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

The crystal structure of proteolytically modified human ACT has been solved at 2.7-A resolution (Baumann et al., 1991). The final model consists of 374 amino acids, 126 solvent molecules and 5 sugar residues. Asn70 is glycosylated and Asn104 is probably glycosylated. The role of carbohydrates in serpin function may be 3-fold: secretion, removal from circulation and recognition by receptors for complex uptake (Travis et al., 1990). Experiments with recombinant, non-glycosylated ACT have shown that glycosylation has no effect on the association rates of ACT with its target proteases (Rubin et al., 1990). The X-ray diffraction studies also revealed that a certain ACT region is involved in DNA binding, although the physiologic relevance of this binding is still unknown. Using a plethora of techniques, scientists are starting to understand the role of ACT in health and disease. It is 14 years since ACT was first purified (Travis et al., 1978) and 9 years since its gene was cloned (Chandra et al., 1983). We have learned considerably about this protease inhibitor in humans and rodents; in inflammation, cancer and AD; as binding to proteases (irreversibly), to the A beta (irreversibly) and to DNA. However, there are still open avenues for research. These include: finding the proteases that ACT inhibits in brain, identifying the cellular receptors which bind ACT-protease complexes and elucidating the DNA-binding phenomenon. Recently, 4 mutations have been found in APP. The first mutation at position 22 of A beta was detected in HCHWA-D by Levy et al. (1991).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of the acute-phase protein alpha 1-antichymotrypsin in brain dysfunction and injury. 145 55

The TT cell line of human medullary thyroid carcinoma, that retains some of the differentiated functions of thyroid C cells including the synthesis and secretion of calcitonin, was found to contain and release into the culture medium cysteine proteinase inhibitor(s), cystatin(s). The major inhibitor, which is similar to, if not identical with, cystatin C, is constitutively released, or secreted, by TT cells. The rate of secretion of cystatin, quantified by titration of inhibition of papain, was stimulated by dibutyryladenosine 3':5'-cyclic monophosphate, forskolin, the calcium ionophore A 23187, and by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Neither forskolin nor TPA had, however, an effect on the level of the inhibitor in TT cells. Treatment with n-butyrate strongly inhibited the proliferation of TT cells, and led, in 4 to 7 days, to a doubling of the intracellular concentration of cystatins. Northern blot hybridizations to a 32P-labeled riboprobe complementary to human cystatin C cDNA indicated that cAMP, forskolin, and TPA had no effect on the steady-state levels of cystatin C mRNA. These data indicate that release of cystatin(s) from TT cells is regulated by cAMP-calcium-protein kinase C mechanisms that appear to be similar to those that regulate the secretion of calcitonin from these cells. However, in contrast to the calcitonin gene, the expression of the cystatin C gene in these cells is not regulated by cAMP or TPA. By a combination of acetone fractionation, affinity chromatography on Cm-papain-Sepharose, and gel exclusion chromatography a protein of approximately 14 kilodaltons was isolated from TT cells that reacted with antibodies against human cystatin C, and strongly inhibited papain. Cystain secreted by TT cells also had a molecular weight of 14 kilodaltons, and reacted with anti-human cystatin C antibodies. The physiologic and pathologic roles of cystatins in different cell types remain to be established. The TT cells provide a suitable cell type to study the regulation of the expression of the cystatin gene and the mechanism of cystatin release.
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PMID:Cysteine proteinase inhibitor in cultured human medullary thyroid carcinoma cells. 160 39

Okadaic acid, dinophysistoxin-1 (35-methylokadaic acid), and calyculin A are the okadaic acid class of non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, which do not bind to the phorbol ester receptors in cell membranes or activate protein kinase C in vitro. They have potent tumor-promoting activities on mouse skin, as strong as TPA-type tumor promoters, such as TPA, teleocidin, and aplysiatoxin. DNA samples isolated from tumors induced by dimethylbenz[alpha]anthracene and each of the okadaic acid class tumor promoters had the same mutation at the second nucleotide of codon 61 (CAA to CTA) in the c-H-ras gene. Okadaic acid receptors, protein phosphatases 1 and 2A, are present in the particulate as well as cytosolic fractions of various mouse tissues. The apparent "activation" of protein kinases by the okadaic acid class tumor promoters, after their incubation with 32P-ATP, protein kinases, and protein phosphatases, was observed. This activation was caused by inhibition of protein phosphatases 1 and 2A by the okadaic acid class tumor promoters. Treatment of primary human fibroblasts and human keratinocytes with the okadaic acid class tumor promoters induced the hyperphosphorylation of a 60-kDa protein in nuclear and cytosolic fractions, due to the inhibition of protein phosphatases. The 60-kDa protein is a proteolytic fragment of nucleolin, a major nonhistone protein and is designated as "N-60." The mechanisms of action of the okadaic acid class tumor promoters are discussed with emphasis on the inhibition of protein phosphatase activity.
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PMID:Mechanisms of action of okadaic acid class tumor promoters on mouse skin. 166 50

The four D-2-amino-4,5-methano-adipates 26, 27, 32, 33 were synthesized and their biological activity at the N-methyl-D-aspartate (NMDA) receptor was assessed. The synthesis involved as a key step a rhodium acetate dimer catalyzed addition of ethyl diazoacetate to the protected D-allylglycine (17). In vitro receptor binding using L-[3H]glutamate as the radioligand provided affinity data, while modulation of [3H]TCP binding was used as a functional assay. The analogues were also evaluated in [3H]kainate and [3H]AMPA binding to assess selectivity over non-NMDA glutamate receptors. Three of the four diastereoisomer, D-CAA B (27), C (32) and D (33) were shown to have agonist properties at the NMDA-site, while the fourth, (2R,4R,5R) D-CAA A (26) was characterized as an NMDA-site atypic antagonist.
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PMID:Synthesis, absolute configuration and activity at N-methyl-D-aspartic acid (NMDA) receptor of the four D-2-amino-4,5-methano-adipate diastereoisomers. 166 58

10 derivations of rat tracheal epithelial (RTE) cells, including normal cells, normal primary cultures, 7 tumorigenic cell lines and 1 nontumorigenic cell line transformed in vitro by treatment with 7,12-dimethylbenz[a]anthracene (DMBA), benzo[a]pyrene (BP) and/or 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined for oncogene alterations. No abnormalities of Ha-ras or Ki-ras were seen that were suggestive of amplification, rearrangement or the presence of RFLPs. Analysis of specific-point mutations in Ha-ras using Pst I digestion (codon 12, GGA to GCA) or Ha-ras and Ki-ras using Xba I (codon 61, CAA to CTA) were negative. In one cell line derived by DMBA treatment, changes in the c-myc restriction digest pattern were seen after incubation with Bam HI and Hind III. Northern analysis revealed consistent differences between normal and transformed cells when probed with Ha-ras; c-myc expression was of low intensity, and the expression of Ki-ras could not be detected. Transfection of RTE cell DNAs into NIH/3T3 cells did not result in the appearance of morphologic transformants. The studies suggest that Ha-ras or Ki-ras codon 61 A to T transversions (CAA to CTA) are not associated with the immortal/tumorigenic phenotype in RTE cells transformed by DMBA or TPA, and are in contrast to results reported in some other biological systems.
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PMID:Oncogene alterations in in vitro transformed rat tracheal epithelial cells. 169 45

A 203-base-pair sequence 5' of the latency-associated transcripts (LATs) of herpes simplex virus type 1 contains a 7-base consensus sequence TGCGTCA that is identical to the cAMP-response element of the proenkephalin gene. This consensus sequence is at -38 relative to the putative 5' end of the LATs with a TATA box at the -24 position. In transient chloramphenicol acetyltransferase assays in rat pheochromocytoma (PC12) cells, this enhancer region stimulated gene expression up to 3-fold in the presence of dibutyryl cAMP, forskolin, nerve growth factor, or phorbol 12-myristate 13-acetate. Mutation of the cAMP-response element to TGCG-CAA resulted in a 4-fold reduction of basal activity and a complete loss of inducible stimulation. In DNA gel retardation assays, purified cAMP-response element-binding protein and a nuclear protein from PC12 cells were shown to bind specifically to this element. Furthermore, it was demonstrated that the reactivation of wild-type herpes simplex virus type 1 from dissociated latently infected murine trigeminal ganglia was significantly accelerated (P less than 0.005) by the addition of cAMP analogs or adenylate cyclase activators. However, these reagents did not accelerate reactivation of a deletion mutant that lacks the putative cAMP-response element-containing promoter region, transcriptional start site, and 1015 base pairs of the LATs. These studies demonstrate that the promoter region of the LATs contains a functional cAMP-response element and that expression of the LATs is likely controlled by second messenger signal transduction and imply a role for cAMP in triggering viral reactivation.
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PMID:The promoter of the latency-associated transcripts of herpes simplex virus type 1 contains a functional cAMP-response element: role of the latency-associated transcripts and cAMP in reactivation of viral latency. 184 42

Three okadaic acid class tumor promoters, okadaic acid, dinophysistoxin-1, and calyculin A, have potent tumor-promoting activity in two-stage carcinogenesis experiments on mouse skin. DNA isolated from tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) and each of these tumor promoters revealed the same mutation at the second nucleotide of codon 61 (CAA----CTA) in the c-Ha-ras gene, determined by the polymerase chain reaction procedure and DNA sequencing. Three potent 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, TPA, teleocidin, and aplysiatoxin, showed the same effects. These results provide strong evidence that this mutation in the c-Ha-ras gene is due to a direct effect of DMBA rather than a selective effect of specific tumor promoters.
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PMID:Codon 61 mutations in the c-Harvey-ras gene in mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene plus okadaic acid class tumor promoters. 250 60

SENCAR mice, developed by selective breeding for high susceptibility to skin carcinogenesis by initiation with 7,12-dimethylbenz[a]anthracene and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA), form squamous papillomas in approximately 20% of animals treated repeatedly with TPA, without chemical initiation. DNA from eight skin tumors produced by a TPA-only protocol and four cell lines derived from these tumors was amplified by polymerase chain reaction and analyzed by discriminative oligonucleotide hybridization using oligomers specific for various c-rasHa gene codon 61 sequences. Five tumors and three cell lines had CAA (wild-type) to CGA mutations. In addition, one tumor had a CAA to CTA mutation, for a total of six of eight tumors having an activating mutation at this codon. Two tumors and one cell line had no codon 61 mutations detectable by this method. Since tumors derived from promotion-only protocols presumably originated from constitutively initiated cells, we examined tumor-free skins of untreated newborn and eight-month-old retired breeders and of 78-88-week-old SENCAR mice of both sexes, which were treated with TPA for 10 weeks starting at age 16-28 weeks and were untreated thereafter. Only the wild-type c-rasHa gene codon 61 sequence was seen, suggesting that the constitutively initiated cell population, if present, is below the limit of detection by this method.
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PMID:SENCAR mouse skin tumors produced by promotion alone have A to G mutations in codon 61 of the c-rasHa gene. 752 83

Our previous study on chimeric mutants of alpha-galactosidase suggested that two peptide regions encoded by exons 1-2 and 6 of the enzyme gene contribute to substrate recognition (Ishii, S. et al. (1994) Biochim. Biophys. Acta 1204, 265-270). In this study, we constructed five single amino acid substitutions for functional analysis of the amino acid residues around glutamine-279, the mutation site detected in an atypical Fabry disease patient. Two mutants, Q280S (Gln280-->Ser; CAA-->TCA) and T282A (Thr282-->Ala; ACT-->GCT), showed increased Km and decreased thermostability as compared with normal enzyme. Circular dichroism spectrum was not modified. An additional chimeric mutation in the exon 1-2 region by substitution with the homologous sequence of alpha-N-acetylgalactosaminidase cDNA restored catalytic activity and thermostability in both mutants. These data indicated the functional significance of glutamine-280 and threonine-282 for expressing the activity and stability of alpha-galactosidase molecule, and also the presence of an intramolecular interaction between the two peptide regions encoded by exons 1-2 and 6.
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PMID:The functional role of glutamine-280 and threonine-282 in human alpha-galactosidase. 772 39

Factors influencing the serum concentrations of low molecular weight proteins (LMWP) during long-term hemodialysis were studied in 112 patients undergoing dialysis for an average of 61.1 months (range 1 to 243). These patients were treated with AN69, cellulose acetate, cuprophan or polysulfone membranes. The following proteins were measured in serum before and after a four hour dialysis session: cystatin C (CYST C), beta 2-microglobulin (beta 2 m), Clara cell protein (CC16) and retinol-binding protein (RBP). Predialysis levels of the four proteins were markedly elevated. In simple regression analysis, pre-dialysis serum concentrations of beta 2 m and CC16 weakly correlated with the duration of dialysis treatment, but these relations completely disappeared when a stepwise regression analysis was performed using as predictors age, sex, residual diuresis, body weight loss (BWL), duration of hemodialysis and the type or ultrafiltration coefficient (UFC) of the membranes. The only significant determinants which emerged from this analysis were the residual diuresis and age which negatively correlated with CYST C, beta 2m and CC16 (residual diuresis only), and sex which influenced CYST C. During the dialysis session, the microproteins underwent changes that were related to their molecular radius, the membrane UFC and the BWL. After adjustment for the latter, high flux membranes (UFC > or = 15 ml/h.m2.mm Hg) allowed up to 50% of CYST C and 25% of beta 2m to be removed. No significant elimination of CC16 and RBP was evident. On the basis of these results, we estimated the effective pore radius of high flux membranes between 1.5 and 1.7 nm and that of low flux membranes as below 1.5 nm.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Determinants of the serum concentrations of low molecular weight proteins in patients on maintenance hemodialysis. 793 17


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