conserved regions and consensus sequences. Two unusual features have been found: there is an apparent intron in the D-loop of the tRNA(Gly)(UCC), and the tRNA(Glu)(UUC) contains GATTC in its T-loop.
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PMID:Nucleotide sequences of transfer RNA genes in the Pisum sativum chloroplast DNA. 2430 49


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