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 structural organization of the gene for the human cysteine-proteinase inhibitor cystatin C was studied. Restriction-endonuclease digests of human genomic DNA hybridized with human cystatin C cDNA and genomic probes produced patterns consistent with a single cystatin C gene and, also, the presence of six closely related sequences in the human genome. A 30 kb restriction map covering the genomic region of the cystatin C gene was constructed. The positions of three polymorphic restriction sites, found at examination of digests of genomic DNA from 79 subjects, were localized in the flanking regions of the gene. The gene was cloned and the nucleotide sequence of a 7.3 kb genomic segment was determined, containing the three exons of the cystatin C structural gene as well as 1.0 kb of 5'-flanking and 2.0 kb of 3'-flanking sequences. Northern-blot experiments revealed that the cystatin C gene is expressed in every human tissue examined, including kidney, liver, pancreas, intestine, stomach, antrum, lung and placenta. The highest cystatin C expression was seen in seminal vesicles. The apparently non-tissue-specific expression of this cysteine-proteinase inhibitor gene is discussed with respect to the structure of its 5'-flanking region, which shares several features with those of housekeeping genes.
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PMID:Structure and expression of the human cystatin C gene. 236 74

We report the molecular characterization of a homeobox-containing gene that maps at 84A in the proximal region of the Antennapedia-complex. The structure and complete sequence are presented. Deletion analysis indicates that the cloned gene, F24, most likely corresponds to the labial (lab) gene. Northern blot experiments show a single approximately 3-kb transcript that is expressed at all embryonic stages from cellular blastoderm onwards and during larval development. The homeobox is split by an intron in the region which encodes the putative DNA-binding helix, a splicing position for homeobox-containing genes which is unique so far. The 5' part of the gene contains four M-repeat sequences (CAA/G repeats) in the protein-coding region. In situ hybridization to the transcripts during embryogenesis reveals two domains of expression. The anterior one is located in parts of the developing head, mainly in the hypopharyngeal organ and in anterior parts of the mandibular lobe, and is restricted to the ectoderm. The posterior domain is part of the posterior midgut primordium (endoderm), that invaginates and later contacts the endoderm cells from the anterior midgut invagination.
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PMID:Molecular structure and spatial expression of a homeobox gene from the labial region of the Antennapedia-complex. 246 Dec 99

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

A Dictyostelium discoideum repetitive element composed of long repeats of the codon (AAC) is found in developmentally regulated transcripts. The concentration of (AAC) sequences is low in mRNA from dormant spores and growing cells and increases markedly during spore germination and multicellular development. The sequence hybridizes to many different sized Dictyostelium DNA restriction fragments indicating that it is scattered throughout the genome. Four cDNA clones isolated contain (AAC) sequences in the deduced coding region. Interestingly, the (AAC)-rich sequences are present in all three reading frames in the deduced proteins, i.e., AAC (asparagine), ACA (threonine) and CAA (glutamine). Three of the clones contain only one of these in-frame so that the individual proteins carry either asparagine, threonine, or glutamine clusters, not mixtures. However, one clone is both glutamine- and asparagine-rich. The (AAC) portion of the transcripts are reiterated 300 times in the haploid genome while the other portions of the cDNAs represent single copy genes, whose sequences show no similarity other than the (AAC) repeats. The repeated sequence is similar to the opa or M sequence found in Drosophila melanogaster notch and homeo box genes and in fly developmentally regulated transcripts. The transcripts are present on polysomes suggesting that they are translated. Although the function of these repeats is unknown, long amino acid repeats are a characteristic feature of extracellular proteins of lower eukaryotes.
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PMID:Nucleotide sequences of Dictyostelium discoideum developmentally regulated cDNAs rich in (AAC) imply proteins that contain clusters of asparagine, glutamine, or threonine. 251 21

Expression of the human cysteine proteinase inhibitor, cystatin C (CysC) in the cytoplasm of Escherichia coli was studied using a cDNA fragment encoding the cysteine proteinase inhibitor controlled by the phage lambda pR/cI857 system. The yield of CysC was low, probably due to proteolytic degradation. By fusing the cysC cDNA to a DNA fragment encoding the signal peptide of the E. coli outer membrane protein A, it was possible to produce a substantial amount of CysC in the periplasm. The processing of the signal peptide was shown to be quantitative and to result in CysC with the correct N-terminal amino acid. Yields higher than 1000 micrograms CysC/ml can be obtained by initiating the product formation at a moderate temperature (40 degrees C) late in an optimized fermentation process. A method that gives selective extraction of the periplasmic proteins and at the same time stabilizes CysC has been used.
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PMID:High-level expression of active human cystatin C in Escherichia coli. 252 67

The complete DNA sequence of the Micrococcus luteus spectinomycin (spc) operon and its adjacent regions has been determined. The sequence has revealed the presence of genes that are homologous to those of the Escherichia coli ribosomal and related proteins, L14, L24, L5, S8, L6, L18, S5, L30, L15, and secretion protein Y (sec Y), and the gene for adenylate kinase (adk). The gene arrangement in the spc operon is essentially the same as that of E. coli except for the absence in the M. luteus spc operon of the genes for S14 and X protein that exist in the E. coli spc operon. SecY and adk seem to be composed of another operon (adk operon) with at least an open reading frame. The deduced amino acid sequences for these ribosomal proteins are well conserved among the two species (40-65% identity). Reflecting the high genomic guanine and cytosine (GC) content of M. luteus (74%), the codon usage of the genes is extremely biased toward use of G and C, about 94% of the codon third positions being G or C. Seven codons, AUA, AAA, AGA, UUA, GUA, CUA, and CAA, all of which have A at the codon third positions, are completely absent in the M. luteus genes examined. Out of 11 genes in the M. luteus spc and adk operons, 5 (10) use GUG (UGA) and 6 (1) use AUG (UAA) as an initiation (termination) codon.
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PMID:Spectinomycin operon of Micrococcus luteus: evolutionary implications of organization and novel codon usage. 253 72

Activated N-ras gene was isolated from human hepatoma tissue by DNA transfection assay coupled with the neomycin selection method and molecular cloning and a point mutation in the codon 61 (CAA----AAA) was noted. However, examination of the proportion of the mutated N-ras gene in the tumor part by molecular cloning and by hybridization using synthetic oligonucleotide probes indicated that the mutated gene occurred with very low frequency. The activated N-ras gene appears located only in a small fraction of the tumor cells. The experimental data indicate activation of this gene as possibly not the major cause of carcinoma, but rather a manifestation of tumor heterogeneity.
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PMID:Activated N-ras gene was found in human hepatoma tissue but only in a small fraction of the tumor cells. 253 92

Cystatin C is an inhibitor of lysosomal cysteine proteases and consists of 120 amino acids. A variant of cystatin C lacking the first NH2-terminal residues and having one amino acid substitution at position 68 forms amyloid deposits mainly in the walls of brain arteries, causing fatal strokes in Icelandic patients with familial cerebral hemorrhage secondary to a form of an autosomal dominant amyloidosis. To understand the molecular basis of the genetic defect, the gene encoding cystatin C was isolated from genomic DNA libraries made from normal tissue and the brain of an Icelandic patient with hereditary cerebral hemorrhage with amyloidosis (HCHWA-I). The data indicate that the cystatin C gene encodes a polypeptide of 146 amino acids, of which the first 26 correspond to a secretory peptide signal sequence. The gene contains two intervening sequences that interrupt the coding region at amino acids 55 and 93. Comparison with genes encoding salivary cystatins and kininogen proteins show sequence homology and conservation of exon-intron structure. Except for a mutation in the second exon (CAG instead of CTG in the normal gene, resulting in the substitution of glutamine for a leucine residue), the gene cloned from the brain of the Icelandic patient is identical to the normal cystatin C gene. Thus, HCHWA-I is the first familial type of amyloidosis related to a point mutation in a gene encoding for an inhibitor. The mutation in the structural gene encoding cystatin C appears to be the primary defect in this inherited disorder causing amyloid fibril formation and accumulation followed by cerebral hemorrhage.
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PMID:Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases. 254 Dec 23

Hereditary cystatin C amyloid angiopathy has recently been shown to be caused by a point mutation in the cystatin C gene. To determine the chromosomal localization of the gene, 20 human-rodent somatic cell hybrids and a full-length cystatin C cDNA probe were used. Southern blot analysis of BamHI digested cell hybrid DNA revealed that the probe recognizes a 10.6 kb human specific fragment and that this fragment cosegregates with human chromosome 20. Therefore, the human cystatin C gene (CST3) was assigned to chromosome 20.
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PMID:The human cystatin C gene (CST3), mutated in hereditary cystatin C amyloid angiopathy, is located on chromosome 20. 256 73

Lung and liver tumors were induced in female A/J mice after treatment for 7 weeks (3 times/week, i.p.) with either 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (50 mg/kg) or nitrosodimethylamine (NDMA) (3 mg/kg). Both compounds can be activated via alpha-hydroxylation to methylating agents, while NNK may also undergo hydroxylation at the N-methyl carbon to form a pyridyloxobutylated adduct. The purpose of these studies was to identify and characterize the activated oncogenes present in tumors induced by NDMA and NNK. Following transfection of high molecular weight DNA onto NIH/3T3 mouse fibroblasts, transforming genes were detected in 90% of both NNK- (10 of 11) and NDMA- (9 of 10) induced lung tumors. In contrast, transformation of NIH/3T3 fibroblasts was observed only in 40% (2 of 5) and 13% (1 of 8) of the liver tumors from NNK- and NDMA-treated mice, respectively. Southern blot analysis indicated that the transforming gene present in all lung tumors was an activated K-ras oncogene. Both rearranged bands and amplified signals were detected in the transfectants. The one transformant from the NDMA-induced liver tumor contained an activated K-ras gene. In contrast, the two liver transformants from NNK-induced tumors did not contain an activated ras or raf gene. Hybridization with oligonucleotide probes that were centered around either codon 12 or 61 of the K-ras gene were utilized to localize the mutations. Activation of this gene appeared to occur largely via a mutation in codon 12 (15 of 20 transformants) and was observed with a similar frequency in pulmonary tumors induced by either compound. The remaining mutations were found in codon 61. The specific mutation within these two codons was determined by amplifying the exon containing the base change, followed by direct sequencing. With one exception the mutation observed in codon 12 was a GC to AT transition (GGT to GAT). One transformant contained a GC to TA transversion. The activating mutation detected in codon 61 was always an AT to GC transition of the middle A (CAA to CGA). The GC to AT mutation observed in codon 12 is consistent with the formation of the O6-methylguanine adduct. Similar concentrations (23 to 32 pmol/mumol deoxyguanosine) of this promutagenic adduct were detected in lungs during treatment with either NNK or NDMA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Relationship between the formation of promutagenic adducts and the activation of the K-ras protooncogene in lung tumors from A/J mice treated with nitrosamines. 267 Feb 1


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